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Li C, Yu J, Issa R, Wang L, Ning M, Yin S, Li J, Wu C, Chen Y. CoronaVac-induced antibodies that facilitate Fc-mediated neutrophil phagocytosis track with COVID-19 disease resolution. Emerg Microbes Infect 2025; 14:2434567. [PMID: 39584817 PMCID: PMC11731273 DOI: 10.1080/22221751.2024.2434567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/15/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants raise concerns about decreased vaccine efficacy, vaccines continue to confer robust protection in humans, implying that immunity beyond neutralization contributes to vaccine efficacy. In addition to neutralization, antibodies can mediate various Fc-dependent effector functions, including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP) and antibody-dependent cellular cytotoxicity (ADCC). However, the specific role of each Fc-mediated effector function in contributing to COVID-19 disease attenuation in human remains unclear. To fully define the potential immune correlates of Fc-mediated effector functions, we comprehensively analysed the above Fc-mediated effector functions in two study cohorts. In the CoronaVac vaccinee cohort, individuals without breakthrough infection exhibited higher levels of ADCP and ADNP activities with a greater degree of cross-reactivity compared to those who had breakthrough infection. A predictive model was established incorporating ADNP activity and IgG titre, achieving an area under the curve (AUC) of 0.837. In the COVID-19 patient cohort, BA.5-specific ADCP and ADNP responses were significantly reduced in COVID-19 patients with fatal outcomes compared to milder outcomes. The prognostic model incorporating WT, BA.5, and XBB.1.5 spike-specific ADNP demonstrated effective predictive ability, achieving an AUC of 0.890. Meanwhile, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in the acute phases of infection highlighted remarkably upregulation of neutrophil activity and phagocytic function, further reinforcing the essential role of ADNP. Collectively, our findings underscored Fc-mediated effector activities, especially neutrophil phagocytosis, as significant antibody biomarkers for the risk of SARS-CoV-2 breakthrough infection and COVID-19 prognosis.
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Affiliation(s)
- Chuang Li
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Jie Yu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, People’s Republic of China
| | - Rahma Issa
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
- Department of Pharmacy, Ismailia Teaching Oncology Hospital (GOTHI), Ismailia, Egypt
| | - Lili Wang
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, People’s Republic of China
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Nanjing, People’s Republic of China
| | - Mingzhe Ning
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, People’s Republic of China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
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Loggini A, Hornik J, Henson J, Wesler J, Hornik A. Association between neutrophil-to-lymphocyte ratio and hematoma expansion in spontaneous intracerebral hemorrhage: A systematic review and meta-analysis. World J Crit Care Med 2025; 14:99445. [DOI: 10.5492/wjccm.v14.i2.99445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Hematoma expansion (HE) typically portends a poor prognosis in spontaneous intracerebral hemorrhage (ICH). Several radiographic and laboratory values have been proposed as predictive markers of HE.
AIM To perform a systematic review and meta-analysis on the association of neutrophil-to-lymphocyte ratio (NLR) and HE in ICH. A secondary outcome examined was the association of NLR and perihematomal (PHE) growth.
METHODS Three databases were searched (PubMed, EMBASE, and Cochrane) for studies evaluating the effect of NLR on HE and PHE growth. The inverse variance method was applied to estimate an overall effect for each specific outcome by combining weighted averages of the individual studies’ estimates of the logarithm odds ratio (OR). Given heterogeneity of the studies, a random effect was applied. Risk of bias was analyzed using the Newcastle-Ottawa Scale. The study was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. The protocol was registered in PROSPERO (No. CRD42024549924).
RESULTS Eleven retrospective cohort studies involving 2953 patients were included in the meta-analysis. Among those, HE was investigated in eight studies, whereas PHE growth was evaluated in three. Blood sample was obtained on admission in ten studies, and at 24 hours in one study. There was no consensus on cut-off value among the studies. NLR was found to be significantly associated with higher odds of HE (OR = 1.09, 95%CI: 1.04-1.15, I2 = 86%, P < 0.01), and PHE growth (OR = 1.28, 95%CI: 1.19-1.38, I2 = 0%, P < 0.01). Qualitative analysis of each outcome revealed overall moderate risk of bias mainly due to lack of control for systemic confounders.
CONCLUSION The available literature suggests that a possible association may exist between NLR on admission and HE, and PHE growth. Future studies controlled for systemic confounders should be designed to consolidate this finding. If confirmed, NLR could be added as a readily available and inexpensive biomarker to identify a subgroup of patients at higher risk of developing HE.
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Affiliation(s)
- Andrea Loggini
- Brain and Spine Institute, Southern Illinois Healthcare, Carbondale, IL 62901, United States
- Southern Illinois University School of Medicine, Carbondale, IL 62901, United States
| | - Jonatan Hornik
- Brain and Spine Institute, Southern Illinois Healthcare, Carbondale, IL 62901, United States
- Southern Illinois University School of Medicine, Carbondale, IL 62901, United States
| | - Jessie Henson
- Brain and Spine Institute, Southern Illinois Healthcare, Carbondale, IL 62901, United States
| | - Julie Wesler
- Brain and Spine Institute, Southern Illinois Healthcare, Carbondale, IL 62901, United States
| | - Alejandro Hornik
- Brain and Spine Institute, Southern Illinois Healthcare, Carbondale, IL 62901, United States
- Southern Illinois University School of Medicine, Carbondale, IL 62901, United States
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Seplovich G, Bouchi Y, de Rivero Vaccari JP, Pareja JCM, Reisner A, Blackwell L, Mechref Y, Wang KK, Tyndall JA, Tharakan B, Kobeissy F. Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Neural Regen Res 2025; 20:1644-1664. [PMID: 39104096 PMCID: PMC11688549 DOI: 10.4103/nrr.nrr-d-24-00107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/20/2024] [Accepted: 06/03/2024] [Indexed: 08/07/2024] Open
Abstract
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
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Affiliation(s)
| | - Yazan Bouchi
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Juan Pablo de Rivero Vaccari
- Department of Neurological Surgery and the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jennifer C. Munoz Pareja
- Division of Pediatric Critical Care, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andrew Reisner
- Department of Pediatrics, Emory University, Atlanta, GA, USA
- Department of Neurosurgery, Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Laura Blackwell
- Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
| | - Kevin K. Wang
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | | | - Binu Tharakan
- Department of Surgery, Morehouse School of Medicine, Atlanta, GA, USA
| | - Firas Kobeissy
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA
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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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Wang S, Zheng H, Zhao J, Xie J. Role of lysine lactylation in neoplastic and inflammatory pulmonary diseases (Review). Int J Mol Med 2025; 55:71. [PMID: 40052587 PMCID: PMC11913435 DOI: 10.3892/ijmm.2025.5512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/20/2025] [Indexed: 03/19/2025] Open
Abstract
Protein lysine lactylation is a ubiquitous and post‑translational modification of lysine residues that involves the addition of a lactyl group on both histone and non‑histone proteins. This process plays a pivotal role in human health and disease and was first discovered in 2019. This epigenetic modification regulates gene transcription from chromatin or directly influences non‑histone proteins by modulating protein‑DNA/protein interactions, activity and stability. The dual functions of lactylation in both histone and non‑histone proteins establish it as a crucial mechanism involved in various cellular processes, such as cell proliferation, differentiation, immune and inflammatory responses and metabolism. Specific enzymes, referred to as 'writers' and 'erasers', catalyze the addition or removal of lactyl groups at designated lysine sites, thereby dynamically modulating lactylation through alterations in their enzymatic activities. The respiratory system has a remarkably intricate metabolic profile. Numerous pulmonary diseases feature an atypical transition towards glycolytic metabolism, which is linked to an overproduction of lactate, a possible substrate for lactylation. However, there has yet to be a comprehensive review elucidating the full impact of lactylation on the onset, progression and potential treatment of neoplastic and inflammatory pulmonary diseases. In the present review, an extensive overview of the discovery of lactylation and advancements in research on the existing lactylation sites were discussed. Furthermore, the review particularly investigated the potential roles and mechanisms of histone and non‑histone lactylation in various neoplastic and inflammatory pulmonary diseases, including non‑small cell lung cancers, malignant pleural effusion, pulmonary fibrosis, acute lung injury and asthma, to excavate the new therapeutic effects of post‑translational modification on various pulmonary diseases.
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Affiliation(s)
| | | | - Jianping Zhao
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Jungang Xie
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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6
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Parolini C. Pathophysiology of bone remodelling cycle: Role of immune system and lipids. Biochem Pharmacol 2025; 235:116844. [PMID: 40044049 DOI: 10.1016/j.bcp.2025.116844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/31/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.
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Affiliation(s)
- Cinzia Parolini
- Department of Pharmacological and Biomolecular Sciences, 'Rodolfo Paoletti', via Balzaretti 9 - Università degli Studi di Milano 20133 Milano, Italy.
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Li X, Wu F, Yu D, Su X, Wang K, Huang Z, Lu Z. Archaea-inspired deoxyribonuclease I liposomes prevent multiple organ dysfunction in sepsis. J Control Release 2025; 380:1109-1126. [PMID: 39986474 DOI: 10.1016/j.jconrel.2025.02.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025]
Abstract
Neutrophil extracellular traps (NETs) and circulating cell-free DNA (cfDNA) are pivotal in driving excessive inflammation and organ damage during sepsis, with their levels correlating positively with sepsis severity in both patients and murine models. Despite the ability of deoxyribonuclease I (DNase I) to degrade NETs and cfDNA, its short half-life and rapid degradation limit its therapeutic effectiveness. To address this challenge, we developed a methyl-branched liposome fused with a red blood cell membrane for the systemic delivery of DNase I (DNase I/Rm-Lipo). The efficacy of DNase I/Rm-Lipo was evaluated in the stimulated immune cells and septic model. The data confirmed that DNase I/Rm-Lipo efficiently removed excess NETs and cfDNA in activated neutrophils. Following injection, DNase I/Rm-Lipo exhibited an extended circulation time, effectively suppressing neutrophil activation and regulating macrophage polarization to mitigate inflammation and prevent organ dysfunction in septic mice. These findings highlight the therapeutic potential of DNase I/Rm-Lipo as a promising candidate for sepsis management by targeting the degradation of NETs and cfDNA.
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Affiliation(s)
- Xinze Li
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325035, China
| | - Fan Wu
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325035, China
| | - Dedong Yu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiayi Su
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325035, China
| | - Kaikai Wang
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325035, China
| | - Zhiwei Huang
- Central Laboratory, the Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People's Hospital, Lishui 323000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Zhongqiu Lu
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325035, China.
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Luo J, Chen K, Nong X. Potential regulation of artesunate on bone metabolism through suppressing inflammatory infiltration in type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2025; 47:147-158. [PMID: 39762719 DOI: 10.1080/08923973.2024.2444953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 12/15/2024] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Osteoimmunology is an emerging field that explores the interplay between bone and the immune system. The immune system plays a critical role in the pathogenesis of diabetes and significantly affects bone homeostasis. Artesunate, a first-line treatment for malaria, is known for its low toxicity and multifunctional properties. Increasing evidence suggests that artesunate possesses anti-inflammatory, immunoregulatory, and osteogenic effects. This review aims to explore the relationship between immune regulation and bone metabolism in type 2 diabetes (T2DM) and to investigate the potential therapeutic application of artesunate. METHODS This review systematically examines literature from PubMed/Medline, Elsevier, Web of Science, Embase, the International Diabetes Federation, and other relevant databases. RESULTS This review synthesizes evidence from multiple sources to delineate the relationship between T lymphocytes and T2DM, the regulation of T lymphocyte subsets in bone metabolism, and the effects of artesunate on both T lymphocytes and bone metabolism. Recent studies suggest a bidirectional regulatory relationship between T2DM and T lymphocytes (CD4+ T and CD8+ T) during the onset and progression of the disease, with inflammatory and anti-inflammatory cytokines serving as key mediators. T lymphocyte subsets and their cytokines play a pivotal role in regulating osteogenesis and osteoclastogenesis in pathological conditions. Furthermore, artesunate has shown promise in modulating inflammatory infiltration and bone metabolism. CONCLUSION The accumulated evidence indicates that artesunate exerts regulatory effects on bone metabolism in T2DM by influencing T lymphocyte differentiation.
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Affiliation(s)
- Jinghong Luo
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Kun Chen
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaolin Nong
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning, Guangxi, China
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Kuley R, Duvvuri B, Hasnain S, Dow ER, Koch AE, Higgs RE, Krishnan V, Lood C. Neutrophil Activation Markers and Rheumatoid Arthritis Treatment Response to the JAK1/2 Inhibitor Baricitinib. Arthritis Rheumatol 2025; 77:395-404. [PMID: 39431356 DOI: 10.1002/art.43042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/27/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024]
Abstract
OBJECTIVE Neutrophils play an important role in regulating immune and inflammatory responses in patients with rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation and whether a neutrophil activation score could predict treatment response. METHODS Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using enzyme-linked immunosorbent assay in plasma from patients with RA (n = 271) and healthy controls (n = 39). For patients with RA, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after receiving placebo and 2 and 4 mg baricitinib. Whole-blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil-related transcripts (n = 1,651). RESULTS Baseline levels of plasma neutrophil markers were elevated in patients with RA compared to healthy controls (P < 0.001). Receiving baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in patients with RA responding to treatment, as determined by American College of Rheumatology 20% improvement criteria. Whole-blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and Fcα receptor I upon reception of baricitinib in three randomized clinical trials involving patients with at various stages of disease-modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs (eg, a neutrophil activation score, at baseline, could predict treatment response to baricitinib). In contrast, C-reactive protein levels could not distinguish between responders and nonresponders. CONCLUSION Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine in treating patients with RA, not only based on symptoms but also based on immunophenotyping.
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Affiliation(s)
- Runa Kuley
- University of Washington, Seattle, and Centre for Life Sciences, Mahindra University, Hyderabad, India
| | | | - Sabeeha Hasnain
- Centre for Life Sciences, Mahindra University, Hyderabad, India
| | - Ernst R Dow
- Eli Lilly and Company, Indianapolis, Indiana
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Brayan MT, Alejandro AA, Quesada-Gómez C, Chaves-Olarte E, Elías BC. Polymorphonuclear neutrophil depletion in ileal tissues reduces the immunopathology induced by Clostridioides difficile toxins. Anaerobe 2025; 92:102947. [PMID: 40023364 DOI: 10.1016/j.anaerobe.2025.102947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 01/28/2025] [Accepted: 02/16/2025] [Indexed: 03/04/2025]
Abstract
INTRODUCTION Clostridioides difficile, a leading cause of healthcare-associated infections, causes significant morbidity and mortality. Its pathogenesis centers on TcdA and TcdB toxins, which disrupt intestinal integrity, trigger inflammation, and promote extensive neutrophil infiltration. OBJECTIVE The main objective of this study was to evaluate the role of PMNs in CDI using neutrophil depletion in a murine-ileal-ligated loop. METHODS Mice were treated with C. difficile toxins TcdA, TcdB, and TcdBv, with PMN depletion achieved via intraperitoneal injections of Ly6G/Ly6C antibody. Histopathological analysis, cytokine quantification, and MPO activity assays were performed to assess the inflammatory and tissue damage responses. RESULTS PMN depletion significantly reduced histopathological damage and proinflammatory responses. TcdA induced the highest inflammation and epithelial damage, while TcdB showed lower activity, except for MPO. TcdBvNAP1's activity was comparable to that of TcdBNAP1 but less than TcdA. The findings indicate that TcdA's enterotoxin effects are more damaging than TcdBs from different strains and confirm the critical role of PMNs in CDI pathogenesis. CONCLUSION Our results show that PMN depletion reduced inflammatory responses and tissue damage, highlighting potential therapeutic strategies targeting PMN regulation. Further research on PMN extracellular traps (NETs) and their role in CDI is necessary to develop comprehensive treatments. Future studies should focus on combined in vivo and in vitro approaches to fully understand the pathological mechanisms and identify effective biomarkers for CDI therapy.
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Affiliation(s)
- Montoya-Torres Brayan
- International Center for Food Industry Excellence (ICFIE), Department of Animal and Food Sciences, Texas Tech University, Lubbock, TX, 79409, USA; Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Costa Rica
| | - Alfaro-Alarcón Alejandro
- Departamento de Patología, Escuela de Medicina Veterinaria, Universidad Nacional, Costa Rica; Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany
| | - Carlos Quesada-Gómez
- Centro de Investigación en Enfermedades Tropicales, Facultad de Microbiología, Universidad de Costa Rica, Costa Rica
| | - Esteban Chaves-Olarte
- Centro de Investigación en Enfermedades Tropicales, Facultad de Microbiología, Universidad de Costa Rica, Costa Rica
| | - Barquero-Calvo Elías
- Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Costa Rica.
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Zhang T, Sun Y, Xia J, Fan H, Shi D, Wu Q, Huang M, Hou XY. Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries. EMBO Mol Med 2025:10.1038/s44321-025-00220-8. [PMID: 40169896 DOI: 10.1038/s44321-025-00220-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/01/2025] [Accepted: 03/10/2025] [Indexed: 04/03/2025] Open
Abstract
Circulating neutrophils are responsible for poor neurological outcomes and have been implicated in respiratory morbidity after acute ischemic stroke (AIS). However, the molecular mechanisms regulating neutrophil responses and their pathological relevance in post-stroke complications remain unclear. In this study, we investigated the involvement of hematopoietic progenitor kinase 1 (HPK1) in neutrophil responses and mobilization, as well as subsequent lung and cerebral injuries following AIS. We found that lipopolysaccharide treatment triggered neutrophil activation in an HPK1-dependent manner. HPK1 enhanced intrinsic NF-κB/STAT3/p38-MAPK pathways and gasdermin D cleavage, leading to neutrophil hyperactivation. Following AIS, HPK1 promoted the mobilization of CXCR2high bone marrow neutrophils. HPK1 loss inhibited peripheral neutrophil hyperactivation, neutrophil infiltration, and aggregation of neutrophil extracellular traps, progressively alleviating systemic inflammation and impairments in mouse pulmonary and neurological functions. Furthermore, HPK1 pharmacological inhibition attenuated post-stroke pulmonary and neurological impairments in mice. Our findings revealed that HPK1 upregulates neutrophil mobilization and various responses, promoting post-stroke systemic inflammation and tissue injury. This study highlights HPK1 as a therapeutic target for improving pulmonary and neurological functions after AIS.
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Affiliation(s)
- Tingting Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Ying Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Jing Xia
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Hongye Fan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Dingfang Shi
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China
| | - Qian Wu
- The Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Ming Huang
- Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
| | - Xiao-Yu Hou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
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12
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She Y, Wu P, Wan W, Liu H, Liu R, Wang T, Wang M, Shen L, Yang Y, Huang X, Zhang X, Tian Y, Zhang K. Polysaccharides, proteins and DNA based stimulus responsive hydrogels promoting wound healing and repair: A review. Int J Biol Macromol 2025; 304:140961. [PMID: 39952504 DOI: 10.1016/j.ijbiomac.2025.140961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
The healing of various wounds remains a serious challenge in the medical field, hydrogel has high hydrophilicity and biocompatibility due to its unique network structure, which shows a strong advantage in the field of wound healing. Stimulus responsive hydrogels are particularly effective，which can control the material properties according to the external stimulus source, and provide more targeted treatment for different wounds. Here, we review physiological mechanisms of wound healing and the relationship between polysaccharides, proteins and DNA based stimulus responsive hydrogels and wound healing, materials commonly used of polysaccharides, proteins and DNA based stimulus responsive hydrogels, mechanisms of stimulus responsive hydrogels formation and network structure types, common properties of polysaccharides, proteins and DNA based stimulus responsive hydrogels for promoting wound healing and discuss their applications in medicine. Finally, the limitations and application prospects of polysaccharides, proteins and DNA based stimulus responsive hydrogels were discussed and evaluated. The review focuses on the biomedical use of polysaccharides, proteins and DNA based stimulus responsive hydrogels in wound healing and repair, and provides insights for the development of clinical related materials.
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Affiliation(s)
- Yumo She
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Peng Wu
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Wenyu Wan
- Key Laboratory of Immunodermatology, Ministry of Education, Department of Dermatology, The First Hospital of China Medical University, China; Key Laboratory of Immunodermatology, National Health Commission of the People's Republic of China, The First Hospital of China Medical University, China; National and Local Joint Engineering Research Center of Immunodermatological Theranostics, The First Hospital of China Medical University, China
| | - He Liu
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110169, China
| | - Ruonan Liu
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110169, China
| | - Tingting Wang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Mengyao Wang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Lufan Shen
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Yuanyuan Yang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Xingyong Huang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Xiaoyue Zhang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China
| | - Ye Tian
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110169, China; Foshan Graduate School of Innovation, Northeastern University, Foshan 528300, China.
| | - Kai Zhang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, China; Engineering Research Center of Ministry of Education for Minimally Invasive Gastrointestinal Endoscopic Techniques, Shengjing Hospital of China Medical University, China.
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13
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Cai XY, Zheng CX, Guo H, Fan SY, Huang XY, Chen J, Liu JX, Gao YR, Liu AQ, Liu JN, Zhang XH, Ma C, Wang H, Fu F, Peng P, Xu HK, Sui BD, Xuan K, Jin Y. Inflammation-triggered Gli1 + stem cells engage with extracellular vesicles to prime aberrant neutrophils to exacerbate periodontal immunopathology. Cell Mol Immunol 2025; 22:371-389. [PMID: 40016585 PMCID: PMC11955562 DOI: 10.1038/s41423-025-01271-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/12/2025] [Indexed: 03/01/2025] Open
Abstract
Periodontitis is a prevalent and progressive detrimental disease characterized by chronic inflammation, and the immunopathological mechanisms are not yet fully understood. Mesenchymal stem cells (MSCs) play crucial roles as immunoregulators and maintain tissue homeostasis and regeneration, but their in vivo function in immunopathology and periodontal tissue deterioration is still unclear. Here, we utilized multiple transgenic mouse models to specifically mark, ablate and modulate Gli1+ cells, a critical and representative subset of MSCs in the periodontium, to explore their specific role in periodontal immunopathology. We revealed that Gli1+ cells, upon challenge with an inflammatory microenvironment, significantly induce rapid trafficking and aberrant activation of neutrophils, thus exacerbating alveolar bone destruction. Mechanistically, extracellular vesicles (EVs) released by Gli1+ cells act as crucial immune regulators in periodontal tissue, mediating the recruitment and activation of neutrophils through increased neutrophil generation of reactive oxygen species and stimulation of nuclear factor kappa-B signaling. Furthermore, we discovered that CXC motif chemokine ligand 1 (CXCL1) is exposed on the surface of EVs derived from inflammation-challenged Gli1+ cells to prime aberrant neutrophils via the CXCL1-CXC motif chemokine receptor 2 (CXCR2) axis. Importantly, specific inhibition of EV release from Gli1+ cells or pharmacological therapy with GANT61 ameliorates periodontal inflammation and alveolar bone loss. Collectively, our findings identify previously unrecognized roles of Gli1+ cells in orchestrating infiltration and promoting aberrant activation of neutrophils under inflammation, which provides pathological insights and potential therapeutic targets for periodontitis.
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Affiliation(s)
- Xin-Yue Cai
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chen-Xi Zheng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Hao Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Si-Yuan Fan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiao-Yao Huang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Ji Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Oral Implantology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jie-Xi Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yu-Ru Gao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - An-Qi Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jia-Ning Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiao-Hui Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chao Ma
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Hao Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Fei Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Peng Peng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Hao-Kun Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Bing-Dong Sui
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
| | - Kun Xuan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi key Laboratory of Stomatology, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
| | - Yan Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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14
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Al Shahrani M, AboHassan M, Gahtani R, Alshahrani MY, Suliman M, Ahmad I, Saeed M. High-throughput screening and in vitro evaluation of CSB-0914; a novel small molecule NF-κB inhibitor attenuating inflammatory responses through NF-κB, Nrf2 and HO-1 cross-talk. J Biomol Struct Dyn 2025; 43:2762-2771. [PMID: 38127429 DOI: 10.1080/07391102.2023.2294377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023]
Abstract
Unpleasant side effects of standard inflammatory drugs urges search for novel therapeutic candidates. This study aims in identifying novel anti-inflammatory NF-κB inhibitor by high-throughput computational and in-vitro pre-clinical approaches. Lead candidate selection was conducted by the use of computational docking molecular-dynamic simulations. The RBL-2H3 cell line, derived from rat basophils, was used to evaluate the release of cytokines and degranulation. The study focused on the study of neutrophil elastase and its role in cellular motility. Flow cytometry was utilized to evaluate the activation of basophils and the expression of critical signaling proteins. High throughput screening identified CSB-0914 to stably bind NF-κB-p50 subunit. Dose based loss in T NF-α and IL-2 release were observed in RBL-2H3 cells in addition to degranulation inhibition by CSB-0914. The compound demonstrated significant efficacy in reducing basophil activation assay induced by FcεRI receptors, with an IC50 value of 98.41 nM.. A dose dependent decrease in neutrophil migration and elastase were observed when treated with CSB- 0914. The compound was effective in decreasing. Upon stimulation, RBL-2H3 cells exhibited phosphorylation of NF-κB p-65 as well as upregulation of the Nrf2 and HO-1 signaling pathways. Collectively, our study has successfully identified a novel inhibitor called CSB-0914 that effectively regulates inflammatory responses. These reactions are primarily mediated by the interplay between NF-κB, Nrf2, and HO-1. The findings of this study provide support for the need to conduct more research on CSB-0914 with the aim of its development as a pharmaceutical agent for anti-inflammatory purposes.
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Affiliation(s)
- Mesfer Al Shahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Mohammad AboHassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Reem Gahtani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Mohd Saeed
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
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15
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Folorunso OS, Sinha NR, Singh A, Xi L, Pulimamidi VK, Cho WJ, Mittal SK, Chauhan SK. Tissue Inhibitor of Metalloproteinase 2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:754-769. [PMID: 39732392 DOI: 10.1016/j.ajpath.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/10/2024] [Accepted: 11/06/2024] [Indexed: 12/30/2024]
Abstract
Tissue inhibitors of metalloproteinases (TIMPs) modulate extracellular matrix remodeling for maintaining homeostasis and promoting cell migration and proliferation. Pathologic conditions can alter TIMP homeostasis and aggravate disease progression. The roles of TIMPs have been studied in tissue-related disorders; however, their contributions to tissue repair during corneal injury are undefined. Here, the TIMP expression in human corneal epithelial cells under homeostatic and inflammatory milieus was profiled to examine their contribution to the healing of injured corneal epithelia. Transcriptionally, TIMP2 was highly expressed in human corneal epithelial cells when stimulated with 100 ng/mL IL1B or scratch wounded. Unlike TIMP1, recombinant TIMP2 (rTIMP2) significantly promoted epithelial cell wound closure compared with untreated and TIMP2-neutralizing conditions. At 12 hours, the Ki-67+ cells significantly increased threefold in number compared with untreated cells, suggesting that rTIMP2 is associated with cell proliferation. Furthermore, rTIMP2 treatment significantly suppressed inflammatory cytokine expression (IL1B, IL6, IL8, and TNFA) and injury-induced matrix metalloproteinases (MMP1, MMP2, MMP3, MMP9, MMP10, and MMP13). Topical treatment of injured mouse cornea with 0.1 mg/mL rTIMP2 significantly promoted corneal re-epithelialization and improved tissue integrity. The treatment suppressed the expression of inflammatory cytokines and MMPs, as well as the infiltration of neutrophils at the injury site. These findings indicate that TIMP2 promotes faster wound healing by suppressing injury-induced inflammation and MMP expression, suggesting a potential therapeutic target for corneal wound management.
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Affiliation(s)
- Olufemi S Folorunso
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Nishant R Sinha
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Aastha Singh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Lei Xi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Vinay K Pulimamidi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - WonKyung J Cho
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Sharad K Mittal
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
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16
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Zhu W, Yang Z, Zhou S, Zhang J, Xu Z, Xiong W, Liu P. Modic changes: From potential molecular mechanisms to future research directions (Review). Mol Med Rep 2025; 31:90. [PMID: 39918002 PMCID: PMC11836598 DOI: 10.3892/mmr.2025.13455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Low back pain (LBP) is a leading cause of disability worldwide. Although not all patients with Modic changes (MCs) experience LBP, MC is often closely associated with LBP and disc degeneration. In clinical practice, the focus is usually on symptoms related to MC, which are hypothesized to be associated with LBP; however, the link between MC and nerve compression remains unclear. In cases of intervertebral disc herniation, nerve compression is often the definitive cause of symptoms. Recent advances have shed light on the pathophysiology of MC, partially elucidating its underlying mechanisms. The pathogenesis of MC involves complex bone marrow‑disc interactions, resulting in bone marrow inflammation and edema. Over time, hematopoietic cells are gradually replaced by adipocytes, ultimately resulting in localized bone marrow sclerosis. This process creates a barrier between the intervertebral disc and the bone marrow, thereby enhancing the stability of the vertebral body. The latest understanding of the pathophysiology of MC suggests that chronic inflammation plays a significant role in its development and hypothesizes that the complement system may contribute to its pathological progression. However, this hypothesis requires further research to be confirmed. The present review we proposed a pathological model based on current research, encompassing the transition from Modic type 1 changes (MC1) to Modic type 2 changes (MC2). It discussed key cellular functions and their alterations in the pathogenesis of MC and outlined potential future research directions to further elucidate its mechanisms. Additionally, it reviewed the current clinical staging and pathogenesis of MC, recommended the development of an updated staging system and explored the prospects of integrating emerging artificial intelligence technologies.
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Affiliation(s)
- Weijian Zhu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhou Yang
- Department of Orthopedics, Hongxin Harmony Hospital, Li Chuan, Hubei 445400 P.R. China
| | - Sirui Zhou
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
| | - Jinming Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhihao Xu
- Department of Hepatobiliary Surgery, Huaqiao Hospital, Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Wei Xiong
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ping Liu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
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17
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Wang F, Zhang Y, Sun M, Li M, Wang Y, Zhang D, Yao S. Single-cell sequencing reveals the same heterogeneity of neutrophils in heatstroke-induced lung and liver injury. Mucosal Immunol 2025:S1933-0219(25)00031-5. [PMID: 40158777 DOI: 10.1016/j.mucimm.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/23/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Abstract
Heatstroke (HS) is typically considered a sepsis-like syndrome caused by hyperthermia, often accompanied by multiple organ dysfunctions (MODS). To explore the mechanisms of MODS, we established a mouse model of HS by exposing mice to a hyperthermic and high-humidity environment. Then, we utilized single-cell RNA sequencing (scRNA-seq) to depict the cellular landscape of HS mice lung tissue and liver tissue. We found that the enhancement of neutrophil infiltration mediated by the "Cxcr2-Cxcl2″ receptor-ligand pair is a prominent feature of HS-induced lung injury. By effectively suppressing the recruitment of neutrophils in HS-induced lung injury, the application of Cxcr2 inhibitor held positive implications for improving HS-induced lung injury. In addition to the chemotactic effect of immune cells on neutrophils, we identified a subcluster of fibroblasts labeled as Col14a1+, which possessed notable chemotactic factor-secretion characteristics and likely exerted a role in the early stages of neutrophil infiltration. Furthermore, our study unveiled significant heterogeneity among neutrophils within the HS-induced lung injury. Particularly, Cd177 + neutrophils exhibited a dominant presence, characterized by heightened pro-inflammatory responses and oxidative stress. In heatstroke-induced liver injury, neutrophils exhibited similar heterogeneous characteristics. Cd177 + neutrophils exhibited an enhanced ability to produce neutrophil extracellular traps (NETs) while lowering the levels of NETs can significantly improve heatstroke-induced lung and liver injury. Additionally, our study identified Cebpe as a key transcriptional regulatory factor in Cd177 + neutrophil differentiation. Knockdown of the expression of Cebpe can suppress the Cd177 + neutrophil differentiation and decrease the expression levels of NETs. Our research indicated a common heterogeneity in neutrophils during MODS in HS. Cd177 + neutrophils contributed to organ damage in HS, and Cebpe may serve as a crucial intervention target in the treatment of HS.
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Affiliation(s)
- Fuquan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
| | - Yan Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Miaomiao Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Mengyu Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Yu Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Dingyu Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China.
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China.
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18
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Leinweber B, Pilorz V, Olejniczak I, Skrum L, Begemann K, Heyde I, Stenger S, Sadik CD, Oster H. Bmal1 deficiency in neutrophils alleviates symptoms induced by high-fat diet. iScience 2025; 28:112038. [PMID: 40124497 PMCID: PMC11930374 DOI: 10.1016/j.isci.2025.112038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 12/24/2024] [Accepted: 02/12/2025] [Indexed: 03/25/2025] Open
Abstract
Physiological processes, including metabolism and immune responses, are generated by the circadian clock, driven by clock genes. Disrupting circadian rhythms through a high-fat diet promotes obesity and inflammation. Studies show that deleting the clock gene, brain, and muscle ARNT-like 1 (Bmal1) in adipose tissue leads to overeating and weight gain. We now show that Bmal1 deletion in neutrophils protects against diet-induced obesity and reduces inflammatory macrophage infiltration into epididymal white adipose tissue (eWAT), despite increased food intake over 20 weeks of a high-fat diet. This protection is linked to enhanced energy expenditure, increased UCP1 expression in iBAT, improved insulin sensitivity, and altered expression of genes encoding chemokine receptors CXCR2, CXCR4, and the ligand Cxcl2 in eWAT. Our findings reveal a key role of Bmal1 in neutrophils in regulating high-fat diet-induced adipose inflammation and emphasize circadian regulation's importance in immuno-metabolic function.
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Affiliation(s)
- Brinja Leinweber
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Violetta Pilorz
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Iwona Olejniczak
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Ludmila Skrum
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Kimberly Begemann
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Isabel Heyde
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Sarah Stenger
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
| | - Christian David Sadik
- University of Lübeck, Department of Dermatology, Allergy, and Venereology Ratzeburger Allee, 23562 Luebeck, Germany
| | - Henrik Oster
- University of Lübeck, Institute of Neurobiology, Center of Brain, Behaviour and Metabolism, Marie-Curie-Strasse, 23562 Luebeck, Germany
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19
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Hu X, Kang B, Wang M, Lin H, Liu Z, Zhang Z, Gu J, Mai Y, Guo X, Ma W, Yan H, Wang S, Huang J, Wang J, Zhang J, Zhang T, Feng B, Zhu Y, Pan G. Human induced pluripotent stem cells derived neutrophils display strong anti-microbial potencies. CELL REGENERATION (LONDON, ENGLAND) 2025; 14:8. [PMID: 40113653 PMCID: PMC11926315 DOI: 10.1186/s13619-025-00227-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
Neutrophils are essential innate immune cells with unusual anti-microbial properties while dysfunctions of neutrophils lead to severe health problems such as lethal infections. Generation of neutrophils from human induced pluripotent stem cells (hiPSCs) is highly promising to produce off-the-shelf neutrophils for transfusion therapies. However, the anti-microbial potencies of hiPSCs derived neutrophils (iNEUs) remain less documented. Here, we develop a scalable approach to generate iNEUs in a chemical defined condition. iNEUs display typical neutrophil characters in terms of phagocytosis, migration, formation of neutrophil extracellular traps (NETs), etc. Importantly, iNEUs display a strong killing potency against various bacteria such as K.pneumoniae, P.aeruginosa, E.coli and S.aureus. Moreover, transfusions of iNEUs in mice with neutrophil dysfunction largely enhance their survival in lethal infection of different bacteria. Together, our data show that hiPSCs derived neutrophils hold strong anti-microbial potencies to protect severe infections under neutrophil dysfunction conditions.
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Affiliation(s)
- Xing Hu
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Baoqiang Kang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Mingquan Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Huaisong Lin
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Zhiyong Liu
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Zhishuai Zhang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Jiaming Gu
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yuchan Mai
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Xinrui Guo
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Wanli Ma
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Han Yan
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Shuoting Wang
- The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China
| | - Jingxi Huang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Junwei Wang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jian Zhang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Tianyu Zhang
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Bo Feng
- School of Biomedical Sciences, Faculty of Medicine, CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Room 105A, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, NT, Hong Kong SAR, China
| | - Yanling Zhu
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
| | - Guangjin Pan
- National Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China.
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
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20
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Zhang Q, Shen Y, Zhang C, Zhang H, Li X, Yang S, Dai C, Yu X, Lou J, Feng J, Hu C, Lin Z, Li X, Zhou X. Immunoengineered mitochondria for efficient therapy of acute organ injuries via modulation of inflammation and cell repair. SCIENCE ADVANCES 2025; 11:eadj1896. [PMID: 40106554 DOI: 10.1126/sciadv.adj1896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 02/11/2025] [Indexed: 03/22/2025]
Abstract
Acute organ injuries represent a major public health concern, driven by inflammation and mitochondrial dysfunction, leading to cell damage and organ failure. In this study, we engineered neutrophil membrane-fused mitochondria (nMITO), which combine the injury-targeting and anti-inflammatory properties of neutrophil membrane proteins with the cell repairing function of mitochondria. nMITO effectively blocked inflammatory cascades and restored mitochondrial function, targeting both key mechanisms in acute organ injuries. In addition, nMITO selectively targeted damaged endothelial cells via β-integrins and were delivered to injured tissues through tunneling nanotubes, enhancing their regulatory effects on inflammation and cell damage. In mouse models of acute myocardial injury, liver injury, and pancreatitis, nMITO notably reduced inflammatory responses and repaired tissue damage. These findings suggest that nMITO is a promising therapeutic strategy for managing acute organ injuries.
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Affiliation(s)
- Qing Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine & Rehabilitation School, Kunming Medical University, Kunming 650500, PR China
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China
| | - Yan Shen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Chengyuan Zhang
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine & Rehabilitation School, Kunming Medical University, Kunming 650500, PR China
| | - Hanyi Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Xuemei Li
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Shengqian Yang
- Institute of Materia Medica College of Pharmacy, Army Medical University, Chongqing 400038, PR China
| | - Chen Dai
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Xiuyan Yu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Jie Lou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Jinwei Feng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Chenglu Hu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, PR China
| | - Zhihua Lin
- Chongqing University of Chinese Medicine, Chongqing 402760, PR China
| | - Xiaohui Li
- Institute of Materia Medica College of Pharmacy, Army Medical University, Chongqing 400038, PR China
| | - Xing Zhou
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine & Rehabilitation School, Kunming Medical University, Kunming 650500, PR China
- School of Pharmaceutical Sciences & Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, PR China
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21
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Jian N, Yu L, Ma L, Zheng B, Huang W. BCG therapy in bladder cancer and its tumor microenvironment interactions. Clin Microbiol Rev 2025:e0021224. [PMID: 40111053 DOI: 10.1128/cmr.00212-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025] Open
Abstract
SUMMARYBacillus Calmette-Guérin (BCG) has been the standard treatment for non-muscle-invasive bladder cancer for over 30 years. Despite its proven efficacy, challenges persist, including unclear mechanisms of action, resistance in 30%-50% of patients, and significant side effects. This review presents an updated and balanced discussion of the antitumor mechanisms of BCG, focusing on its direct effects on bladder cancer and its interactions with various cell types within the bladder tumor microenvironment. Notably, recent research on the interactions between BCG and the bladder microbiome is also incorporated. We further summarize and analyze the latest preclinical and clinical studies regarding both intrinsic and adaptive resistance to BCG in bladder cancer. Based on the current understanding of BCG's therapeutic principles and resistance mechanisms, we systematically explore strategies to improve BCG-based tumor immunotherapy. These include the development of recombinant BCG, combination therapy with different drugs, optimization of therapeutic regimens and management, and the exploration of new approaches by targeting changes in the bladder microbiota and its metabolites. These measures aim to effectively address the BCG resistance in bladder cancer, reduce its toxicity, and ultimately enhance the clinical anti-tumor efficacy. Bacterial therapy, represented by genetically engineered oncolytic bacteria, has gradually emerged in the field of cancer treatment in recent years. As the only bacterial drug successfully approved for oncology use, BCG has provided decades of clinical experience. By consolidating lessons from BCG's successes and limitations, we hope to provide valuable insights for the development and application of bacterial therapies in cancer treatment.
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Affiliation(s)
- Ni Jian
- Synthetic Biology Research Center, Institute for Advanced Study, International Cancer Center of Shenzhen University, Shenzhen, China
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Lei Yu
- Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Lijuan Ma
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Binbin Zheng
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Weiren Huang
- Synthetic Biology Research Center, Institute for Advanced Study, International Cancer Center of Shenzhen University, Shenzhen, China
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau, China
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22
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Hsu AY, Huang Q, Pi X, Fu J, Raghunathan K, Ghimire L, Balasubramanian A, Xie X, Yu H, Loison F, Haridas V, Zha J, Liu F, Park SY, Bagale K, Ren Q, Fan Y, Zheng Y, Cancelas JA, Chai L, Stowell SR, Chen K, Xu R, Wang X, Xu Y, Zhang L, Cheng T, Ma F, Thiagarajah JR, Wu H, Feng S, Luo HR. Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution. Cell 2025; 188:1623-1641.e26. [PMID: 39938514 PMCID: PMC11934499 DOI: 10.1016/j.cell.2025.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 08/23/2024] [Accepted: 01/13/2025] [Indexed: 02/14/2025]
Abstract
Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface "do not eat me" signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55+ LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.
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Affiliation(s)
- Alan Y Hsu
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Qingxiang Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Xiong Pi
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 20115, USA
| | - Jianing Fu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 20115, USA
| | - Krishnan Raghunathan
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 20115, USA
| | - Laxman Ghimire
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Arumugam Balasubramanian
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Xuemei Xie
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Hongbo Yu
- Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, West Roxbury, Boston, MA 02132, USA
| | - Fabien Loison
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Viraga Haridas
- Flow and Imaging Cytometry Resources, Boston Children's Hospital, Boston, MA 02115, USA
| | - Jiali Zha
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Fei Liu
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Shin-Young Park
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Kamal Bagale
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Yuping Fan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Yi Zheng
- Experimental Hematology and Cancer Biology Research, Cincinnati Children's Hospital Medical Center, Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Jose A Cancelas
- Experimental Hematology and Cancer Biology Research, Cincinnati Children's Hospital Medical Center, Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Connell and O'Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Li Chai
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Sean R Stowell
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Kanchao Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Rong Xu
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA
| | - Xiaoxue Wang
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Yuanfu Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Lianghui Zhang
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Fengxia Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Jay R Thiagarajah
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 20115, USA; Congenital Enteropathy Program, Boston Children's Hospital, PediCODE Consortium, Harvard Digestive Disease Center, Boston, MA, USA
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 20115, USA
| | - Sizhou Feng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
| | - Hongbo R Luo
- Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA.
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Simmons SR, Lenhard AP, Battaglia MC, Bou Ghanem EN. Adenosine 2B receptor signaling impairs vaccine-mediated protection against pneumococcal infection in young hosts by blunting neutrophil killing of antibody opsonized bacteria. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.18.643957. [PMID: 40166282 PMCID: PMC11956959 DOI: 10.1101/2025.03.18.643957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Background/Objective Neutrophils are essential for vaccine-mediated protection against pneumococcal infection and impairment in their antibacterial function contributes to reduced vaccine efficacy during aging. However, the signaling pathways controlling neutrophil responses in vaccinated hosts are not fully understood. The extracellular adenosine pathway is a known regulator of neutrophils in naïve hosts. The aim of this study was to test the role of this pathway in neutrophil function and protection against infection upon vaccination across host age. Methods To test the role of adenosine in the antimicrobial activity of neutrophils against antibody-opsonized pneumococci, we used bone marrow derived neutrophils isolated from wild type or specific adenosine receptors knock-out mice. To measure the effect of adenosine receptor signaling in vivo , we treated vaccinated mice with agonists or antagonists specific to the different adenosine receptors prior to pulmonary challenge with pneumococci and assessed bacterial burden and clinical score post infection. Results We found that signaling via the adenosine 2B (A2BR) but not A2A or A1 receptor diminished intracellular pneumococcal killing following antibody-mediated uptake in young hosts. In vivo , agonism of A2BR significantly worsened pneumococcal infection outcome in young, vaccinated mice. In contrast, A2BR signaling had no effect on intracellular bacterial killing by neutrophils from aged mice. Further, in vivo A2BR inhibition had no effect on pneumococcal disease progression in aged, vaccinated mice. Conclusions A2BR signaling reduced pneumococcal vaccine-mediated protection by impairing neutrophil antimicrobial activity against antibody-opsonized bacteria in young hosts. However, inhibiting this pathway was not sufficient to boost responses in aged hosts.
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24
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Yu Q, Zhang Q, Zhu J, Pan F, Zhang H, Chen L, Shen J, Liu Y, Ji Z, Zhu Y, Chen Q, Yang Y. Inhalable neutrophil-mimicking nanoparticles for chronic obstructive pulmonary disease treatment. J Control Release 2025; 381:113648. [PMID: 40118116 DOI: 10.1016/j.jconrel.2025.113648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/28/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) is an intractable disease with thick mucus layer in bronchi and alveoli, frequently accompanied by bacterial infection. Anti-bacterial drugs with mucus penetrating are urgently needed for efficient COPD treatment. Here, a neutrophil-mimicking nanovehicle was developed by coating neutrophil membrane onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing antibiotics levofloxacin (LVX). Neutrophil membrane coated nanoparticles (LVX@PLGA@Mem) reserved most of the membrane proteins and related membrane functions of neutrophil, exhibiting pro-inflammatory cytokines neutralization, inflammation inhibition, successfully delivering LVX through the mucus layer and achieving satisfactory anti-infection effects. Thus, LVX@PLGA@Mem after inhalation could remarkably reduce inflammation and infection in the lung with COPD. Therefore, neutrophil mimicking nanovehicles may be a feasible and desirable drug carrier for lung-related disease treatment in further clinic.
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Affiliation(s)
- Qifan Yu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Qiang Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China; School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Jiafei Zhu
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Feng Pan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Han Zhang
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Linfu Chen
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Jingjing Shen
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yanbin Liu
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Zhaoxin Ji
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yuming Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Qian Chen
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; School of Materials Science and Engineering, Tongji University, Shanghai 201804, China.
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25
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OuYang L, Lin Z, He X, Sun J, Liao J, Liao Y, Xie X, Hu W, Zeng R, Tao R, Liu M, Sun Y, Mi B, Liu G. Conductive Hydrogel Inspires Neutrophil Extracellular Traps to Combat Bacterial Infections in Wounds. ACS NANO 2025; 19:9868-9884. [PMID: 40029999 PMCID: PMC11924340 DOI: 10.1021/acsnano.4c14487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Thetreatment of infected wounds is currently a major challenge in clinical medicine, and enhancing antimicrobial and angiogenic capacity is one of the most common strategies. However, the current treatment makes it difficult to balance the antimicrobial effect in the early stage and the angiogenic effect in the later stages of wound healing, leading to an increased rate of poor prognosis. Here, we present a nanoconductive hydrogel EF@S-HGM, consisting of HGM with ECGS, FMLP, and SWCNT. The host-guest supramolecular macromolecule (HGM) hydrogel is biocompatible and can be injected in situ in the wound. The endothelial cell growth factor (ECGS) accelerates vascular remodeling and repairs wounds by promoting the proliferation of endothelial cells. N-Formyl-Met-Leu-Phe (FMLP) recruits neutrophils and increases the antimicrobial capacity. Single-walled carbon nanotubes (SWCNT) make the hydrogel conductive, enabling the hydrogel to utilize the endogenous electric field in the wound to recruit multiple kinds of cells. In addition, we found that the EF@S-HGM hydrogel activates the glucocorticoid receptor senescence pathway and promotes the formation of NET, which enhances the antimicrobial effect. As tissue-engineered skin, the conductive hydrogel EF@S-HGM is a promising material for regenerative medicine that may provide a potential option for the treatment and care of infected wounds and significantly improve patient outcomes and prognosis.
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Affiliation(s)
- Lizhi OuYang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Xi He
- Union Hospital, Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China
| | - Jiaqi Sun
- Union Hospital, Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiewen Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Yuheng Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Xudong Xie
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Weixian Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ruiyin Zeng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ranyang Tao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Mengfei Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Yun Sun
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
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Hu H, Lu F, Guan X, Jiang X, Wen C, Wang L. Baicalein Ameliorates Experimental Ulcerative Colitis Recurrency by Downregulating Neonatal Fc Receptor via the NF-κB Signaling Pathway. ACS OMEGA 2025; 10:10701-10712. [PMID: 40124052 PMCID: PMC11923634 DOI: 10.1021/acsomega.5c00243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/25/2025]
Abstract
Ulcerative colitis (UC) is a chronic autoimmune disease (AID) that causes mild to moderate unpredictable symptoms, including diarrhea and abdominal pain. Against neonatal Fc receptor (FcRn) has been proven to be a unique AID treatment strategy by decreasing the effects of pathogenic autoantibody. Our previous study revealed that FcRn inhibition is beneficial in UC treatment through reducing colonic neutrophil extracellular trap (NET) formation via accelerating serum antineutrophil cytoplasm antibodies (ANCA) clearance. In this study, we initially confirmed the specific impact of downregulating FcRn in preventing UC relapse by injecting rAAV, which is carrying Fcgrt-shRNA, in mice. Next, we investigated the inhibition effects and regulation mechanisms of baicalein (BCL) on FcRn and assessed its capacity to withstand UC recurrence using NCM460 cells and dextran sodium sulfate-induced mice models by determining the expression of FcRn and its related transcription factors. We also measured colonic NET-associated protein (NAP) expression and serum concentrations of IgG, ANCA, TNF-α, IL-1β, and c-reactive protein (CRP). UC inflammation severity was determined by using the disease activity index (DAI) and histopathological score (HS). BCL treatment remarkably decreased the mRNA and protein contents of FcRn, p50, and p65 but did not impact STAT1 expression or the phosphorylation of IκB and STAT1. Long-term BCL administration inhibited colonic FcRn expression and reduced serum ANCA levels, colonic NAP expression, serum inflammation-related indexes (including TNF-α, IL-1β, and CRP), and DAI and HS scores in UC mice during inflammation relapse better than salazosulfapyridine. Our study indicates that BCL ameliorates UC recurrency by inhibiting FcRn expression via p50/p65 heterodimer-mediated NF-κB signaling.
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Affiliation(s)
- Haoyang Hu
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- National
Key Laboratory of Diagnosis and Treatment of Severe Infectious Disease,
National Clinical Research Center for Infectious Diseases, Collaborative
Innovation Center for Diagnosis and Treatment of Infectious Diseases,
The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Fuliang Lu
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xudong Guan
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xuehua Jiang
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chengming Wen
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- School
of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Ling Wang
- Department
of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of
Drug-Targeting and Drug Delivery System of the Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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Serhatlioglu F, Yilmaz Y, Baran O, Yilmaz H, Kelesoglu S. Inflammatory Markers and Postoperative New-Onset Atrial Fibrillation: Prognostic Predictions of Neutrophil Percent to Albumin Ratio in Patients with CABG. Diagnostics (Basel) 2025; 15:741. [PMID: 40150085 PMCID: PMC11941466 DOI: 10.3390/diagnostics15060741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 02/27/2025] [Accepted: 03/11/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Postoperative new-onset atrial fibrillation (AF) (PNOAF) is the most common complication after coronary artery bypass graft (CABG), and its incidence has been reported as up to 50% in studies. In this study, we investigated whether there was a relationship between PNOAF and the neutrophil percentage to albumin ratio (NPAR) levels after on-pump CABG. Methods: A total of 454 patients who underwent CABG were included in the study. NPAR was calculated by dividing the neutrophil count by the albumin value. Results: It was determined that 93 patients developed PNOAF (20.4%). When the patient groups that developed and did not develop PNOAF were compared in terms of laboratory findings, C-reactive protein (CRP) values (4.0 mg/L (2.8-7.9) vs. 2.9 mg/L (1.1-6.7), <0.001), neutrophil/lymphocyte ratio (NLR) (2.2 (1.2-4.2) vs. 1.4 (0.7-3.1), <0.001), platelets-to-lymphocyte ratio (112 (72-177) vs. 92 (69-122), <0.001) and NPAR (2.29 (1.68-3.8) vs. 1.09 (0.79-1.81), <0.001), were found to be statistically significantly higher in the group that developed PNOAF. ROC analysis showed that the cut-off value for NPAR for the development of PNOAF was 1.86 with 78% sensitivity and 72% specificity (area under the ROC curve = 0.778, 95% CI (0.728-0.828), p < 0.001). Conclusions: NPAR, which can be detected by a simple venous blood test, has shown a strong predictive value for PNOAF in patients with CABG.
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Affiliation(s)
- Faruk Serhatlioglu
- Department of Cardiovascular Surgery, Faculty of Medicine, Nigde Omer Halisdemir University, Nigde 51240, Türkiye;
| | - Yucel Yilmaz
- Department of Cardiology, University of Health Sciences, Kayseri City Training and Research Hospital, Kayseri 38080, Türkiye; (Y.Y.); (O.B.)
| | - Oguzhan Baran
- Department of Cardiology, University of Health Sciences, Kayseri City Training and Research Hospital, Kayseri 38080, Türkiye; (Y.Y.); (O.B.)
| | - Halis Yilmaz
- Department of Cardiovascular Surgery, Faculty of Medicine, Erciyes University, Kayseri 38030, Türkiye;
| | - Saban Kelesoglu
- Department of Cardiology, School of Medicine, Erciyes University, Kayseri 38030, Türkiye
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28
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Fu Y, Wan M, Zhu Y, Hao D, Wan Q, Niu W, Ren Z, Xu K, Qin W, Sun S, Yi W, Jiao K, Tay F, Niu L. mtNET-mineral complex: a building block of calculus. Sci Bull (Beijing) 2025; 70:652-656. [PMID: 39794173 DOI: 10.1016/j.scib.2024.12.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/11/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025]
Affiliation(s)
- Yutong Fu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Meichen Wan
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Yina Zhu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Dongxiao Hao
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Qianqian Wan
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Wen Niu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Zhaoyang Ren
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Kehui Xu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Weijun Qin
- Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Shiren Sun
- Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Wei Yi
- Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Kai Jiao
- Department of Stomatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
| | - Franklin Tay
- The Dental College of Georgia, Augusta University, Augusta, 30912, USA
| | - Lina Niu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
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29
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Lin D, Howard A, Raihane AS, Di Napoli M, Cáceres E, Ortiz M, Davis J, Abdelrahman AN, Divani AA. Traumatic Brain Injury and Gut Microbiome: The Role of the Gut-Brain Axis in Neurodegenerative Processes. Curr Neurol Neurosci Rep 2025; 25:23. [PMID: 40087204 DOI: 10.1007/s11910-025-01410-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 03/17/2025]
Abstract
PURPOSE OF REVIEW A deeper understanding of the communication network between the gut microbiome and the central nervous system, termed the gut-brain axis (GBA), has revealed new potential targets for intervention to prevent the development of neurodegenerative disease associated with tramatic brain injury (TBI). This review aims to comprehensively examine the role of GBA post-traumatic brain injury (TBI). RECENT FINDINGS The GBA functions through neural, metabolic, immune, and endocrine systems, creating bidirectional signaling pathways that modulate brain and gastrointestinal (GI) tract physiology. TBI perturbs these signaling pathways, producing pathophysiological feedback loops in the GBA leading to dysbiosis (i.e., a perturbed gut microbiome, impaired brain-blood barrier, impaired intestinal epithelial barrier (i.e., "leaky gut"), and a maladaptive, systemic inflammatory response. Damage to the CNS associated with TBI leads to GI dysmotility, which promotes small intestinal bacterial overgrowth (SIBO). SIBO has been associated with the early stages of neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Many of the bacteria associated with this overgrowth promote inflammation and, in rodent models, have been shown to compromise the structural integrity of the intestinal mucosal barrier, causing malabsorption of essential nutrients and further exacerbating dysbiosis. TBI-induced pathophysiology is strongly associated with an increased risk of neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, which represents a significant public health burden and challenge for patients and their families. A healthy gut microbiome has been shown to promote improved recovery from TBI and prevent the development of neurodegenerative disease, as well as other chronic complications. The role of the gut microbiome in brain health post-TBI demonstrates the potential for microbiome-targeted interventions to mitigate TBI-associated comorbidities. Promising new evidence on prebiotics, probiotics, diet, and fecal microbiota transplantation may lead to new therapeutic options for improving the quality of life for patients with TBI. Still, many of these preliminary findings must be explored further in clinical settings. This review covers the current understanding of the GBA in the setting of TBI and how the gut microbiome may provide a novel therapeutic target for treatment in this patient population.
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Affiliation(s)
- Derek Lin
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Andrea Howard
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Ahmed S Raihane
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Mario Di Napoli
- Neurological Service, dell'Annunziata Hospital, Sulmona, L'Aquila, Italy
| | - Eder Cáceres
- Bioscience, School of Engineering, Universidad de La Sabana, Chía, Colombia
- Department of Critical Care, Clínica Universidad de La Sabana, Chía, Colombia
- Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Chía, Colombia
| | - Michael Ortiz
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Justin Davis
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Allae N Abdelrahman
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Afshin A Divani
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA.
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30
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Song Z, Clemens RA, Zhang Y, Chen J, Wang Y, Dinauer MC, Meng S. Investigating pulmonary neutrophil responses to inflammation in mice via flow cytometry. J Leukoc Biol 2025; 117:qiae189. [PMID: 39212489 DOI: 10.1093/jleuko/qiae189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/20/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024] Open
Abstract
Neutrophils play a crucial role in maintaining lung health by defending against infections and participating in inflammation processes. Here we describe a detailed protocol for evaluating pulmonary neutrophil phenotype using a murine model of sterile inflammation induced by the fungal cell wall particle zymosan. We provide step-by-step instructions for the isolation of single cells from both lung tissues and airspaces, followed by comprehensive staining techniques for both cell surface markers and intracellular components. This protocol facilitates the sorting and detailed characterization of lung neutrophils via flow cytometry, making it suitable for downstream applications such as mRNA extraction, single-cell sequencing, and analysis of neutrophil heterogeneity. We also identify and discuss essential considerations for conducting successful neutrophil flow cytometry experiments. This work is aimed at researchers exploring the intricate functions of neutrophils in the lung under physiological and pathological conditions with the aid of flow cytometry.
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Affiliation(s)
- Zhimin Song
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, No. 195, Dongfeng West Road, Guangzhou, Guangdong 510180, China
- Department of Basic Science Research, Guangzhou National Laboratory, No. 9, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong 510005, China
| | - Regina A Clemens
- Departments of Pediatrics, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, PO Box 8208, St. Louis, MO 63110, United States
| | - Yun Zhang
- Department of Basic Science Research, Guangzhou National Laboratory, No. 9, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong 510005, China
| | - Jingjing Chen
- Department of Basic Science Research, Guangzhou National Laboratory, No. 9, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong 510005, China
| | - Yaofeng Wang
- Department of Basic Science Research, Guangzhou National Laboratory, No. 9, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong 510005, China
| | - Mary C Dinauer
- Departments of Pediatrics, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, PO Box 8208, St. Louis, MO 63110, United States
- Departments of Pathology and Immunology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, PO Box 8208, St. Louis, MO 63110, United States
| | - Shu Meng
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, No. 195, Dongfeng West Road, Guangzhou, Guangdong 510180, China
- Department of Basic Science Research, Guangzhou National Laboratory, No. 9, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong 510005, China
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Jovanovski D, Wohlgemuth L, Lessing PML, Hüsken D, Koller AS, Thomaß BD, Müller P, Mannes M, Nungeß S, Jovanovska M, Mühling B, Liebold A, Huber-Lang M, Messerer DAC. Multimodal monitoring of neutrophil activity during cardiac surgery. Front Immunol 2025; 16:1504944. [PMID: 40151619 PMCID: PMC11947689 DOI: 10.3389/fimmu.2025.1504944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 02/17/2025] [Indexed: 03/29/2025] Open
Abstract
Cardiac surgery and the associated ischemia-reperfusion injury trigger an inflammatory response, which, in turn, can contribute to organ damage, prolonged hospitalization, and mortality. Therefore, the present study performed comprehensive monitoring of neutrophil-related inflammation in patients who underwent aortic valve surgery, including extracorporeal circulation. Neutrophil-related inflammation, as well as alterations in cellular physiology, phenotype, and function, were analyzed by flow cytometry, ELISA, and microscopy. Neutrophil activation occurred intraoperatively and preceded the upregulation of conventional inflammatory markers such as C-reactive protein and interleukin-6. Perioperatively, neutrophils maintained a stable response to platelet-activating factor (PAF) with regard to CD11b and CD66b expression but showed a decreased response in CD10. Postoperatively, neutrophils exhibited marked alterations in PAF-induced depolarization, while reactive oxygen species generation and phagocytic activity remained largely stable. Surprisingly, platelet-neutrophil complex formation was severely impaired intraoperatively but returned to normal levels postoperatively. Further studies are needed to elucidate the implications of these intraoperative and postoperative changes in neutrophil and platelet activity with respect to a potential immune dysfunction that temporarily increases susceptibility to infectious or hemostatic complications.
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Affiliation(s)
- Darko Jovanovski
- Department of Cardiothoracic and Vascular Surgery, University Hospital Ulm, Ulm, Germany
| | - Lisa Wohlgemuth
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | | | - Dominik Hüsken
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | | | - Bertram Dietrich Thomaß
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | - Paul Müller
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | - Marco Mannes
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | - Sandra Nungeß
- Institute of Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Marta Jovanovska
- Department of Cardiothoracic and Vascular Surgery, University Hospital Ulm, Ulm, Germany
| | - Bernd Mühling
- Department of Cardiothoracic and Vascular Surgery, University Hospital Ulm, Ulm, Germany
| | - Andreas Liebold
- Department of Cardiothoracic and Vascular Surgery, University Hospital Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
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Cherrak Y, Younes AA, Perez-Molphe-Montoya E, Maurer L, Yilmaz K, Enz U, Zeder C, Kiefer P, Christen P, Gül E, Vorholt JA, von Mering C, Hardt WD. Neutrophil recruitment during intestinal inflammation primes Salmonella elimination by commensal E. coli in a context-dependent manner. Cell Host Microbe 2025; 33:358-372.e4. [PMID: 40023150 DOI: 10.1016/j.chom.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/19/2024] [Accepted: 02/05/2025] [Indexed: 03/04/2025]
Abstract
Foodborne bacterial diarrhea involves complex pathogen-microbiota-host interactions. Pathogen-displacing probiotics are increasingly popular, but heterogeneous patient outcomes highlighted the need to understand individualized host-probiotic activity. Using the mouse gut commensal Escherichia coli 8178 and the human probiotic E. coli Nissle 1917, we found that the degree of protection against the enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm) varies across mice with distinct gut microbiotas. Pathogen clearance is linked to enteropathy severity and subsequent recruitment of intraluminal neutrophils, which differs in a microbiota-dependent manner. By combining mouse knockout and antibody-mediated depletion models with bacterial genetics, we show that neutrophils and host-derived reactive oxygen species directly influence E. coli-mediated S. Tm displacement by potentiating siderophore-bound toxin killing. Our work demonstrates how host immune factors shape pathogen-displacing probiotic efficiency while also revealing an unconventional antagonistic interaction where a gut commensal and the host synergize to displace an enteric pathogen.
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Affiliation(s)
- Yassine Cherrak
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
| | - Andrew Abi Younes
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Eugenio Perez-Molphe-Montoya
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Luca Maurer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Koray Yilmaz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ursina Enz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christophe Zeder
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Science and Technology, 8092 Zurich, Switzerland
| | - Patrick Kiefer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Philipp Christen
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ersin Gül
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Julia A Vorholt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christian von Mering
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Wolf-Dietrich Hardt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
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Chen S, Wu A, Shen X, Kong J, Huang Y. Disrupting the dangerous alliance: Dual anti-inflammatory and anticoagulant strategy targets platelet-neutrophil crosstalk in sepsis. J Control Release 2025; 379:814-831. [PMID: 39848591 DOI: 10.1016/j.jconrel.2025.01.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/13/2025] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
Sepsis is a life-threatening disease characterized by excessive systemic inflammation and coagulopathy. Platelets and neutrophils form a "dangerous alliance" through crosstalk, promoting the inflammatory cytokine storm and coagulation disorders during sepsis. Platelet-neutrophil crosstalk leads to the formation of platelet-neutrophil complexes (PNCs), which are the central "protagonists" of this "dangerous alliance." These PNCs further enhance the crosstalk between platelets and neutrophils, amplifying immune and coagulation responses through positive feedback loops. Although some targeted therapies have been reported recently, they primarily focus on inducing neutrophil apoptosis or degrading existing neutrophil extracellular traps (NETs). Limited strategies are available for targeting platelets and suppressing sepsis-associated PNCs. Herein, we propose a two-pronged approach to intercept platelet-neutrophil crosstalk by simultaneously targeting drugs to both platelets and neutrophils of the "dangerous alliance." This strategy not only effectively alleviates inflammation induced by platelet-neutrophil crosstalk but also reduces PNC formation, thereby dismantling the structural scaffold of microthrombi. In a sepsis mouse model, this approach significantly decreased markers of platelet-neutrophil crosstalk, reduced the cytokine storm, and lowered the risk of thrombosis. Moreover, it alleviated organ damage caused by PNC infiltration and prolonged the survival of septic mice. Overall, this work combines anti-inflammatory and anticoagulant therapies to effectively disrupt the "dangerous alliance" between platelets and neutrophils, offering a promising strategy for treating sepsis.
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Affiliation(s)
- Sa Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Aijia Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xinran Shen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jinxia Kong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China..
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Ye T, Wu Z, Liu X, Wu J, Fu Q, Cao J, Zhang D, Shi P. Engineered mesenchymal stromal cells with bispecific polyvalent peptides suppress excessive neutrophil infiltration and boost therapy. SCIENCE ADVANCES 2025; 11:eadt7387. [PMID: 40053594 PMCID: PMC11887798 DOI: 10.1126/sciadv.adt7387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/31/2025] [Indexed: 03/09/2025]
Abstract
Excessive neutrophil infiltration can exacerbate inflammation and tissue damage, contributing to conditions like autoimmune disorders and liver diseases. Mesenchymal stromal cells (MSCs) share homing mechanisms with neutrophils, showing promise for treating such diseases. However, ex vivo expanded MSCs often suffer from reduced homing efficiency due to the loss of essential ligands. Here, we engineer MSCs with P-selectin and E-selectin targeting peptides, assembling them into bispecific polyvalent structures using DNA self-assembly technology. This modification allows engineered MSCs to compete with chemotactic neutrophils for selectin binding sites on endothelial cells. In a mouse model of acute liver failure, engineered MSCs effectively home to the damaged liver and substantially inhibit excessive neutrophil infiltration. The combination of inhibiting neutrophil infiltration and the MSCs' inherent therapeutic properties lead to superior therapeutic outcomes. Single-cell RNA sequencing reveals that engineered MSCs elevate the levels of Marco_macrophage, which have neutrophil-inhibitory effects. Our study offers a perspective for advancing MSC-based therapies in tissue repair.
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Affiliation(s)
- Tenghui Ye
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
| | - Zixin Wu
- Department of General Surgery, Guangzhou Digestive Disease Center, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Xi Liu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
| | - Jiamin Wu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
| | - Qin Fu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
| | - Jie Cao
- Department of General Surgery, Guangzhou Digestive Disease Center, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Di Zhang
- Department of General Surgery (Colorectal Surgery), Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Peng Shi
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, PR China
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Tang J, Li J, Hou Z, He R, Li B, Gong J, Xie Y, Meng W, Liu Y, Ouchi T, Li L, Li B. Dasatinib and Quercetin Mitigate Age-Related Alveolar Bone Inflammaging and Neutrophil Infiltration. Oral Dis 2025. [PMID: 40051132 DOI: 10.1111/odi.15291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 01/23/2025] [Accepted: 02/05/2025] [Indexed: 03/17/2025]
Abstract
OBJECTIVE Age-related alveolar bone resorption poses a major dental health challenge, yet its mechanisms and treatments are poorly understood. This study investigates the impact of dasatinib and quercetin (D + Q) treatment on senescent cells (SnCs), senescence-associated secretory phenotype (SASP), and neutrophil infiltration in aged alveolar bone, aiming to develop new strategies for combating age-related bone resorption. METHODS C57BL/6 mice (2 and 18 months) were used to examine alveolar bone resorption, inflammaging, and neutrophil infiltration. Aged mice received D + Q treatment to assess therapeutic effects. Key measurements included cementoenamel junction to the alveolar bone crest (CEJ-ABC) distance, periodontal ligament (PDL) thickness, osteometabolism markers, SnCs accumulation, SASP expression, and neutrophil infiltration. RESULTS Aged alveolar bone showed increased CEJ-ABC distance, atrophied periodontal ligament, and unbalanced osteometabolism, along with elevated SnCs, SASP, and neutrophils compared to young controls. D + Q treatment improved these conditions by reducing CEJ-ABC distance, enhancing periodontal ligament health, and boosting bone metabolism. It also lowered the expression of SnCs, SASP, and neutrophil markers. CONCLUSION D + Q treatment effectively mitigates alveolar bone aging by clearing SnCs, lowering SASP levels, and reducing neutrophil aggregation, presenting a novel approach for age-related bone resorption.
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Affiliation(s)
- Jinru Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jingya Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zeyu Hou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Rong He
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bingzhi Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiajing Gong
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuhang Xie
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wanrong Meng
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yunkun Liu
- Hospital of Stomatology, Zunyi Medical University, Zunyi, China
| | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, Tokyo, Japan
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Hong Y, Shi JQ, Feng S, Huang SQ, Yuan ZH, Liu S, Zhang XH, Zhou JS, Jiang T, Zhao HD, Zhang YD. The systemic inflammation markers as potential predictors of disease progression and survival time in amyotrophic lateral sclerosis. Front Neurosci 2025; 19:1552949. [PMID: 40109661 PMCID: PMC11919871 DOI: 10.3389/fnins.2025.1552949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 02/17/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal and untreatable neurodegenerative disease with only 3-5 years' survival time after diagnosis. Inflammation has been proven to play important roles in ALS progression. However, the relationship between systemic inflammation markers and ALS has not been well established, especially in Chinese ALS patients. The present study aimed to assess the predictive value of systemic inflammation markers including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) for Chinese amyotrophic lateral sclerosis (ALS). Methods Seventy-two Chinese ALS patients and 73 controls were included in this study. The rate of disease progression was calculated as the change of Revised ALS Functional Rating Scale (ALSFRS-R) score per month. Patients were classified into fast progressors if the progression rate > 1.0 point/month and slow progressors if progression rate ≤ 1.0 point/month. The value of NLR, PLR, LMR, and SII were measured based on blood cell counts. The association between systemic inflammation markers and disease progression rate was confirmed by logistic regression analysis. Kaplan-Meier curve and Cox regression models were used to evaluate factors affecting the survival outcome of ALS patients. Results For Chinese ALS patients, NLR, PLR and SII were higher, LMR was lower when compared with controls. All these four markers were proved to be independent correlated with fast progression of ALS. Both Kaplan-Meier curve and Cox regression analysis indicated that higher NLR and lower LMR were associated with shorter survival time in the ALS patients. Discussion In conclusion, the systemic inflammation markers, especially NLR and LMR might be independent markers for rapid progression and shorter survival time in Chinese ALS patients.
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Affiliation(s)
- Ye Hong
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian-Quan Shi
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shuai Feng
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shi-Qi Huang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhen-Hua Yuan
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shen Liu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao-Hao Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jun-Shan Zhou
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong-Dong Zhao
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ying-Dong Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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Kaur G, Tiwari P, Singla S, Panghal A, Jena G. The intervention of NLRP3 inflammasome inhibitor: oridonin against azoxymethane and dextran sulfate sodium-induced colitis-associated colorectal cancer in male BALB/c mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03871-z. [PMID: 40035821 DOI: 10.1007/s00210-025-03871-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/31/2025] [Indexed: 03/06/2025]
Abstract
Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance.
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Affiliation(s)
- Gurpreet Kaur
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Priyanka Tiwari
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Shivani Singla
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Archna Panghal
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Gopabandhu Jena
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India.
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Zhu J, Shi R, Li X, Liu M, Yu L, Bai Y, Zhang Y, Wang W, Chen L, Shi G, Liu Z, Guo Y, Fan J, Yang S, Jin X, Zhang F, Zong X, Tang X, Chen J, Ma T, Xiao B, Wang D. Association between neutrophil percentage-to-albumin ratio and mortality in Hemodialysis patients: insights from a prospective cohort study. BMC Nephrol 2025; 26:112. [PMID: 40038629 DOI: 10.1186/s12882-025-04027-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/19/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND The neutrophil percentage-to-albumin ratio (NPAR) emerges as a novel inflammation marker, demonstrating prognostic ability in a variety of cardiovascular diseases. However, its impact on mortality among patients undergoing maintenance hemodialysis (MHD) remains uncertain. Our research aims to determine whether NPAR is a reliable predictor of mortality in MHD patients. METHODS A total of 1803 MHD patients were recruited in this prospective cohort. Patients were stratified into three groups based on baseline NPAR levels. The association between NPAR and all-cause and cardiovascular mortality was evaluated using multivariate Cox proportional risk model and sensitivity analysis. NPAR's predictive performance was assessed using the receiver operating characteristic (ROC) curve, compared to several conventional biomarkers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil count, and serum albumin. The area under the curve (AUC) values of NPAR and these biomarkers were compared using the DeLong's test. RESULTS Throughout a median follow-up period of 28 months, 239 (13.3%) patients died, with 91 (5.0%) dying of cardiovascular disease. Both all-cause mortality and cardiovascular mortality exhibited remarkably higher within the high NPAR group compared to the middle and low NPAR groups in the multivariate Cox regression analysis. The adjusted hazard ratio was 1.550 (95% CI: 1.110-2.166, P = 0.010) for all-cause mortality and 1.844 (95% CI: 1.058-3.212, P = 0.031) for cardiovascular mortality. This association was further corroborated by sensitivity analyses. The AUC values of NPAR for all-cause mortality and cardiovascular mortality were 0.612 (95% CI: 0.572-0.652, P < 0.001) and 0.618 (95% CI: 0.557-0.678, P < 0.001), separately. The p-values for comparing NPAR's AUC with those of NLR, PLR, neutrophils, and albumin were 0.307, 0.094, 0.014, and 0.154 for all-cause mortality, and 0.879, 0.126, 0.119, and 0.596 for cardiovascular mortality. CONCLUSION High NPAR level was independently associated with a higher increased risk of death in MHD patients.
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Affiliation(s)
- Jiaxin Zhu
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
- Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Rui Shi
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
- Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Xunliang Li
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
- Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Mengqian Liu
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
- Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Linfei Yu
- Department of Nephrology, The People's Hospital of Taihu, 196 Renmin Road, Taihu County, 246400, China
| | - Youwei Bai
- Department of Nephrology, Lu'an People's Hospital of Anhui Province, 73 Mozitan Road, Lu'an, 237000, China
| | - Yong Zhang
- Department of Nephrology, Lujiang County Hospital of TCM, 350 Zhouyu Avenue, Lujiang County, 231501, China
| | - Wei Wang
- Department of Nephrology, The People's Hospital of Xuancheng City, 51 Dabatang Road, Xuancheng, 242099, China
| | - Lei Chen
- Department of Nephrology, Hefei Jinnan Kidney Hospital, Northeast of the intersection of Fozhang Road and Beihai Road, Hefei, 230071, China
| | - Guangcai Shi
- Department of Nephrology, The Fifth People's Hospital of Hefei, Yuxi Road, Hefei, 230011, China
| | - Zhi Liu
- Department of Nephrology, The First Affiliated Hospital of Anhui University of Science & Technology, 203 Huaibin Road, Huainan, 232000, China
| | - Yuwen Guo
- Department of Nephrology, Lujiang County People's Hospital, 32 Wenmingzhong Road, Lujiang, 231501, China
| | - Jihui Fan
- Department of Nephrology, Huaibei People's Hospital, 66 Huaihai West Road, Huaibei, 235000, China
| | - Shanfei Yang
- Department of Nephrology, Northeast of the Intersection of Binyang Avenue and Dongjin Avenue, Shouxian County Hospital, Shouxian County, 232200, China
| | - Xiping Jin
- Department of Nephrology, Huainan Chao Yang Hospital, 15 Renmin South Road, Huainan, 232007, China
| | - Fan Zhang
- Department of Nephrology, Dongzhi County People's Hospital, 70 Jianshe Road, Dongzhi County, 247299, China
| | - Xiaoying Zong
- Department of Nephrology, The Second Affiliated Hospital of Bengbu Medical College, 633 Longhua Road, Bengbu, 233017, China
| | - Xiaofei Tang
- Department of Nephrology, Maanshan People's Hospital, 45 Hubei Road, Maanshan City, 243099, China
| | - Jiande Chen
- Department of Nephrology, Ningguo People's Hospital, 76 Jinhe East Road, Ningguo City, 242300, China
| | - Tao Ma
- Department of Nephrology, No. 2 People's Hospital of Fuyang City, No 1088 West Yinghe Road, Fuyang, 236015, China
| | - Bei Xiao
- Department of Nephrology, Hefei First People's Hospital, 3200 Changsha Road, Binhu New District, Hefei, 230092, China
| | - Deguang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China.
- Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China.
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Mir M, Faiz S, Bommakanti AG, Sheshadri A. Pulmonary Immunocompromise in Stem Cell Transplantation and Cellular Therapy. Clin Chest Med 2025; 46:129-147. [PMID: 39890284 DOI: 10.1016/j.ccm.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2025]
Abstract
Hematopoietic cell transplantation (HCT) and cellular therapies, such as chimeric-antigen receptor T-cell (CAR-T) treatments, are potentially curative treatments for certain hematologic malignancies and some nonmalignant disorders. However, pulmonary complications, both infectious and noninfectious, remain a significant cause of morbidity and mortality in patients who receive cellular therapies. This review article provides an overview of pulmonary complications encountered in the context of HCT and CAR-T. The authors discuss mechanisms of underlying immunocompromise that lead to a rise in infections. Additionally, they highlight key noninfectious complications of HCT that can mimic acute infections and suggest diagnostic approaches and preventive strategies to distinguish these entities promptly.
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Affiliation(s)
- Mahnoor Mir
- Divisions of Critical Care, Pulmonary and Sleep Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Saadia Faiz
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anuradha G Bommakanti
- Divisions of Critical Care, Pulmonary and Sleep Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ajay Sheshadri
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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40
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Luo R, Wang B, Luo R. Zearalenone delays tissue regeneration by dysregulating neutrophil balance in zebrafish (Danio rerio) larvae. Comp Biochem Physiol C Toxicol Pharmacol 2025; 289:110105. [PMID: 39701198 DOI: 10.1016/j.cbpc.2024.110105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/23/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024]
Abstract
Zearalenone (ZEA), a common mycotoxin, poses significant environmental and health risks. While its toxicological effects are well-studied, its impact on regeneration remains unclear. This study explored ZEA's effects on zebrafish (Danio rerio) larvae, focusing on developmental toxicity, immunotoxicity, and tissue regeneration. Embryos were exposed to 0, 0.5, 1, and 1.5 μM ZEA from 6 to 72 h post-fertilization (hpf). Although hatching and survival rates remained unaffected, malformations, including body axis bending and pericardial edema, increased dose-dependently, with 4.44 % abnormalities observed at 1.5 μM (p = 0.01). Heart rates also declined significantly at 1.5 μM (75.40 vs. 72.53 beats/30s, p = 0.0054). Immunotoxicity was assessed using Tg(mpx: eGFP) zebrafish to monitor neutrophil responses post-injury. ZEA exposure led to increased neutrophil counts (229.87 vs. 330.80, p < 0.0001) and chemotaxis (21.15 % vs. 34.57 %, p < 0.0001). RNA sequencing of 0 and 1.5 μM groups revealed disrupted redox balance and oxygen transport, with down-regulation of hbae1, hbbe2, and hbae3 and up-regulation of hif1a, indicating hypoxia involvement. Elevated reactive oxygen species (ROS), reduced antioxidant enzyme activity, and increased apoptosis were also observed. Tail fin regeneration assays showed delayed regeneration at 1 and 1.5 μM ZEA, linked to impaired immune function and oxidative stress. These findings highlight ZEA's adverse effects on developmental and regenerative processes, underscoring its environmental and health implications and the need for further research.
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Affiliation(s)
- Rui Luo
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bo Wang
- Department of Medical Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Luo
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Xue P, Wang J, Fu Y, He H, Gan Q, Liu C. Material-Mediated Immunotherapy to Regulate Bone Aging and Promote Bone Repair. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2409886. [PMID: 39981851 DOI: 10.1002/smll.202409886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/19/2025] [Indexed: 02/22/2025]
Abstract
As the global population ages, an increasing number of elderly people are experiencing weakened bone regenerative capabilities, resulting in slower bone repair processes and associated risks of various complications. This review outlines the research progress on biomaterials that promote bone repair through immunotherapy. This review examines how manufacturing technologies such as 3D printing, electrospinning, and microfluidic technology contribute to enhancing the therapeutic effects of these biomaterials. Following this, it provides detailed introductions to various anti-osteoporosis drug delivery systems, such as injectable hydrogels, nanoparticles, and engineered exosomes, as well as bone tissue engineering materials and coatings used in immunomodulation. Moreover, it critically analyzes the current limitations of biomaterial-mediated bone immunotherapy and explores future research directions for material-mediated bone immunotherapy. This review aims to inspire new approaches and broaden perspectives in addressing the challenges of bone repair and aging by exploring innovative biomaterial-mediated immunotherapy strategies.
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Affiliation(s)
- Pengfei Xue
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Jiayi Wang
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Yu Fu
- School of Aerospace Engineering and Applied Mechanics, Tongji University, Zhangwu Road 100, Shanghai, 200092, China
| | - Hongyan He
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Qi Gan
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, P. R. China
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42
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Wang G, Zhang D, He Z, Mao B, Hu X, Chen L, Yang Q, Zhou Z, Zhang Y, Linghu K, Tang C, Xu Z, Liu D, Song J, Wang H, Lin Y, Li R, Lin JW, Chen L. Machine learning-based prediction reveals kinase MAP4K4 regulates neutrophil differentiation through phosphorylating apoptosis-related proteins. PLoS Comput Biol 2025; 21:e1012877. [PMID: 40096134 PMCID: PMC11957395 DOI: 10.1371/journal.pcbi.1012877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 03/31/2025] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Neutrophils, an essential innate immune cell type with a short lifespan, rely on continuous replenishment from bone marrow (BM) precursors. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the molecular regulators involved in the differentiation process remain poorly understood. Here we developed a random forest-based machine-learning pipeline, NeuRGI (Neutrophil Regulatory Gene Identifier), which utilized Positive-Unlabeled Learning (PU-learning) and neural network-based in silico gene knockout to identify neutrophil regulators. We interrogated features including gene expression dynamics, physiological characteristics, pathological relatedness, and gene conservation for the model training. Our identified pipeline leads to identifying Mitogen-Activated Protein Kinase-4 (MAP4K4) as a novel neutrophil differentiation regulator. The loss of MAP4K4 in hematopoietic stem cells and progenitors in mice induced neutropenia and impeded the differentiation of neutrophils in the bone marrow. By modulating the phosphorylation level of proteins involved in cell apoptosis, such as STAT5A, MAP4K4 delicately regulates cell apoptosis during the process of neutrophil differentiation. Our work presents a novel regulatory mechanism in neutrophil differentiation and provides a robust prediction model that can be applied to other cellular differentiation processes.
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Affiliation(s)
- Guihua Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dan Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhifeng He
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Mao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiao Hu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Chen
- Biosafety Laboratory of West China Hospital, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qingxin Yang
- Biosafety Laboratory of West China Hospital, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhen Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yating Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kepan Linghu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chao Tang
- Biosafety Laboratory of West China Hospital, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zijie Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Defu Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junwei Song
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huiying Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yishan Lin
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruihan Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jing-Wen Lin
- Biosafety Laboratory of West China Hospital, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lu Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
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Yuan X, Zhou M, Liu X, Fan J, Chen L, Luo J, Li S, Zhou L. Identification of Biomarkers for Response to Interferon in Chronic Hepatitis B Based on Bioinformatics Analysis and Machine Learning. Viral Immunol 2025; 38:61-69. [PMID: 39992204 DOI: 10.1089/vim.2024.0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025] Open
Abstract
Interferon (IFN) is a pivotal agent against hepatitis B virus (HBV) in clinic, but there is a lack of accurate biomarkers to predict the response to IFN therapy in patients with chronic hepatitis B (CHB). Our study aimed to investigate potential targets for IFN therapy and to explore the network of interactions associated with IFN response. MicroRNA (miRNA) (GSE29911) and messenger RNA (GSE27555) datasets were used to screen the differentially expressed miRNAs (DEmiRNAs) and differentially expressed genes (DEGs). The random forest and k-nearest neighbors algorithm were used to further screen the core DEmiRNAs and build a prediction model. A Protein-Protein Interaction (PPI) network based on the STRING database was constructed and visualized by the Cytoscape software. Then, we collected transcription factors (TFs) from the TransmiR database to construct the TF-miRNA-hub gene regulatory network. Finally, real-time quantitative polymerase chain reaction was used to verify the expression of four miRNAs in HepG2-NTCP and Huh-7, and the effect of IFN treatment on four miRNAs' expression was preliminarily explored. Eighteen DEmiRNAs in GSE29911 and 700 DEGs in GSE27555 were identified. Boruta feature selection identified four miRNAs (miR-873, miR-200a, miR-30b, and let-7g) from 18 DEmiRNAs. We identified 48 TFs, 4 miRNAs, and 10 hub genes and constructed a TF-miRNA-hub gene network to suggest the mechanism of IFN response. According to the experimental results, miR-873 was upregulated and IFN treatment could inhibit it in HBV-transfected cells (p < 0.05). We constructed a TF-miRNA-hub gene regulatory network, and our results demonstrate that miR-873 was identified as a potential biomarker of IFN response in patients with CHB. This information provides an initial basis for understanding the complex IFN response regulatory mechanisms.
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Affiliation(s)
- Xiaoqin Yuan
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Mingsha Zhou
- Chongqing Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine (Chongqing Beibei Hospital of Traditional Chinese Medicine), Medical Records and Statistics Department, Chongqing, China
| | - Xing Liu
- Jiulongpo District Center for Disease Control and Prevention, Immunization Planning Department, Chongqing, China
| | - Jie Fan
- Chongqing Medical and Pharmaceutical College, School of Public Health and Emergency Management, Chongqing, China
| | - Lijuan Chen
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Jia Luo
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Shan Li
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Li Zhou
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
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Aviv A, Verhulst S. Telomeres in Space. Aging Cell 2025; 24:e70030. [PMID: 40022541 PMCID: PMC11896355 DOI: 10.1111/acel.70030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 01/31/2025] [Accepted: 02/06/2025] [Indexed: 03/03/2025] Open
Abstract
Recent studies have reported that the spaceflight environment lengthens leukocyte telomeres. We propose that this baffling finding reflects changes in the composition of leukocyte subsets rather than an actual increase in telomere length within individual leukocytes. Since leukocyte telomere length is associated with aging-related diseases and longevity in humans, it is crucial to understand the underlying factors driving telomere length changes in space.
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Affiliation(s)
- Abraham Aviv
- Center of Human Development and Aging, New Jersey Medical SchoolRutgers State University of New JerseyNewarkNew JerseyUSA
| | - Simon Verhulst
- Groningen Institute for Evolutionary Life SciencesUniversity of GroningenGroningenthe Netherlands
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45
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Cui X, Song Y, Han J, Yuan Z. The multifaceted role of SMAD4 in immune cell function. Biochem Biophys Rep 2025; 41:101902. [PMID: 39802394 PMCID: PMC11721226 DOI: 10.1016/j.bbrep.2024.101902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.
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Affiliation(s)
- Xinmu Cui
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Yu Song
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Jianfeng Han
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
- Cellular Biomedicine Group Inc, Shanghai, 201203, China
| | - Zhaoxin Yuan
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
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46
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Wang Y, Wu J, Shao T, Su D, Ma X, Yu Z, Li N. PROGNOSTIC IMPLICATIONS OF CHANGES IN PLATELET TRAJECTORIES IN PATIENTS WITH SEPSIS: A RETROSPECTIVE ANALYSIS USING THE MEDICAL INFORMATION MART FOR INTENSIVE CARE IV DATABASE. Shock 2025; 63:371-378. [PMID: 39450919 DOI: 10.1097/shk.0000000000002493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
ABSTRACT Objective: Patients with sepsis often experience reductions or increases in platelet counts, but the implications of these temporal patterns on prognosis remain unclear. The aim of this study was to investigate the impact of changes in platelet trajectories on the clinical prognosis of sepsis. Methods: This study was a retrospective analysis using data from the Medical Information Mart for Intensive Care IV database. Patients with sepsis were identified from the database, and their platelet trajectories were categorized into four distinct models based on the changes in platelet counts over a period of 14 days after diagnosis of sepsis. The effect of these trajectories on patient prognosis was subsequently evaluated. Results: A total of 15,250 patients with sepsis were included to construct a model, and the following four distinct platelet count trajectories were identified: normal platelet levels (phenotype 1); persistently low platelet levels (phenotype 2); gradually increasing platelet levels exceeding the normal range (phenotype 3); and consistently significantly elevated platelet levels (phenotype 4). Statistically significant differences were found in the 28-day mortality, in-hospital mortality, and 90-day mortality among the four phenotypes. Multivariate regression analysis showed that compared to the group with normal platelet levels (phenotype 1), the group with persistently low platelet levels (phenotype 2) had higher in-hospital mortality (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16-1.54), 28-day mortality (OR = 1.69, 95% CI: 1.47-1.94), and 90-day mortality (OR = 1.50, 95% CI: 1.32-1.69). There was no difference in in-hospital mortality between phenotypes 3 and 4 compared to phenotype 1, although phenotype 4 showed an increase in 28-day mortality ( P < 0.05), and phenotype 3 showed a decreasing trend in 90-day mortality ( P < 0.05). The results of inverse probability weighting adjusted by regression were basically consistent with the above findings, except that there was no statistical difference in 28-day mortality between phenotype 4 and phenotype 1. In the subgroups based on age, weight, and antiplatelet drugs or therapies, there was an interaction between platelet levels and these factors. Conclusions: In patients with sepsis, a decrease in platelet count is associated with increased mortality, while a moderate increase in platelet count can reduce 90-day mortality. However, for patients with persistently elevated platelet counts, caution is advised when using antiplatelet drugs or therapies, as it may increase mortality.
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Affiliation(s)
- Yingxin Wang
- Department of Critical Care Medicine, Affiliated Hospital of Hebei University, BaoDing, China
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Zheng Y, Zhuang Z, Zhou R, Zheng L, Li C, Zhou R, Gao Y, Zhang L, Zheng Y, Zhao L, Rizvi SFA, Yang B, Jiang L, Lin J, Wang A, Zhou W, Cheng H, Li D, Chu C, Thompson EW, Wu Y, Liu G, Zeng Y, Wang P. Next-Generation Oral Ulcer Management: Integrating Cold Atmospheric Plasma (CAP) with Nanogel-Based Pharmaceuticals for Inflammation Regulation. Adv Healthc Mater 2025; 14:e2403223. [PMID: 39901375 DOI: 10.1002/adhm.202403223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/19/2024] [Indexed: 02/05/2025]
Abstract
Oral ulcers, affecting 27.9% of adults, can lead to malnutrition and dehydration, especially in individuals with diabetes, cancer, viral infections, and autoimmune diseases. Existing treatments-including oral films, sprays, frosts, and powders-often fail to be effective due to rapid dilution and clearance in the moist oral environment. This study is the first to investigate the use of Cold Atmospheric Plasma (CAP) for treating oral ulcers and its underlying molecular mechanisms. A novel high-bioavailability, mucoadhesive therapy combining handheld three dimensions (3D) multi-microhole CAP is developed with a nanogel-based pharmaceutical system containing glucose oxidase (GOx) and catalase (CAT), termed GCN. These results showed that both CAP alone and CAP combined with GCN significantly accelerate oral ulcer healing, modulate immune responses, and activate the Epidermal Growth Factor Receptor (EGFR) in acetic acid-induced oral ulcers, outperforming untreated controls and the conventional medication, Watermelon Frost (WF). Furthermore, the CAP+GCN combination enhances therapeutic effects by promoting fibroblast generation. CAP pretreatment also enhances cell permeability and nanoparticle uptake, improving tissue adhesion. These findings are validated in primary Human Gingival Fibroblasts (HGF) and Human Periodontal Ligament Stem Cells (PDLSC) from healthy donors, as well as an oral ulcer model in rats, demonstrating superior biocompatibility and safety.
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Affiliation(s)
- Yanfen Zheng
- Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Department of Pharmacy, Stomatological Hospital of Xiamen Medical College, Xiamen, 361008, China
| | - Ziqi Zhuang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Renwu Zhou
- State Key Laboratory of Electrical Insulation and Power Equipment, Center for Plasma Biomedicine, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Luo Zheng
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Changhong Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Rusen Zhou
- State Key Laboratory of Electrical Insulation and Power Equipment, Center for Plasma Biomedicine, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yuting Gao
- State Key Laboratory of Electrical Insulation and Power Equipment, Center for Plasma Biomedicine, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Liang Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Department of Dermatology, The Fourth Affiliated Hospital of Harbin Medical University, No.37, Yiyuan Street, Nangang District, Harbin, 150001, China
| | - Yating Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Liqian Zhao
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Syed Faheem Askari Rizvi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Bocheng Yang
- Division of Plastic Surgery, Zhongshan Hospital Xiamen University, Xiamen, 361001, China
| | - Lili Jiang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Jinyong Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Anqi Wang
- Department of Dermatology, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - Wei Zhou
- School of Chemistry and Chemical Engineering, Inner Mongolia University of Science & Technology, Baotou, 014010, China
| | - Hongwei Cheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- University of Macau, N23 Building, Avenida da Universidade, Taipa, Macau, 999078, China
- Zhuhai UM Science & Technology Research Institute, University of Macau, Macau, 999078, China
| | - Dong Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, 361021, China
| | - Chengchao Chu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
- The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Erik W Thompson
- School of Biomedical Sciences and Centre for Genomics and Personalised Health, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, 4059, Australia
- Translational Research Institute, Woolloongabba, Queensland, 4102, Australia
| | - Yunlong Wu
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Gang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Yun Zeng
- Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Department of Pharmacy, Stomatological Hospital of Xiamen Medical College, Xiamen, 361008, China
| | - Peiyu Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
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Shen R, Jiang Y, Liu G, Gao S, Sun H, Wu X, Gu J, Wu H, Mo K, Niu X, Ben-Ami R, Shang W, Zhang J, Wang J, Miao C, Wang Z, Chen W. Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406218. [PMID: 39887584 PMCID: PMC11923989 DOI: 10.1002/advs.202406218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 12/05/2024] [Indexed: 02/01/2025]
Abstract
Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis. Although immunosuppressive genes are upregulated in different immune cells, only neutrophils dramatically increase in the BALF of patients in immunosuppressive phase of sepsis. Five neutrophil subpopulations in BALF are identified, among which CXCR2+ and CD274 (PD-L1 coding gene)+IL1RN+ neutrophil subpopulations increased significantly during septic immunosuppression. Interestingly, a developmental trajectory from CXCR2+ to CD274+IL1RN+ neutrophil subpopulation is disclosed. Moreover, the therapeutic effect of CXCR2 blockade is observed on the survival of septic mice, along with a decreased number of PD-L1+ neutrophils. Taken together, the CXCR2+ neutrophil subpopulation is discovered as a contributor to immunosuppression in sepsis and identified it as a potential therapeutic target in sepsis treatment.
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Affiliation(s)
- Rong Shen
- Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, 510515, China
| | - Yi Jiang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Guanglong Liu
- Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, 510515, China
| | - Shenjia Gao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Hao Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Xinyi Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Jiahui Gu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Han Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Ke Mo
- Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, Hong Kong, 999077, China
| | - Xing Niu
- Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, Hong Kong, 999077, China
| | - Ronen Ben-Ami
- Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Wanjing Shang
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20814, USA
| | - Jie Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Jun Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
| | - Zhizhang Wang
- Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, 510515, China
| | - Wankun Chen
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, 200032, China
- Department of Anesthesiology, Shanghai Geriatric Medical Center, Shanghai, 201104, China
- Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 201700, China
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Liu Y, Liu W, Yang Y, Liu H, Liu J, Liu Y. The association between dietary dark green vegetable intake and cognitive function in US older adults. NUTR BULL 2025; 50:69-81. [PMID: 39572249 DOI: 10.1111/nbu.12720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 09/26/2024] [Accepted: 10/30/2024] [Indexed: 02/13/2025]
Abstract
Dark green vegetables include dark green leafy vegetables and broccoli. They are sources of many essential nutrients, including vitamins A, B and C, folate, fibre, carotenoids and flavonoids. This study aimed to explore the association between dietary dark green vegetable intake and cognitive function in US older adults. We included 2344 older adults (≥60 years old) from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 cycles. Dark green vegetable consumption was assessed using a continuous variable (cups/day) and two categorical variables. The first categorical variable classified participants into non-consumers and consumers based on whether they consumed dark green vegetables. The second categorical variable grouped participants into four levels of dark green vegetable consumption (non-consumers, consumers with low intakes, consumers with moderate intakes and consumers with high intakes). We used five continuous variables with non-normal distribution to assess cognitive function, including a composite z-score and the standardised scores of four individual cognitive tests. The four cognitive tests included the Immediate Recall Test (IRT), the Delayed Recall Test (DRT), the Animal Mobility Test (AFT) and the Digit Symbol Substitution Test (DSST). The standardised scores of the four cognitive tests were calculated using the mean and standard deviation of each cognitive test score. The composite z-score was calculated by averaging the standardised scores of four cognitive tests to evaluate global cognition. We used multiple linear regression models to examine the association between dietary dark green vegetable intake and cognitive function. Our findings indicated that dark green vegetable intake was positively associated with global cognition (β [95% CI]: 0.17 [0.04, 0.30]; p = 0.016) and IRT (β [95% CI]: 0.26 [0.08, 0.43]; p = 0.009) and DRT (β [95% CI]: 0.21 [0.05, 0.36]; p = 0.012) standardised scores. Individuals with high intake of dark green vegetables showed notably better global cognition (β [95% CI]: 0.16 [0.05, 0.28]; p = 0.010) and showed higher IRT (β [95% CI]: 0.22 [0.07, 0.38]; p = 0.010) and DRT standardised scores (β [95% CI]: 0.21 [0.07, 0.36]; p = 0.007) compared with the non-consumers. Blood neutrophil counts mediated the cognitive benefits of dark green vegetables (Proportion: 9.5%, p = 0.006). In conclusion, our findings suggest that dark green vegetable consumption may have favourable effects on cognitive function in US older adults, especially on immediate and delayed learning abilities. The underlying mechanisms include the ability of dark green vegetables to reduce blood neutrophil levels, an indicator of decreased systemic inflammation. Increasing dietary intake of dark green vegetables may be a beneficial intervention to improve cognitive health in the older US population.
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Affiliation(s)
- Yuqian Liu
- Qilu Hospital of Shandong University, Jinan, China
| | - Wen Liu
- Qilu Hospital of Shandong University, Jinan, China
| | - Yang Yang
- Qilu Hospital of Shandong University, Jinan, China
| | - Heyin Liu
- Qilu Hospital of Shandong University, Jinan, China
| | - Jinde Liu
- Qilu Hospital of Shandong University, Jinan, China
| | - Yiming Liu
- Qilu Hospital of Shandong University, Jinan, China
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50
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Pareek D, Zeyaullah M, Patra S, Alagu O, Singh G, Wasnik K, Gupta PS, Paik P. Mesoporous polymeric nanoparticles for effective treatment of inflammatory diseases: an in vivo study. J Mater Chem B 2025; 13:3094-3113. [PMID: 39902477 DOI: 10.1039/d4tb02012j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2025]
Abstract
Acute inflammatory diseases require suitable medicine over the existing therapeutics. In this line, the present work is focused on developing polymeric nanomedicine for the treatment of inflammatory disorders. Herein, cell viable nanoparticles (GlyNPs) of size 180-250 nm in diameter and pore size of 4-5 nm in diameter, based on glycine and acryloyl chloride, have been developed and proved to be a potential anti-inflammatory agent without using any conventional drugs. These particles exhibit colloidal stability (with a zeta potential of -35.6 mV). A network pharmacology-based computational study has been executed on 9076 genes and proteins responsible for inflammatory diseases, out of which 10 are selected that have a major role in rheumatoid arthritis (RA). In silico docking study has been conducted to find out the targeted efficiency of the GlyNPs considering 10 inflammation-specific markers, namely IL-6, IL-1β, TNF-α, TLR-4, STAT-1, MAPK-8, MAPK-14, iNOS, NF-κβ and COX-2. The results revealed that the GlyNPs could be an excellent anti-inflammatory component similar to aspirin. The in vitro inflammation activity of these GlyNPs has also been checked on an inflammation model generated by LPS in RAW 264.7 macrophages. Then, the in vitro anti-inflammation efficiency has been checked with 10-150 μg mL-1 of GlyNP doses. The treatment efficiency has been checked on inflammation-responsible immune markers (NO level, NF-κβ, INF-γ, IL-6, IL-10, and TNF-α) and it was found that the GlyNPs are an excellent component in reducing inflammation. The in vivo therapeutic response of GlyNPs on the induced rheumatoid arthritis (RA) model has been evaluated by measuring the morphological, biochemical and immune-cytokine and interferon levels responsible for the inflammation, using a 2 g kg-1 dose (sample to weight of rat). The anti-inflammatory efficiency of GlyNPs without using additional drugs was found to be excellent. Thus, GlyNPs could be paramount for the potential treatment of various inflammatory diseases.
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Affiliation(s)
- Divya Pareek
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Md Zeyaullah
- Department of Zoology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221005, India
| | - Sukanya Patra
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Oviya Alagu
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Gurmeet Singh
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Kirti Wasnik
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Prem Shankar Gupta
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
| | - Pradip Paik
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh 221 005, India.
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