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Shou C, Sun Y, Zhang Q, Zhang W, Yan Q, Xu T, Li H. S100A9 Inhibition Mitigates Acute Pancreatitis by Suppressing RAGE Expression and Subsequently Ameliorating Inflammation. Inflammation 2024:10.1007/s10753-024-02194-0. [PMID: 39690365 DOI: 10.1007/s10753-024-02194-0] [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: 09/26/2024] [Revised: 10/27/2024] [Accepted: 11/14/2024] [Indexed: 12/19/2024]
Abstract
Acute pancreatitis (AP) is a common acute inflammatory abdominal condition. Severe acute pancreatitis (SAP) can provoke a systemic inflammatory response and lead to multiple organ failure. The S100A9 protein, recognized as a major inflammatory biomarker, plays a significant role in both infection and inflammatory responses. Despite its known role in inflammation, the precise role of S100A9 in AP remains poorly understood. This study aimed to elucidate the potential role of S100A9 in AP and investigate the underlying mechanism. We employed a mouse model of AP and the AR42J cell line to investigate the functional role of S100A9. The effect of S100A9 on pancreatic injury and the expression of inflammatory factors (IL-6, IL-1β, and TNF-α) was assessed through targeted inhibition of S100A9 expression in the mouse model of AP. Furthermore, the modulatory effect of cerulein-induced inflammatory responses on AR42J cells was assessed after adding the S100A9 recombinant protein. In the mouse model of AP, targeted inhibition of S100A9 markedly ameliorated pancreatic injury and significantly decreased the expression levels of IL-6, IL-1β, and TNF-α. Moreover, increased levels of S100A9 were positively correlated with elevated expression of receptor for advanced glycation endproducts (RAGE) in pancreatic acinar cells. In AR42J cells, the introduction of S100A9 recombinant protein enhanced RAGE expression and exacerbated cerulein-induced inflammatory response. S100A9 inhibition significantly alleviated the pancreatic inflammatory response by downregulating RAGE expression, thereby improving AP.
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Affiliation(s)
- Chenfeng Shou
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Research Center of Minimally Invasive Intervention, Anhui Medical University, Hefei, 230032, China
| | - Yuansong Sun
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Research Center of Minimally Invasive Intervention, Anhui Medical University, Hefei, 230032, China
| | - Qiao Zhang
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Research Center of Minimally Invasive Intervention, Anhui Medical University, Hefei, 230032, China
| | - Wenqiang Zhang
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Research Center of Minimally Invasive Intervention, Anhui Medical University, Hefei, 230032, China
| | - Qi Yan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
| | - Tao Xu
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China.
| | - He Li
- Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
- Research Center of Minimally Invasive Intervention, Anhui Medical University, Hefei, 230032, China.
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Guo Y, Sun Y, Li Z, Zuo C, Liu X, Chen Y, Xun Z, Liu J, Mei Y, Min JJ, Wen M, Zheng JH, Tan W. S100a8/a9 regulated by LPS/TLR4 axis plays an important role in Salmonella-based tumor therapy and host defense. Int J Cancer 2024; 155:2080-2093. [PMID: 39129048 DOI: 10.1002/ijc.35128] [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: 04/22/2024] [Revised: 06/02/2024] [Accepted: 07/08/2024] [Indexed: 08/13/2024]
Abstract
Bacteria are ideal anticancer agents and carriers due to their unique capabilities that are convenient in genetic manipulation, tumor-specific targeting, and deep-tissue penetration. However, the specific molecular mechanisms of bacteria-mediated cancer therapy (BMCT) have not been clarified. In this study, we found that TLR4 signaling pathway is critical for Salmonella-mediated tumor targeting, tumor suppression, and liver and spleen protection. TLR4 knockout in mice decreased the levels of cytokines and chemokines, such as S100a8, S100a9, TNF-α, and IL-1β, in tumor microenvironments (TMEs) after Salmonella treatment, which inhibited tumor cell death and nutrient release, led to reduced bacterial contents in tumors and attenuated antitumor efficacy in a negative feedback manner. Importantly, we found that S100a8 and S100a9 played a leading role in Salmonella-mediated cancer therapy (SMCT). The antitumor efficacy was abrogated and liver damage was prominent when blocked with a specific inhibitor. These findings elucidated the mechanism of Salmonella-mediated tumor targeting, suppression, and host antibacterial defense, providing insights into clinical cancer therapeutics.
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Affiliation(s)
- Yanxia Guo
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Yujie Sun
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Zhongying Li
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Chaohui Zuo
- Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital, Changsha, Hunan, China
| | - Xiaoqing Liu
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Yu Chen
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Zhen Xun
- College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Jinling Liu
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
- College of Biology, Hunan University, Changsha, China
| | - Yang Mei
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Jung-Joon Min
- Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Min Wen
- Department of Neurosurgery, the second affiliated hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jin Hai Zheng
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Wenzhi Tan
- The Affiliated Xiangtan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China
- School of Food Science and Bioengineering, Changsha University of Science & Technology, Changsha, Hunan, China
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Dong K, Jang J, Shannon CP, Ng R, Tebbutt SJ, Quon BS. Blood Transcriptomic and Inflammatory Protein Biomarkers Associated with Imminent Pulmonary Exacerbation Risk in Cystic Fibrosis. Ann Am Thorac Soc 2024; 21:1688-1697. [PMID: 39137349 DOI: 10.1513/annalsats.202402-215oc] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 08/13/2024] [Indexed: 08/15/2024] Open
Abstract
Rationale: The factors that lead to poor pulmonary exacerbation (PEx) outcomes in individuals with cystic fibrosis (CF) are still being investigated; however, delayed diagnosis and treatment are likely contributory. Identifying individuals at imminent risk of PEx could enable closer monitoring and/or earlier initiation of therapies to improve outcomes. Objectives: The goal of this study was to develop blood-based biomarkers that associate with imminent PEx risk in individuals with CF. Methods: We examined the whole-blood transcriptome and 55 inflammatory proteins from plasma and serum on 72 blood samples from 53 individuals with CF. Biomarker candidate genes and proteins were selected from 14 individuals with CF with paired stable and PEx visits (cohort 1). The biomarker candidates were then estimated and tested to classify individuals with CF who would experience a PEx within 4 months of a stable clinic visit or not (cohort 2). Results: A 16-gene panel and 9-protein panel were identified that could distinguish paired stable and PEx visits (area under the receiver operating characteristic curve [AUC] ± standard error = 0.83 ± 0.28 and 0.92 ± 0.18, respectively). These two panels also demonstrated strong performance in classifying individuals with CF who would experience a PEx within 4 months of a clinically stable visit or not (16-gene panel: AUC = 0.88; 9-protein panel: AUC = 0.83). In comparison, serum calprotectin and clinical variables (i.e., sex, precent predicted forced expiratory volume in 1 s, and the number of IV antibiotics in the preceding year) had AUCs of 0.75 and 0.71, respectively. Conclusions: Blood-based mRNA and protein biomarkers demonstrated strong performance in classifying individuals with CF at risk of imminent PEx. If the findings from this study can be validated, there is the potential to use blood biomarkers to enable more personalized disease activity monitoring in CF.
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Affiliation(s)
- Kang Dong
- Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
| | - Jiah Jang
- Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
| | - Casey P Shannon
- PROOF Centre of Excellence, Providence Research, Vancouver, British Columbia, Canada; and
| | - Raymond Ng
- PROOF Centre of Excellence, Providence Research, Vancouver, British Columbia, Canada; and
| | - Scott J Tebbutt
- Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
- PROOF Centre of Excellence, Providence Research, Vancouver, British Columbia, Canada; and
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bradley S Quon
- Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Zhang X, Teng J, Chen Z, Zhao C, Jiang L, Zhang Q. S100A9 Affects Milk Protein Content by Regulating Amino Acid Transporters and the PI3K-Akt, WNT, and mTOR Signaling Pathways. Genes (Basel) 2024; 15:1486. [PMID: 39596686 PMCID: PMC11594203 DOI: 10.3390/genes15111486] [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: 09/23/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Calgranulin B (S100A9) was found to be strongly associated with milk protein percentage in dairy cattle in our previous genome-wide association study. METHODS SNPs in S100A9 were identified via pooled sequencing, and genotyping of 1054 cows was performed individually using MassArray with MALDI-TOFMS technology. Association analyses between the S100A9 SNPs and five milk production traits were conducted using SAS 9.2 software. Functional studies of S100A9 were conducted using quantitative PCR, Western blot, CCK-8, and immunofluorescence assays. RESULTS In the present study, we further verified that two SNPs in S100A9, g.17115387 C>A and g.17115176 C>A, were significantly associated with milk protein percentage. We found that S100A9 could affect the expressions of caseins CSN1S1, CSN2, and CSN3 in MAC-T cells by regulating the expressions of amino acid transporter genes. We investigated the effects of S100A9 on the PI3K-Akt, WNT, and mTOR pathways, which are well known to play important roles in mammary gland development and milk protein synthesis. Our results suggest that S100A9 regulates the expressions of the relevant genes in these pathways, and thus potentially influences the protein synthesis in the mammary gland. CONCLUSIONS This study demonstrates the important role of the S100A9 gene in the milk protein trait of dairy cattle and provides new insights into the molecular mechanism of milk protein content.
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Affiliation(s)
- Xinyi Zhang
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science, Shandong Agricultural University, Tai’an 271018, China; (X.Z.); (J.T.); (Z.C.); (C.Z.)
| | - Jun Teng
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science, Shandong Agricultural University, Tai’an 271018, China; (X.Z.); (J.T.); (Z.C.); (C.Z.)
| | - Zhujun Chen
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science, Shandong Agricultural University, Tai’an 271018, China; (X.Z.); (J.T.); (Z.C.); (C.Z.)
| | - Changheng Zhao
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science, Shandong Agricultural University, Tai’an 271018, China; (X.Z.); (J.T.); (Z.C.); (C.Z.)
| | - Li Jiang
- State Key Laboratory of Animal Biotech Breeding, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| | - Qin Zhang
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science, Shandong Agricultural University, Tai’an 271018, China; (X.Z.); (J.T.); (Z.C.); (C.Z.)
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Tampé JF, Monni E, Palma-Tortosa S, Brogårdh E, Böiers C, Lindgren AG, Kokaia Z. Human monocyte subtype expression of neuroinflammation- and regeneration-related genes is linked to age and sex. PLoS One 2024; 19:e0300946. [PMID: 39475881 PMCID: PMC11524521 DOI: 10.1371/journal.pone.0300946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 09/22/2024] [Indexed: 11/02/2024] Open
Abstract
Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of NK-cells increased in females. The proportion of B-cells decreased in both sexes with age. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes.
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Affiliation(s)
- Juliane F. Tampé
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Emanuela Monni
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sara Palma-Tortosa
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Emil Brogårdh
- Department of Neurology, Skåne University Hospital; Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
| | - Charlotta Böiers
- Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Arne G. Lindgren
- Department of Neurology, Skåne University Hospital; Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
| | - Zaal Kokaia
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
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Ji Q, Li Z, Guo Y, Zhang X. S100A9, as a potential predictor of prognosis and immunotherapy response for GBM, promotes the malignant progression of GBM cells and migration of M2 macrophages. Aging (Albany NY) 2024; 16:11513-11534. [PMID: 39137310 PMCID: PMC11346789 DOI: 10.18632/aging.205949] [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: 07/24/2023] [Accepted: 04/22/2024] [Indexed: 08/15/2024]
Abstract
In the past decades, the therapeutic effect of glioblastoma (GBM) has not been significantly improved. Generous evidence indicates that S100A9 has a wide range of functions in tumors, but its exploration in GBM is less. The purpose of this study is to conduct a comprehensive bioinformatics analysis and cytological experiment on S100A9 in GBM. The expression data and clinical data of GBM samples were downloaded from the public database, and comprehensive bioinformatics analysis was performed on S100A9 in GBM using R software. Wound healing assay and transwell assay were used to detect the migration activity of cells, and colony formation assay, EdU staining, and CCK-8 assay were used to detect the proliferation activity of cells. The effect of S100A9 on the migration activity of M2 macrophages was verified by the cell co-culture method. The protein expression was detected by western blotting and immunohistochemical staining. S100A9 is an independent prognostic factor in GBM patients and is related to poor prognosis. It can be used as an effective tool to predict the response of GBM patients to immune checkpoint inhibitors (ICIs). In addition, S100A9 can promote the malignant progression of GBM and the migration of M2 macrophages. On the whole, our study highlights the potential value of S100A9 in predicting prognosis and immunotherapeutic response in GBM patients. More importantly, S100A9 may promote the malignant progress of GBM by involving in some carcinogenic pathways and remodeling the tumor microenvironment (TME).
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Affiliation(s)
- Qiankun Ji
- Department of Neurosurgery, Zhoukou Central Hospital, Zhoukou, Henan 466000, P.R. China
| | - Zibo Li
- Department of Neurosurgery, Zhoukou Central Hospital, Zhoukou, Henan 466000, P.R. China
| | - Yazhou Guo
- Department of Neurosurgery, Zhoukou Central Hospital, Zhoukou, Henan 466000, P.R. China
| | - Xiaoyang Zhang
- Department of Neurosurgery, Zhoukou Central Hospital, Zhoukou, Henan 466000, P.R. China
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Wang JC, Shi G, Chen C, Wong C, Gotlieb V, Joseph G, Nair KV, Boyapati L, Ladan E, Symanowski JT, Sun L. TLR2 Derangements Likely Play a Significant Role in the Inflammatory Response and Thrombosis in Patients with Ph(-) Classical Myeloproliferative Neoplasm. Mediators Inflamm 2024; 2024:1827127. [PMID: 39157201 PMCID: PMC11329310 DOI: 10.1155/2024/1827127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/17/2024] [Accepted: 06/17/2024] [Indexed: 08/20/2024] Open
Abstract
We investigated the role of toll-like receptors (TLRs) in inflammatory pathways in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-)MPNs). TLR2 expression was increased in ET, PV, and MPN (grouped as (PV + (ET) + MF)), whereas TLR4 was elevated only in MPN. TLR3, 7, and 9 were not elevated. Cultured monocyte-derived dendritic cells and plasma assays in TLR2-elevated patients were found to secrete more cytokines than those from TLR2-normal patients. These facts suggest that TLR2 is the major inflammatory pathways in MPN. We also measured S100A9 and reactive oxygen species (ROS), revealing increased S100A9 in PV, MF, and MPN, while ROS were only increased in MF. These data suggests that MPNs initially involve TLR2, with minor contributions from TLR4, and with S100A9, leading to ROS formation, JAK2 mutation, and progression to MF or leukemia. Furthermore, patients with JAK2 mutations or leukocytosis exhibited higher TLR2 expression. In leukocyte-platelet interactions, cells from MPN patients displayed a stronger response to a TLR2 agonist than TLR4 agonist. A TLR2 inhibitor (but not a TLR4 inhibitor) attenuated this response. Thrombosis incidence was higher in TLR2-elevated patients (29%) than in TLR2-normal patients (19%). These findings suggest that TLR2 likely contributes to thrombosis in MPN.
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Affiliation(s)
- Jen Chin Wang
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Guanfang Shi
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Chi Chen
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Ching Wong
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Vladimir Gotlieb
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Gardith Joseph
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Kiron V Nair
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Lakshmi Boyapati
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Enayati Ladan
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - James T. Symanowski
- Department of Biostatistics and Data SciencesLevine Cancer Institute, Charlotte, NC, USA
| | - Lishi Sun
- Division of Hematology/OncologyBrookdale University Hospital Medical Center, Brooklyn, NY, USA
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Nunes M, Vlok M, Proal A, Kell DB, Pretorius E. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovasc Diabetol 2024; 23:254. [PMID: 39014464 PMCID: PMC11253362 DOI: 10.1186/s12933-024-02315-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/16/2024] [Indexed: 07/18/2024] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms. A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS. We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes - thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S - were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant. The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus.
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Affiliation(s)
- Massimo Nunes
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa
| | - Mare Vlok
- Central Analytical Facility: Mass Spectrometry, Stellenbosch University, Tygerberg Campus, Room 6054, Clinical Building, Francie Van Zijl Drive Tygerberg, Cape Town, 7505, South Africa
| | - Amy Proal
- PolyBio Research Foundation, 7900 SE 28th ST, Suite 412, Mercer Island, DC, 98040, USA
| | - Douglas B Kell
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa.
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St, Liverpool, L69 7ZB, UK.
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Building 220, Chemitorvet 200, 2800, Kongens Lyngby, Denmark.
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa.
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St, Liverpool, L69 7ZB, UK.
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Amich J. The many roles of sulfur in the fungal-host interaction. Curr Opin Microbiol 2024; 79:102489. [PMID: 38754292 DOI: 10.1016/j.mib.2024.102489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 05/18/2024]
Abstract
Sulfur is an essential macronutrient for life, and consequently, all living organisms must acquire it from external sources to thrive and grow. Sulfur is a constituent of a multitude of crucial molecules, such as the S-containing proteinogenic amino acids cysteine and methionine; cofactors and prosthetic groups, such as coenzyme-A and iron-sulfur (Fe-S) clusters; and other essential organic molecules, such as glutathione or S-adenosylmethionine. Additionally, sulfur in cysteine thiols is an active redox group that plays paramount roles in protein stability, enzyme catalysis, and redox homeostasis. Furthermore, H2S is gaining more attention as a crucial signaling molecule that influences metabolism and physiological functions. Given its importance, it is not surprising that sulfur plays key roles in the host-pathogen interaction. However, in contrast to its well-recognized involvement in the plant-pathogen interaction, the specific contributions of sulfur to the human-fungal interaction are much less understood. In this short review, I highlight some of the most important known mechanisms and propose directions for further research.
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Affiliation(s)
- Jorge Amich
- Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.
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Delrue C, Speeckaert R, Delanghe JR, Speeckaert MM. Breath of fresh air: Investigating the link between AGEs, sRAGE, and lung diseases. VITAMINS AND HORMONES 2024; 125:311-365. [PMID: 38997169 DOI: 10.1016/bs.vh.2024.01.003] [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: 07/14/2024]
Abstract
Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.
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Affiliation(s)
- Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
| | | | - Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium; Research Foundation-Flanders (FWO), Brussels, Belgium.
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11
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Tampé JF, Monni E, Palma-Tortosa S, Brogårdh E, Böiers C, Lindgren AG, Kokaia Z. Human monocyte subtype expression of neuroinflammation and regeneration-related genes is linked to age and sex. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.10.584323. [PMID: 38559207 PMCID: PMC10979900 DOI: 10.1101/2024.03.10.584323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Stroke is a leading cause of disability and the third cause of death. The immune system plays an essential role in post-stroke recovery. After an ischemic stroke, monocytes infiltrate the injured brain tissue and can exacerbate or mitigate the damage. Ischemic stroke is more prevalent in the aged population, and the aging brain exhibits an altered immune response. There are also sex disparities in ischemic stroke incidence, outcomes, and recovery, and these differences may be hormone-driven and determined by genetic and epigenetic factors. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of neuronal inflammation- and regeneration-related genes depends on age and sex. A FACS analysis of blood samples from 44 volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of natural killer cells increased in females. The proportion of B-cells decreased in both sexes with age, and subtypes of monocytes were not linked to age or sex. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increased aging. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes.
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Affiliation(s)
- Juliane F. Tampé
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Emanuela Monni
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sara Palma-Tortosa
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Emil Brogårdh
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Charlotta Böiers
- Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Arne G. Lindgren
- Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Zaal Kokaia
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden
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12
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Zhu Z, Mao R, Liu B, Liu H, Shi Z, Zhang K, Liu H, Zhang D, Liu J, Zhao Z, Li K, Yang F, Cao W, Zhang X, Shen C, Sun D, Wang L, Tian H, Ru Y, Feng T, He J, Guo J, Zhang K, Tang Z, Zhang S, Ding C, Han J, Zheng H. Single-cell profiling of African swine fever virus disease in the pig spleen reveals viral and host dynamics. Proc Natl Acad Sci U S A 2024; 121:e2312150121. [PMID: 38412127 PMCID: PMC10927503 DOI: 10.1073/pnas.2312150121] [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: 07/22/2023] [Accepted: 01/08/2024] [Indexed: 02/29/2024] Open
Abstract
African swine fever, one of the major viral diseases of swine, poses an imminent threat to the global pig industry. The high-efficient replication of the causative agent African swine fever virus (ASFV) in various organs in pigs greatly contributes to the disease. However, how ASFV manipulates the cell population to drive high-efficient replication of the virus in vivo remains unclear. Here, we found that the spleen reveals the most severe pathological manifestation with the highest viral loads among various organs in pigs during ASFV infection. By using single-cell-RNA-sequencing technology and multiple methods, we determined that macrophages and monocytes are the major cell types infected by ASFV in the spleen, showing high viral-load heterogeneity. A rare subpopulation of immature monocytes represents the major population infected at late infection stage. ASFV causes massive death of macrophages, but shifts its infection into these monocytes which significantly arise after the infection. The apoptosis, interferon response, and antigen-presentation capacity are inhibited in these monocytes which benefits prolonged infection of ASFV in vivo. Until now, the role of immature monocytes as an important target by ASFV has been overlooked due to that they do not express classical monocyte marker CD14. The present study indicates that the shift of viral infection from macrophages to the immature monocytes is critical for maintaining prolonged ASFV infection in vivo. This study sheds light on ASFV tropism, replication, and infection dynamics, and elicited immune response, which may instruct future research on antiviral strategies.
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Affiliation(s)
- Zixiang Zhu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Ruoqing Mao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- African Swine Fever Regional Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Baohong Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Huanan Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- African Swine Fever Regional Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Zhengwang Shi
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Kunpeng Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Huisheng Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Danyang Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Jia Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Zhenxiang Zhao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Kangli Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Fan Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Weijun Cao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Xiangle Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Chaochao Shen
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Dehui Sun
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Liyuan Wang
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen518124, China
| | - Hong Tian
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Yi Ru
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Tao Feng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Jijun He
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- African Swine Fever Regional Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Jianhong Guo
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- African Swine Fever Regional Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
| | - Keshan Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Zhonglin Tang
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen518124, China
| | - Shilei Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
| | - Chan Ding
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai200241, China
| | - Jun Han
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing100193, China
| | - Haixue Zheng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- African Swine Fever Regional Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou730046, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou730046, China
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13
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Wang Q, Long G, Luo H, Zhu X, Han Y, Shang Y, Zhang D, Gong R. S100A8/A9: An emerging player in sepsis and sepsis-induced organ injury. Biomed Pharmacother 2023; 168:115674. [PMID: 37812889 DOI: 10.1016/j.biopha.2023.115674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/04/2023] [Accepted: 10/06/2023] [Indexed: 10/11/2023] Open
Abstract
Sepsis, the foremost contributor to mortality in intensive care unit patients, arises from an uncontrolled systemic response to invading infections, resulting in extensive harm across multiple organs and systems. Recently, S100A8/A9 has emerged as a promising biomarker for sepsis and sepsis-induced organ injury, and targeting S100A8/A9 appeared to ameliorate inflammation-induced tissue damage and improve adverse outcomes. S100A8/A9, a calcium-binding heterodimer mainly found in neutrophils and monocytes, serves as a causative molecule with pro-inflammatory and immunosuppressive properties, which are vital in the pathogenesis of sepsis. Therefore, improving our comprehension of how S100A8/A9 acts as a pathological player in the development of sepsis is imperative for advancing research on sepsis. Our review is the first-to the best of our knowledge-to discuss the biology of S100A8/A9 and its release mechanisms, summarize recent advances concerning the vital roles of S100A8/A9 in sepsis and the consequential organ damage, and underscore its potential as a promising diagnostic biomarker and therapeutic target for sepsis.
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Affiliation(s)
- Qian Wang
- Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430023, China
| | - Gangyu Long
- Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430023, China
| | - Hong Luo
- Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430023, China
| | - Xiqun Zhu
- Hubei Cancer Hospital, Tongji Medical College, HUST, Wuhan 430079, China
| | - Yang Han
- Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan 430023, China
| | - You Shang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan 430030, China.
| | - Dingyu Zhang
- Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430023, China; Hubei Clinical Research Center for Infectious Diseases, Wuhan 430023, China; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Wuhan 430023, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China.
| | - Rui Gong
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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14
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Zhang T, Huang S, Wang M, Yang N, Zhu H. Integrated untargeted and targeted proteomics to unveil plasma prognostic markers for patients with acute paraquat poisoning: A pilot study. Food Chem Toxicol 2023; 182:114187. [PMID: 37967786 DOI: 10.1016/j.fct.2023.114187] [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: 09/03/2023] [Revised: 11/05/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Paraquat (PQ) is a widely used but strongly toxic herbicide, which can induce multiple organ failure. The overall survival rate of the poisoned patients was only 54.4% due to lack of specific antidotes. Besides, the definite pathogenic mechanism of PQ is still not fully understood. In this pilot study, untargeted and targeted proteomics were integrated to explore the expression characteristics of plasma protein in PQ poisoned patients, and identify the differentially expressed proteins between survivors and non-survivors. A total of 494 plasma proteins were detected, and of which 47 were upregulated and 44 were downregulated in PQ poisoned patients compared to healthy controls. Among them, five differential plasma proteins (S100A9, S100A8, MB, ACTB and RAB11FIP3) were further validated by multiple reaction monitoring (MRM)-based targeted proteomic approach, and three of them (S100A9, S100A8 and ACTB) were confirmed to be correlated with PQ poisoning. Meanwhile, 84 dysregulated plasma proteins were identified in non-survivors compared with survivors. Moreover, targeted proteomic and ROC analysis suggested that ACTB had a good performance in predicting the prognosis of PQ poisoned patients. These findings highlighted the value of label-free and mass spectrometry-based proteomics in screening prognostic biomarkers of PQ poisoning and studying the mechanism of PQ toxicity.
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Affiliation(s)
- Tianqi Zhang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, 210008, China
| | - Siqi Huang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Min Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, 210008, China
| | - Na Yang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, 210008, China.
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, 210008, China.
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15
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Moshfegh CM, Elkhatib SK, Watson GF, Drake J, Taylor ZN, Reed EC, Lauten TH, Clopp AJ, Vladimirov VI, Case AJ. S100a9 Protects Against the Effects of Repeated Social Defeat Stress. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2023; 3:919-929. [PMID: 37881565 PMCID: PMC10593888 DOI: 10.1016/j.bpsgos.2022.12.002] [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: 08/04/2022] [Revised: 11/07/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022] Open
Abstract
Background Posttraumatic stress disorder, a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. We previously found that S100a8 and S100a9 messenger RNA, genes that encode the protein calprotectin, were significantly upregulated in T lymphocytes and positively correlated with inflammatory gene expression and the mitochondrial redox environment in these cells. Therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after psychological trauma. Methods We used a preclinical mouse model of posttraumatic stress disorder known as repeated social defeat stress (RSDS) combined with pharmacological and genetic manipulation of S100a9 (which functionally eliminates calprotectin). A total of 186 animals (93 control, 93 RSDS) were used in these studies. Results Unexpectedly, we observed worsening of behavioral pathology, inflammation, and the mitochondrial redox environment in mice after RSDS compared with wild-type animals. Furthermore, loss of calprotectin significantly enhanced the metabolic demand on T lymphocytes, suggesting that this protein may play an undescribed role in mitochondrial regulation. This was further supported by single-cell RNA sequencing analysis demonstrating that RSDS and loss of S100a9 primarily altered genes associated with mitochondrial function and oxidative phosphorylation. Conclusions These data demonstrate that the loss of calprotectin potentiates the RSDS-induced phenotype, which suggests that its observed upregulation after psychological trauma may provide previously unexplored protective functions.
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Affiliation(s)
- Cassandra M. Moshfegh
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Safwan K. Elkhatib
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Gabrielle F. Watson
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - John Drake
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
| | - Zachary N. Taylor
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
| | - Emily C. Reed
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Tatlock H. Lauten
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Amelia J. Clopp
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Vladimir I. Vladimirov
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
- Department of Psychiatry, University of Arizona, Phoenix, Arizona
- Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland
| | - Adam J. Case
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
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16
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Enriquez KT, Plummer WD, Neufer PD, Chazin WJ, Dupont WD, Skaar EP. Temporal modelling of the biofilm lifecycle (TMBL) establishes kinetic analysis of plate-based bacterial biofilm dynamics. J Microbiol Methods 2023; 212:106808. [PMID: 37595876 PMCID: PMC10528067 DOI: 10.1016/j.mimet.2023.106808] [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: 06/30/2023] [Revised: 08/12/2023] [Accepted: 08/12/2023] [Indexed: 08/20/2023]
Abstract
Bacterial biofilms are critical to pathogenesis and infection. They are associated with rising rates of antimicrobial resistance. Biofilms are correlated with worse clinical outcomes, making them important to infectious diseases research. There is a gap in knowledge surrounding biofilm kinetics and dynamics which makes biofilm research difficult to translate from bench to bedside. To address this gap, this work employs a well-characterized crystal violet biomass accrual and planktonic cell density assay across a clinically relevant time course and expands statistical analysis to include kinetic information in a protocol termed the TMBL (Temporal Mapping of the Biofilm Lifecycle) assay. TMBL's statistical framework quantitatively compares biofilm communities across time, species, and media conditions in a 96-well format. Measurements from TMBL can reliably be condensed into response features that inform the time-dependent behavior of adherent biomass and planktonic cell populations. Staphylococcus aureus and Pseudomonas aeruginosa biofilms were grown in conditions of metal starvation in nutrient-variable media to demonstrate the rigor and translational potential of this strategy. Significant differences in single-species biofilm formation are seen in metal-deplete conditions as compared to their controls which is consistent with the consensus literature on nutritional immunity that metal availability drives transcriptomic and metabolomic changes in numerous pathogens. Taken together, these results suggest that kinetic analysis of biofilm by TMBL represents a statistically and biologically rigorous approach to studying the biofilm lifecycle as a time-dependent process. In addition to current methods to study the impact of microbe and environmental factors on the biofilm lifecycle, this kinetic assay can inform biological discovery in biofilm formation and maintenance.
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Affiliation(s)
- Kyle T Enriquez
- Vanderbilt University Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, United States of America; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States of America; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - W Dale Plummer
- Department of Biostatistics, Vanderbilt University, Nashville, TN, United States of America
| | - Preston D Neufer
- Department of Chemistry, Vanderbilt University, Nashville, TN, United States of America; Department of Biochemistry, Vanderbilt University, Nashville, TN, United States of America
| | - Walter J Chazin
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States of America; Department of Chemistry, Vanderbilt University, Nashville, TN, United States of America; Department of Biochemistry, Vanderbilt University, Nashville, TN, United States of America
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University, Nashville, TN, United States of America
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States of America; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States of America.
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17
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Millán Solano MV, Salinas Lara C, Sánchez-Garibay C, Soto-Rojas LO, Escobedo-Ávila I, Tena-Suck ML, Ortíz-Butrón R, Choreño-Parra JA, Romero-López JP, Meléndez Camargo ME. Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage. Int J Mol Sci 2023; 24:11902. [PMID: 37569277 PMCID: PMC10419139 DOI: 10.3390/ijms241511902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/21/2023] [Accepted: 06/24/2023] [Indexed: 08/13/2023] Open
Abstract
Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB´s) and blood-cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.
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Affiliation(s)
- Mara Verónica Millán Solano
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cos’ıo Villegas, Mexico City 14080, Mexico;
| | - Citlaltepetl Salinas Lara
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, Mexico City 14269, Mexico;
| | - Carlos Sánchez-Garibay
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, Mexico City 14269, Mexico;
| | - Luis O. Soto-Rojas
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Mexico
| | - Itzel Escobedo-Ávila
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Departamento de Neurodesarrollo y Fisiología, Instituto de Fisiología Celular, Universidad Nacional Autonoma de Mexico, Mexico City 04510, Mexico
| | - Martha Lilia Tena-Suck
- Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, Mexico City 14269, Mexico;
| | - Rocío Ortíz-Butrón
- Laboratorio de Neurobiología, Departamento de Fisiología de ENCB, Instituto Politécnico Nacional, Mexico City 07738, Mexico;
| | - José Alberto Choreño-Parra
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cos’ıo Villegas, Mexico City 14080, Mexico;
| | - José Pablo Romero-López
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico; (M.V.M.S.); (C.S.-G.); (L.O.S.-R.); (I.E.-Á.); (J.P.R.-L.)
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Mexico
| | - María Estela Meléndez Camargo
- Laboratorio de Farmacología, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu Esq. Manuel Luis Stampa S/N, U.P. Adolfo López Mateos, Mexico City 07738, Mexico;
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18
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Liang H, Li J, Zhang K. Pathogenic role of S100 proteins in psoriasis. Front Immunol 2023; 14:1191645. [PMID: 37346040 PMCID: PMC10279876 DOI: 10.3389/fimmu.2023.1191645] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/22/2023] [Indexed: 06/23/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin disease. The histopathological features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis.
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Affiliation(s)
- Huifang Liang
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
- State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
| | - Junqin Li
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
- State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
| | - Kaiming Zhang
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
- State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Center Hospital, Taiyuan, China
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19
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Chen Y, Ouyang Y, Li Z, Wang X, Ma J. S100A8 and S100A9 in Cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188891. [PMID: 37001615 DOI: 10.1016/j.bbcan.2023.188891] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023]
Abstract
S100A8 and S100A9 are Ca2+ binding proteins that belong to the S100 family. Primarily expressed in neutrophils and monocytes, S100A8 and S100A9 play critical roles in modulating various inflammatory responses and inflammation-associated diseases. Forming a common heterodimer structure S100A8/A9, S100A8 and S100A9 are widely reported to participate in multiple signaling pathways in tumor cells. Meanwhile, S100A8/A9, S100A8, and S100A9, mainly as promoters, contribute to tumor development, growth and metastasis by interfering with tumor metabolism and the microenvironment. In recent years, the potential of S100A8/A9, S100A9, and S100A8 as tumor diagnostic or prognostic biomarkers has also been demonstrated. In addition, an increasing number of potential therapies targeting S100A8/A9 and related signaling pathways have emerged. In this review, we will first expound on the characteristics of S100A8/A9, S100A9, and S100A8 in-depth, focus on their interactions with tumor cells and microenvironments, and then discuss their clinical applications as biomarkers and therapeutic targets. We also highlight current limitations and look into the future of S100A8/A9 targeted anti-cancer therapy.
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20
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Povroznik JM, Akhter H, Vance JK, Annamanedi M, Dziadowicz SA, Wang L, Divens AM, Hu G, Robinson CM. Interleukin-27-dependent transcriptome signatures during neonatal sepsis. Front Immunol 2023; 14:1124140. [PMID: 36891292 PMCID: PMC9986606 DOI: 10.3389/fimmu.2023.1124140] [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: 12/14/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates.
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Affiliation(s)
- Jessica M. Povroznik
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Halima Akhter
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Jordan K. Vance
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Madhavi Annamanedi
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Sebastian A. Dziadowicz
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Lei Wang
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Ashley M. Divens
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Gangqing Hu
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Cory M. Robinson
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
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21
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Heinze D, Park S, McCracken A, Haratianfar M, Lindstrom J, Villacorta-Martin C, Mithal A, Wang F, Yang MW, Murphy G, Mostoslavsky G. Notch activation during early mesoderm induction modulates emergence of the T/NK cell lineage from human iPSCs. Stem Cell Reports 2022; 17:2610-2628. [PMID: 36332629 PMCID: PMC9768581 DOI: 10.1016/j.stemcr.2022.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022] Open
Abstract
A robust method of producing mature T cells from iPSCs is needed to realize their therapeutic potential. NOTCH1 is known to be required for the production of hematopoietic progenitor cells with T cell potential in vivo. Here we identify a critical window during mesodermal differentiation when Notch activation robustly improves access to definitive hematopoietic progenitors with T/NK cell lineage potential. Low-density progenitors on either OP9-hDLL4 feeder cells or hDLL4-coated plates favored T cell maturation into TCRab+CD3+CD8+ cells that express expected T cell markers, upregulate activation markers, and proliferate in response to T cell stimulus. Single-cell RNAseq shows Notch activation yields a 6-fold increase in multi-potent hematopoietic progenitors that follow a developmental trajectory toward T cells with clear similarity to post-natal human thymocytes. We conclude that early mesodermal Notch activation during hematopoietic differentiation is a missing stimulus with broad implications for producing hematopoietic progenitors with definitive characteristics.
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Affiliation(s)
- Dar Heinze
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - Seonmi Park
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Andrew McCracken
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Mona Haratianfar
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Jonathan Lindstrom
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Carlos Villacorta-Martin
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Aditya Mithal
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Feiya Wang
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Meng Wei Yang
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - George Murphy
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
| | - Gustavo Mostoslavsky
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; Department of Medicine, Section of Gastroenterology at Boston University and Boston Medical Center, Boston, MA, USA.
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22
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Andrade-Talavera Y, Chen G, Pansieri J, Arroyo-García LE, Toleikis Z, Smirnovas V, Johansson J, Morozova-Roche L, Fisahn A. S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS. Prog Neurobiol 2022; 219:102366. [PMID: 36273719 DOI: 10.1016/j.pneurobio.2022.102366] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/20/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
The pro-inflammatory and highly amyloidogenic protein S100A9 is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases leading to cognitive impairment. Molecular chaperone activity of Bri2 BRICHOS has been demonstrated against a range of amyloidogenic polypeptides. Using a combination of thioflavin T fluorescence kinetic assay, atomic force microscopy and immuno electron microscopy we show here that recombinant Bri2 BRICHOS effectively inhibits S100A9 amyloid growth by capping amyloid fibrils. Using ex-vivo neuronal network electrophysiology in mouse brain slices we also show that both native S100A9 and amyloids of S100A9 disrupt cognition-relevant gamma oscillation power and rhythmicity in hippocampal area CA3 in a time- and protein conformation-dependent manner. Both effects were associated with Toll-like receptor 4 (TLR4) activation and were not observed upon TLR4 blockade. Importantly, S100A9 that had co-aggregated with Bri2 BRICHOS did not elicit degradation of gamma oscillations. Taken together, this work provides insights on the potential influence of S100A9 on cognitive dysfunction in Alzheimer's disease (AD) via gamma oscillation impairment from experimentally-induced gamma oscillations, and further highlights Bri2 BRICHOS as a chaperone against detrimental effects of amyloid self-assembly.
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Affiliation(s)
- Yuniesky Andrade-Talavera
- Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, 17164 Solna, Sweden.
| | - Gefei Chen
- Department of Biosciences and Nutrition, Neo, Karolinska Institutet, 141 83 Huddinge, Sweden
| | - Jonathan Pansieri
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | - Luis Enrique Arroyo-García
- Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, 17164 Solna, Sweden
| | - Zigmantas Toleikis
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Vytautas Smirnovas
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Jan Johansson
- Department of Biosciences and Nutrition, Neo, Karolinska Institutet, 141 83 Huddinge, Sweden.
| | | | - André Fisahn
- Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, 17164 Solna, Sweden.
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23
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Miyashita D, Inoue R, Tsuno T, Okuyama T, Kyohara M, Nakahashi-Oda C, Nishiyama K, Fukushima S, Inada Y, Togashi Y, Shibuya A, Terauchi Y, Shirakawa J. Protective effects of S100A8 on sepsis mortality: Links to sepsis risk in obesity and diabetes. iScience 2022; 25:105662. [PMID: 36505926 PMCID: PMC9732389 DOI: 10.1016/j.isci.2022.105662] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/23/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2 cre :S100A8 floxed/floxed ) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes.
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Affiliation(s)
- Daisuke Miyashita
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Chigusa Nakahashi-Oda
- Department of Immunology, Faculty of Medicine, and R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yutaro Inada
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, and R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
- Corresponding author
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24
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Inciarte-Mundo J, Frade-Sosa B, Sanmartí R. From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis. Front Immunol 2022; 13:1001025. [PMID: 36405711 PMCID: PMC9672845 DOI: 10.3389/fimmu.2022.1001025] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/19/2022] [Indexed: 12/30/2022] Open
Abstract
S100A9/S100A8 (calprotectin), a member of the S100 protein family, has been shown to play a pivotal role in innate immunity activation. Calprotectin plays a critical role in the pathogenesis of rheumatoid arthritis (RA), as it triggers chemotaxis, phagocyte migration and modulation of neutrophils and macrophages. Higher calprotectin levels have been found in synovial fluid, plasma, and serum from RA patients. Recent studies have demonstrated better correlations between serum or plasma calprotectin and composite inflammatory disease activity indexes than c-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR). Calprotectin serum levels decreased after treatment, independently of the DMARD type or strategy. Calprotectin has shown the strongest correlations with other sensitive techniques to detect inflammation, such as ultrasound. Calprotectin independently predicts radiographic progression. However, its value as a biomarker of treatment response and flare after tapering is unclear. This update reviews the current understanding of calprotectin in RA and discusses possible applications as a biomarker in clinical practice.
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Affiliation(s)
- José Inciarte-Mundo
- Biological aggression and Response Mechanisms, Inflammatory joint diseases (IJDs), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Beatriz Frade-Sosa
- Rheumatology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Raimon Sanmartí
- Biological aggression and Response Mechanisms, Inflammatory joint diseases (IJDs), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain,Rheumatology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain,*Correspondence: Raimon Sanmartí,
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25
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Helfen A, Rieß J, Fehler O, Stölting M, An Z, Kocman V, Schnepel A, Geyer C, Gerwing M, Masthoff M, Vogl T, Höltke C, Roth J, Ng T, Wildgruber M, Eisenblätter M. In vivo imaging of microenvironmental and anti-PD-L1-mediated dynamics in cancer using S100A8/S100A9 as an imaging biomarker. Neoplasia 2022; 28:100792. [PMID: 35367789 PMCID: PMC8983428 DOI: 10.1016/j.neo.2022.100792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE As a promotor of tumor invasion and tumor microenvironment (TME) formation, the protein complex S100A8/S100A9 is associated with poor prognosis. Our aim was to further evaluate its origin and regulatory effects, and to establish an imaging biomarker for TME activity. METHODS S100A9-/-cells (ko) were created from syngeneic murine breast cancer 4T1 (high malignancy) and 67NR (low malignancy) wildtype (wt) cell lines and implanted into either female BALB/c wildtype or S100A9-/- mice (n = 10 each). Anti-S100A9-Cy5.5-targeted fluorescence reflectance imaging was performed at 0 h and 24 h after injection. Potential early changes of S100A9-presence under immune checkpoint inhibition (anti-PD-L1, n = 7 vs. rat IgG2b as isotype control, n = 3) were evaluated. RESULTS In S100A9-/-mice contrast-to-noise-ratios were significantly reduced for wt and S100A9-/-tumors. No significant differences were detected for 4T1 ko and 67NR ko cells as compared to wildtype cells. Under anti-PD-L1 treatment S100A9 presence significantly decreased compared with the control group. CONCLUSION Our results confirm a secretion of S100A8/S100A9 by the TME, while tumor cells do not apparently release the protein. Under immune checkpoint inhibition S100A9-imaging reports an early decrease of TME activity. Therefore, S100A9-specific imaging may serve as an imaging biomarker for TME formation and activity.
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Affiliation(s)
- Anne Helfen
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany.
| | - Jan Rieß
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Olesja Fehler
- Institute of Immunology, University of Muenster, D-48149 Muenster, Germany
| | - Miriam Stölting
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Zhengwen An
- The CRUK City of London Cancer Centre, SE1 9RT London, UK
| | - Vanessa Kocman
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Annika Schnepel
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Christiane Geyer
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Mirjam Gerwing
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Max Masthoff
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Thomas Vogl
- Institute of Immunology, University of Muenster, D-48149 Muenster, Germany
| | - Carsten Höltke
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany
| | - Johannes Roth
- Institute of Immunology, University of Muenster, D-48149 Muenster, Germany
| | - Tony Ng
- The CRUK City of London Cancer Centre, SE1 9RT London, UK; UCL Cancer Institute, University College London, SE1 9RT London, UK; School of Cancer and Pharmaceutical Sciences, King´s College London, SE1 9RT London, UK
| | - Moritz Wildgruber
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany; Department for Radiology, LMU Munich, D-81377 Munich, Germany
| | - Michel Eisenblätter
- Department of Radiology, University Hospital Muenster, University of Muenster, D-48149 Muenster, Germany; Department of Diagnostic and Interventional Radiology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
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Sarrand J, Baglione L, Parisis D, Soyfoo M. The Involvement of Alarmins in the Pathogenesis of Sjögren's Syndrome. Int J Mol Sci 2022; 23:ijms23105671. [PMID: 35628481 PMCID: PMC9145074 DOI: 10.3390/ijms23105671] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/11/2022] [Accepted: 05/14/2022] [Indexed: 02/01/2023] Open
Abstract
Sjögren’s syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS.
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Affiliation(s)
- Julie Sarrand
- Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (J.S.); (L.B.); (D.P.)
| | - Laurie Baglione
- Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (J.S.); (L.B.); (D.P.)
| | - Dorian Parisis
- Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (J.S.); (L.B.); (D.P.)
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Muhammad Soyfoo
- Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (J.S.); (L.B.); (D.P.)
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Correspondence:
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Biochemistry of human tear film: A review. Exp Eye Res 2022; 220:109101. [DOI: 10.1016/j.exer.2022.109101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/13/2022]
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Motomura K, Romero R, Plazyo O, Garcia-Flores V, Gershater M, Galaz J, Miller D, Gomez-Lopez N. The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes as well as preterm birth and neonatal mortality in mice†. Biol Reprod 2021; 105:1494-1509. [PMID: 34632484 PMCID: PMC8689293 DOI: 10.1093/biolre/ioab188] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/23/2021] [Accepted: 10/06/2021] [Indexed: 01/08/2023] Open
Abstract
Sterile inflammation is triggered by danger signals, or alarmins, released upon cellular stress or necrosis. Sterile inflammation occurring in the amniotic cavity (i.e. sterile intra-amniotic inflammation) is frequently observed in women with spontaneous preterm labor resulting in preterm birth, the leading cause of neonatal morbidity and mortality worldwide; this condition is associated with increased amniotic fluid concentrations of alarmins. However, the mechanisms whereby alarmins induce sterile intra-amniotic inflammation are still under investigation. Herein, we investigated the mechanisms whereby the alarmin S100A12 induces inflammation of the human chorioamniotic membranes in vitro and used a mouse model to establish a causal link between this alarmin and adverse perinatal outcomes. We report that S100A12 initiates sterile inflammation in the chorioamniotic membranes by upregulating the expression of inflammatory mediators such as pro-inflammatory cytokines and pattern recognition receptors. Importantly, S100A12 induced the priming and activation of inflammasomes, resulting in caspase-1 cleavage and the subsequent release of mature IL-1β by the chorioamniotic membranes. This alarmin also caused the activation of the chorioamniotic membranes by promoting MMP-2 activity and collagen degradation. Lastly, the ultrasound-guided intra-amniotic injection of S100A12 at specific concentrations observed in the majority of women with sterile intra-amniotic inflammation induced preterm birth (rates: 17% at 200 ng/sac; 25% at 300 ng/sac; 25% at 400 ng/sac) and neonatal mortality (rates: 22% at 200 ng/sac; 44% at 300 ng/sac; 31% at 400 ng/sac), thus demonstrating a causal link between this alarmin and adverse perinatal outcomes. Collectively, our findings shed light on the inflammatory responses driven by alarmins in the chorioamniotic membranes, providing insight into the immune mechanisms leading to preterm birth in women with sterile intra-amniotic inflammation.
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Affiliation(s)
- Kenichiro Motomura
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
- Detroit Medical Center, Detroit, Michigan, USA
| | - Olesya Plazyo
- Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Valeria Garcia-Flores
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Meyer Gershater
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Jose Galaz
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Oguariri RM, Brann TW, Adelsberger JW, Chen Q, Goswami S, Mele AR, Imamichi T. S100A8 and S100A9, biomarkers of SARS-Cov2-infected patients, suppress HIV replication in primary macrophages. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 34704091 PMCID: PMC8547522 DOI: 10.1101/2021.10.20.464686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
S100A8 and S100A9 are members of the Alarmin family; these proteins are abundantly expressed in neutrophils and form a heterodimer complex. Recently, both proteins were identified as novel biomarkers of SARS-CoV-2 infection and were shown to play key roles in inducing an aggressive inflammatory response by mediating the release of large amounts of pro-inflammatory cytokines, called the “cytokine storm.” Although co-infection with SARS-CoV-2 in people living with HIV-1 may result in an immunocompromised status, the role of the S100A8/A9 complex in HIV-1 replication in primary T cells and macrophages is still unclear. Here, we evaluated the roles of the proteins in HIV replication to elucidate their functions. We found that the complex had no impact on virus replication in both cell types; however, the subunits of S100A8 and S100A9 inhibits HIV in macrophages. These findings provide important insights into the regulation of HIV viral loads in SARS-CoV2 co-infection.
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Navarro E, Udine E, Lopes KDP, Parks M, Riboldi G, Schilder BM, Humphrey J, Snijders GJL, Vialle RA, Zhuang M, Sikder T, Argyrou C, Allan A, Chao MJ, Farrell K, Henderson B, Simon S, Raymond D, Elango S, Ortega RA, Shanker V, Swan M, Zhu CW, Ramdhani R, Walker RH, Tse W, Sano M, Pereira AC, Ahfeldt T, Goate AM, Bressman S, Crary JF, de Witte L, Frucht S, Saunders-Pullman R, Raj T. Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells. NATURE AGING 2021; 1:850-863. [PMID: 35005630 PMCID: PMC8728893 DOI: 10.1038/s43587-021-00110-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 08/05/2021] [Indexed: 12/11/2022]
Abstract
An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
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Affiliation(s)
- Elisa Navarro
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Evan Udine
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Katia de Paiva Lopes
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Madison Parks
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giulietta Riboldi
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
- Universita degli Studi di Milano, Molecular and Translational Medicine, Milan, Italy
| | - Brian M Schilder
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jack Humphrey
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gijsje J L Snijders
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, NY, Bronx, USA
| | - Ricardo A Vialle
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maojuan Zhuang
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tamjeed Sikder
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Charalambos Argyrou
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amanda Allan
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael J Chao
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kurt Farrell
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brooklyn Henderson
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
| | - Sarah Simon
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deborah Raymond
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sonya Elango
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roberto A Ortega
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vicki Shanker
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew Swan
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Carolyn W Zhu
- Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Geriatric Research, Education and Clinical Centers, James J. Peters VA Medical Center, New York, NY, USA
- Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ritesh Ramdhani
- Department of Neurology, Zucker School of Medicine at Hofstra Northwell, New York, NY, USA
| | - Ruth H Walker
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, James J. Peters VA Medical Center, Bronx, NY, USA
| | - Winona Tse
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mary Sano
- Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Geriatric Research, Education and Clinical Centers, James J. Peters VA Medical Center, New York, NY, USA
- Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ana C Pereira
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tim Ahfeldt
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alison M Goate
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Susan Bressman
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John F Crary
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lotje de Witte
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, NY, Bronx, USA
| | - Steven Frucht
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
| | - Rachel Saunders-Pullman
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Towfique Raj
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Sussadee M, Rucksaken R, Havanapan PO, Reamtong O, Thayananuphat A. Changes in tear protein profile in dogs with keratoconjunctivitis sicca following topical treatment using cyclosporine A. Vet World 2021; 14:1711-1717. [PMID: 34316222 PMCID: PMC8304416 DOI: 10.14202/vetworld.2021.1711-1717] [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: 01/13/2021] [Accepted: 05/12/2021] [Indexed: 11/16/2022] Open
Abstract
Background and Aim Keratoconjunctivitis sicca (KCS) is a chronic inflammatory ocular disease that occurs in many dog breeds worldwide. This study aimed to investigate the tear protein pattern of healthy dogs, KCS dogs, and KCS dogs after treatment with cyclosporine A (CsA). Materials and Methods Twenty-eight dogs of any breed were enrolled in the study. The subjects were divided into three groups: Healthy, KCS, and CsA-treated dogs. Tear samples were collected using Schirmer strips. Tear proteins extracted from the strips were analyzed using two-dimensional electrophoresis. For the first dimension, total protein from tears was separated by isoelectric focusing. The second dimension was performed using 12.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The gel images were analyzed and the protein spots of differential expression were manually cut for protein annotation using mass spectrometry. Results In total, 12 protein spots were excised and subjected to protein identification. Associated with KCS, six protein spots were a downregulated protein, namely, lysozyme. The other six protein spots were upregulated in KCS dogs, consisting of heat shock protein beta-1, protein S100-A12, and keratin type II cytoskeletal 1 and 5. After treatment with CsA for 45 days, the lysozyme protein was still decreasing and the inflammation protein (S100-A12) was not identified. Conclusion Inflammatory tear proteins and proteins involved in cellular stress were present in KCS dogs and appeared to be reduced in medicated eyes. Treatment with topical CsA in the short term may not improve the activity of antibacterial proteins. Changes in the expression patterns of these four proteins might be useful for disease severity and progression assessment, as well as for exploring a novel method for dry eye management in dogs.
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Affiliation(s)
- Metita Sussadee
- Department of Veterinary Technology, Faculty of Veterinary Technology, Kasetsart University, Bangkok, Thailand
| | - Rucksak Rucksaken
- Department of Veterinary Technology, Faculty of Veterinary Technology, Kasetsart University, Bangkok, Thailand
| | - Phattara-Orn Havanapan
- Institute of Molecular Biosciences, Mahidol University, Salaya campus, Nakhonpathom, Thailand
| | - Onrapak Reamtong
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Aree Thayananuphat
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, Thailand
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32
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Lévy Y, Wiedemann A, Hejblum BP, Durand M, Lefebvre C, Surénaud M, Lacabaratz C, Perreau M, Foucat E, Déchenaud M, Tisserand P, Blengio F, Hivert B, Gauthier M, Cervantes-Gonzalez M, Bachelet D, Laouénan C, Bouadma L, Timsit JF, Yazdanpanah Y, Pantaleo G, Hocini H, Thiébaut R, the French COVID cohort study group. CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death. iScience 2021; 24:102711. [PMID: 34127958 PMCID: PMC8189740 DOI: 10.1016/j.isci.2021.102711] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/26/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
The identification of patients with coronavirus disease 2019 and high risk of severe disease is a challenge in routine care. We performed cell phenotypic, serum, and RNA sequencing gene expression analyses in severe hospitalized patients (n = 61). Relative to healthy donors, results showed abnormalities of 27 cell populations and an elevation of 42 cytokines, neutrophil chemo-attractants, and inflammatory components in patients. Supervised and unsupervised analyses revealed a high abundance of CD177, a specific neutrophil activation marker, contributing to the clustering of severe patients. Gene abundance correlated with high serum levels of CD177 in severe patients. Higher levels were confirmed in a second cohort and in intensive care unit (ICU) than non-ICU patients (P < 0.001). Longitudinal measurements discriminated between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.
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Affiliation(s)
- Yves Lévy
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France,Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, Service Immunologie Clinique, Créteil, France,Corresponding author
| | - Aurélie Wiedemann
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Boris P. Hejblum
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France,Univ. Bordeaux, Department of Public Health, INSERM U1219 Bordeaux Population Health Research Centre, Inria SISTM, UMR 1219, 146 Rue Leo Saignat, 33076 Bordeaux, France
| | - Mélany Durand
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France,Univ. Bordeaux, Department of Public Health, INSERM U1219 Bordeaux Population Health Research Centre, Inria SISTM, UMR 1219, 146 Rue Leo Saignat, 33076 Bordeaux, France
| | - Cécile Lefebvre
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Mathieu Surénaud
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Christine Lacabaratz
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Matthieu Perreau
- Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Emile Foucat
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Marie Déchenaud
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Pascaline Tisserand
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Fabiola Blengio
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Benjamin Hivert
- Univ. Bordeaux, Department of Public Health, INSERM U1219 Bordeaux Population Health Research Centre, Inria SISTM, UMR 1219, 146 Rue Leo Saignat, 33076 Bordeaux, France
| | - Marine Gauthier
- Univ. Bordeaux, Department of Public Health, INSERM U1219 Bordeaux Population Health Research Centre, Inria SISTM, UMR 1219, 146 Rue Leo Saignat, 33076 Bordeaux, France
| | - Minerva Cervantes-Gonzalez
- AP-HP, Hôpital Bichat, Département Épidémiologie Biostatistiques et Recherche Clinique, INSERM, Centre d’Investigation clinique-Epidémiologie Clinique 1425, F-75018 Paris, France,AP-HP, Hôpital Bichat, Service de Maladies Infectieuses et Tropicales, F-75018 Paris, France,Université de Paris, INSERM, IAME UMR 1137, F-75018 Paris, France
| | - Delphine Bachelet
- AP-HP, Hôpital Bichat, Département Épidémiologie Biostatistiques et Recherche Clinique, INSERM, Centre d’Investigation clinique-Epidémiologie Clinique 1425, F-75018 Paris, France,Université de Paris, INSERM, IAME UMR 1137, F-75018 Paris, France
| | - Cédric Laouénan
- AP-HP, Hôpital Bichat, Département Épidémiologie Biostatistiques et Recherche Clinique, INSERM, Centre d’Investigation clinique-Epidémiologie Clinique 1425, F-75018 Paris, France,Université de Paris, INSERM, IAME UMR 1137, F-75018 Paris, France
| | - Lila Bouadma
- APHP- Hôpital Bichat – Médecine Intensive et Réanimation des Maladies Infectieuses, Paris, France
| | - Jean-François Timsit
- APHP- Hôpital Bichat – Médecine Intensive et Réanimation des Maladies Infectieuses, Paris, France
| | - Yazdan Yazdanpanah
- AP-HP, Hôpital Bichat, Service de Maladies Infectieuses et Tropicales, F-75018 Paris, France,Université de Paris, INSERM, IAME UMR 1137, F-75018 Paris, France
| | - Giuseppe Pantaleo
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France,Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland,Immunology and Allergy Service, Department of Medicine, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Hakim Hocini
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France
| | - Rodolphe Thiébaut
- Vaccine Research Institute, Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Hopital Henri Mondor, 51 Av Marechal de Lattre de Tassigny, 94010 Créteil, France,Univ. Bordeaux, Department of Public Health, INSERM U1219 Bordeaux Population Health Research Centre, Inria SISTM, UMR 1219, 146 Rue Leo Saignat, 33076 Bordeaux, France,CHU de Bordeaux, Pôle de Santé Publique, Service d’Information Médicale, Bordeaux, France,Corresponding author
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Laulund ASB, Trøstrup H, Lerche CJ, Thomsen K, Christophersen L, Calum H, Høiby N, Moser C. Synergistic effect of immunomodulatory S100A8/A9 and ciprofloxacin against Pseudomonas aeruginosa biofilm in a murine chronic wound model. Pathog Dis 2021; 78:5497298. [PMID: 31116394 DOI: 10.1093/femspd/ftz027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/29/2019] [Indexed: 12/20/2022] Open
Abstract
The majority of chronic wounds are associated with bacterial biofilms recalcitrant to antibiotics and host responses. Immunomodulatory S100A8/A9 is suppressed in Pseudomonas aeruginosa biofilm infected wounds. We aimed at investigating a possible additive effect between S100A8/A9 and ciprofloxacin against biofilms. MATERIALS/METHODS Thirty-two mice were injected with alginate-embedded P. aeruginosa following a third-degree burn. The mice were randomized into four groups receiving combination ciprofloxacin and S100A8/A9 or monotherapy ciprofloxacin, S100A8/A9 or a placebo and evaluated by host responses and quantitative bacteriology in wounds. In addition, in vitro checkerboard analysis was performed, with P. aeruginosa and ascending S100A8/A9 and ciprofloxacin concentrations. RESULTS S100A8/A9 augmented the effect of ciprofloxacin in vivo by lowering the bacterial quantity compared to the placebo arm and the two monointervention groups (P < 0.0001). S100A8 and 100A9 were increased in the double-treated group as compared to the monointervention groups (P = 0.032, P = 0.0023). Tissue inhibitor of metalloproteinases-1 and keratinocyte\chemokine chemoattractant-1 were increased in the double-intervention group compared to the S100A8/A9 group (P = 0.050, P = 0.050). No in vitro synergism was detected. CONCLUSION The observed ciprofloxacin-augmenting effect of S100A8/A9 in vivo was not confirmed by checkerboard analysis, indicating dependence on host cells for the S100A8/A9 effect. S100A8/A9 and ciprofloxacin is a promising therapy for optimizing chronic wound treatment.
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Affiliation(s)
- Anne Sofie Boe Laulund
- Department of Plastic Surgery, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Hannah Trøstrup
- Department of Plastic Surgery, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Christian Johann Lerche
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Kim Thomsen
- Department of Plastic Surgery, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Lars Christophersen
- Department of Plastic Surgery, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Henrik Calum
- Department of Clinical Microbiology, Amager and Hvidovre Hospital, Copenhagen University Hospital, Kettegaard Alle 30, 2650 Copenhagen, Denmark
| | - Niels Høiby
- Institute for Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Claus Moser
- Department of Plastic Surgery, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
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Sun M, Liu Y, Song Y, Gao Y, Zhao F, Luo Y, Qian F, Mu G, Tuo Y. The ameliorative effect of Lactobacillus plantarum-12 on DSS-induced murine colitis. Food Funct 2021; 11:5205-5222. [PMID: 32458908 DOI: 10.1039/d0fo00007h] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Some strains of lactobacilli can exert beneficial effects on a host when ingested in an adequate dose, such as immunoregulation and anti-inflammatory activities. In this study, the survival abilities under simulated gastrointestinal conditions, adhesion abilities on HT-29 cell monolayers, and hemolytic activities of four Lactobacillus plantarum strains were assessed. Among the four strains, L. plantarum-12 showed the higher survival rate under simulated gastrointestinal conditions and adhesion index on the HT-29 cell monolayers, exhibited γ-haemolytic activity and had no biological amine producing ability. L. plantarum-12 was administered to dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) Balb/c mice by oral gavage for 10 days. It was observed that the UC Balb/c mice showed symptoms of colonic atrophy, intestinal histopathological change, gut microbial disturbance, and pro-inflammatory cytokine expression. L. plantarum-12 administration remarkably attenuated DSS-induced UC in mice. L. plantarum-12 administration could restore gut microbiota by increasing beneficial bacteria such as Lactobacillus and decreasing intestinal pathogenic bacteria like Proteobacteria. L. plantarum-12 administration could improve immunity via activating the janus kinase-signal transducer and the activator of the transcription (JAK-STAT) pathway and up-regulating adenosine deaminase (ADA) and interferon-induced protein with tetratricopeptide repeats 1 protein (IFIT1), and enforce the intestinal barrier function by up-regulating mucin 2 (MUC2) protein expression. In conclusion, L. plantarum-12 could attenuate DSS-induced UC in Balb/c mice by ameliorating intestinal inflammation, and restoring the disturbed gut microbiota. L. plantarum-12 could be used as promising probiotics to ameliorate colitis.
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Affiliation(s)
- Mengying Sun
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
| | - Yujun Liu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
| | - Yinglong Song
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
| | - Yuan Gao
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
| | - Fujunzhu Zhao
- Food Science Department, Pennsylvania State University, Pennsylvania, USA
| | - Yanghe Luo
- Institute of Food Research, Hezhou University, Hezhou 542899, P. R. China
| | - Fang Qian
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
| | - Guangqing Mu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China. and Dalian probiotics function research key laboratory, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Yanfeng Tuo
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.
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Hu L, Liu Y, Kong X, Wu R, Peng Q, Zhang Y, Zhou L, Duan L. Fusobacterium nucleatum Facilitates M2 Macrophage Polarization and Colorectal Carcinoma Progression by Activating TLR4/NF- κB/S100A9 Cascade. Front Immunol 2021; 12:658681. [PMID: 34093546 PMCID: PMC8176789 DOI: 10.3389/fimmu.2021.658681] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/07/2021] [Indexed: 12/28/2022] Open
Abstract
Fusobacterium nucleatum (Fn) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (Mφ) was involved in CRC progress driven by Fn infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of Fn in Mφ polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of Mφ into the M2-like Mφ phenotype by in vitro study. Histological observation from Fn-positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like Mφ. Fn-induced M2-like Mφ polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn-challenged Mφ and CRC cells. In addition, Fn-challenged M2-like Mφ conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics in vitro and significantly enhanced tumor growth in vivo, all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF-κB signaling pathway mediated Fn-induced S100A9 expression and subsequent M2-like Mφ activation. Collectively, these findings indicate that elevated S100A9 in Fn-infected CRC microenvironment participates in M2-like Mφ polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF-κB/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn-associated CRC.
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Affiliation(s)
- Lijun Hu
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yan Liu
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xuehua Kong
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Rui Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qi Peng
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yan Zhang
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Lan Zhou
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Liang Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Balog A, Varga B, Fülöp F, Lantos I, Toldi G, Vécsei L, Mándi Y. Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1-3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis. Front Immunol 2021; 12:632513. [PMID: 33897688 PMCID: PMC8062753 DOI: 10.3389/fimmu.2021.632513] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/15/2021] [Indexed: 12/15/2022] Open
Abstract
Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function. The aim of the present study is to investigate the complex effects of a newly synthesized KYNA analog—SZR72 on the in vitro production of tumor necrosis factor-α (TNF-α), tumor necrosis factor-stimulated gene-6 (TSG-6), calprotectin (SA1008/9), SA100 12 (EN-RAGE), and HNP1–3 (defensin-α) in the peripheral blood of patients with RA and the various effects of the disease. Methods: Patients with RA (n = 93) were selected based on the DAS28 score, medication, and their rheumatoid factor (RF) status, respectively. Peripheral blood samples from 93 patients with RA and 50 controls were obtained, and activated by heat-inactivated S. aureus. Parallel samples were pretreated before the activation with the KYNA analog N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride. Following the incubation period (18 h), the supernatants were tested for TNF-α, TSG-6, calprotectin, S100A12, and HNP1–3 content by ELISA. Results: SZR72 inhibited the production of the following inflammatory mediators: TNF-α, calprotectin, S100A12, and HNP1–3 in whole blood cultures. This effect was observed in each group of patients in various phases of the disease. The basic (control) levels of these mediators were higher in the blood of patients than in healthy donors. In contrast, lower TSG-6 levels were detected in patients with RA compared to healthy controls. In addition, the KYNA analog exerted a stimulatory effect on the TSG-6 production ex vivo in human whole blood cultures of patients with RA in various phases of the disease. Conclusion: These data further support the immunomodulatory role of KYNA in RA resulting in anti-inflammatory effects and draw the attention to the importance of the synthesis of the KYNA analog, which might have a future therapeutic potential.
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Affiliation(s)
- Attila Balog
- Department of Rheumatology and Immunology, University of Szeged, Szeged, Hungary
| | - Borisz Varga
- Department of Rheumatology and Immunology, University of Szeged, Szeged, Hungary
| | - Ferenc Fülöp
- Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary
| | - Ildikó Lantos
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary
| | - Gergely Toldi
- Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
| | - László Vécsei
- Department of Neurology, University of Szeged, Szeged, Hungary
| | - Yvette Mándi
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary
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The nAChR Chaperone TMEM35a (NACHO) Contributes to the Development of Hyperalgesia in Mice. Neuroscience 2021; 457:74-87. [PMID: 33422618 PMCID: PMC7897319 DOI: 10.1016/j.neuroscience.2020.12.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 01/21/2023]
Abstract
Pain is a major health problem, affecting over fifty million adults in the US alone, with significant economic cost in medical care and lost productivity. Despite evidence implicating nicotinic acetylcholine receptors (nAChRs) in pathological pain, their specific contribution to pain processing in the spinal cord remains unclear given their presence in both neuronal and non-neuronal cell types. Here we investigated if loss of neuronal-specific TMEM35a (NACHO), a novel chaperone for functional expression of the homomeric α7 and assembly of the heteromeric α3, α4, and α6-containing nAChRs, modulates pain in mice. Mice with tmem35a deletion exhibited thermal hyperalgesia and mechanical allodynia. Intrathecal administration of nicotine and the α7-specific agonist, PHA543613, produced analgesic responses to noxious heat and mechanical stimuli in tmem35a KO mice, respectively, suggesting residual expression of these receptors or off-target effects. Since NACHO is expressed only in neurons, these findings indicate that neuronal α7 nAChR in the spinal cord contributes to heat nociception. To further determine the molecular basis underlying the pain phenotype, we analyzed the spinal cord transcriptome. Compared to WT control, the spinal cord of tmem35a KO mice exhibited 72 differentially-expressed genes (DEGs). These DEGs were mapped onto functional gene networks using the knowledge-based database, Ingenuity Pathway Analysis, and suggests increased neuroinflammation as a potential contributing factor for the hyperalgesia in tmem35a KO mice. Collectively, these findings implicate a heightened inflammatory response in the absence of neuronal NACHO activity. Additional studies are needed to determine the precise mechanism by which NACHO in the spinal cord modulates pain.
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38
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Hu J, Zhao Q, Kong LY, Wang J, Yan J, Xia X, Jia Z, Heimberger AB, Li S. Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme. SCIENCE ADVANCES 2021; 7:eabc2511. [PMID: 33571109 PMCID: PMC7840139 DOI: 10.1126/sciadv.abc2511] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 12/04/2020] [Indexed: 05/17/2023]
Abstract
The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8+ T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8+ T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.
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Affiliation(s)
- Jiemiao Hu
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingnan Zhao
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ling-Yuan Kong
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jian Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jun Yan
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xueqing Xia
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhiliang Jia
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amy B Heimberger
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Shulin Li
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Zhong X, Xie F, Chen L, Liu Z, Wang Q. S100A8 and S100A9 promote endothelial cell activation through the RAGE‑mediated mammalian target of rapamycin complex 2 pathway. Mol Med Rep 2020; 22:5293-5303. [PMID: 33174028 PMCID: PMC7646991 DOI: 10.3892/mmr.2020.11595] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
S100 calcium binding protein A8 (S100A8) and A9 (S100A9) belong to the S100 family of calcium-binding proteins and have important roles in inflammation. They increase endothelial cell proliferation, thereby affecting inflammation, angiogenesis and tumorigenesis. However, the mechanism of action of S100A8/9 in endothelial cells needs further study. Therefore, the present study sought to investigate the effects of S100A8/9 on the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) and their mechanism of action. The viability of HUVECs was determined through a Cell Counting Kit-8 assay. The effect of S100A8/9 on the proliferation of HUVECs was detected by flow cytometry. Migration was evaluated by a Transwell migration assay. Apoptosis was evaluated by Annexin V-FITC and PI staining via flow cytometry. Western blot analysis and reverse transcription-quantitative polymerase chain reaction assays were performed to evaluate the activation of the phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mTOR pathway and mTOR complex 2 (mTORC2). We previously confirmed that S100A8/9 were consistently overexpressed at 1 and 7 days post-surgery in a rabbit vein graft model, which is the period when apoptosis changes to proliferation in neointimal hyperplasia. In the present study, proliferation, viability and migration were increased after treating HUVECs with S100A8/9. S100A8/9 stimulated the PI3K/Akt/mTOR pathway and mTORC2, which was significantly suppressed by a receptor for advanced glycation end products (RAGE)-blocking antibody. Furthermore, depleting expression of RAGE or mTORC2 protein components (rapamycin-insensitive companion of mTOR) by small interfering RNA was found to reduce the cell viability, migration and angiogenesis of S100A8/9-treated HUVECs. The development of neointimal hyperplasia is a complex process initiated by damage to endothelial cells. In conclusion, S100A8/9 has an important role in intimal hyperplasia by promoting cell growth and angiogenesis via RAGE signaling and activation of mTORC2.
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Affiliation(s)
- Xiang Zhong
- Department of Cardiac Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Fengwen Xie
- Department of Cardiac Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li Chen
- Department of Ultrasound, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhixing Liu
- Department of Ultrasound, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qun Wang
- Department of Cardiac Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Azizian-Farsani F, Abedpoor N, Hasan Sheikhha M, Gure AO, Nasr-Esfahani MH, Ghaedi K. Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development. Front Oncol 2020; 10:552283. [PMID: 33117687 PMCID: PMC7551201 DOI: 10.3389/fonc.2020.552283] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/β-catenin pathway, and Glycogen synthase kinase 3β, and even microRNAs.
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Affiliation(s)
| | - Navid Abedpoor
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran
| | | | - Ali Osmay Gure
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran
| | - Kamran Ghaedi
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran.,Division of Cellular and Molecular Biology, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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Lou Y, Zheng Y, Fan B, Zhang L, Zhu F, Wang X, Chen Z, Tan X, Wei Q. Serum levels of interleukins and S100A8/A9 correlate with clinical severity in patients with dermatomyositis-associated interstitial lung disease. BMC Pulm Med 2020; 20:196. [PMID: 32680574 PMCID: PMC7368671 DOI: 10.1186/s12890-020-01226-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 07/02/2020] [Indexed: 12/19/2022] Open
Abstract
Background Dermatomyositis (DM) is a systemic autoimmune inflammatory disorder that affects primarily skin, muscle and lung, frequently associated with interstitial lung disease (ILD). The objective of this study is to investigate the association between serum cytokines and clinical severity in patients with DM-ILD. Methods Serum samples of 30 healthy controls, 14 DM patients without ILD and 40 DM patients with ILD were collected. Serum S100A8/A9 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and levels of interleukins were measured by cytometric beads array (CBA). Then we performed multivariate logistic regression analysis to determine factors independently associated with ILD development. Results Serum IL-4, IL-6 and S100A8/A9 levels were significantly higher in DM patients with ILD than those in healthy controls (p = 0.0013, 0.0017 and < 0.0001, respectively). Serum IL-10 level of patients was dramatically lower than that in controls (p = 0.0001). In DM patients, the levels were significantly higher in patients with A/SIP than in those with CIP (p = 0.0046, 0.0339 and 0.0133) or without ILD (p = 0.0165, 0.0370 and < 0.0001). IL-4 (r = 0.1171, p = 0.0040), IL-6 (r = 0.1174, p = 0.0040) and IL-10 (r = − 0.1829, p = 0.0003) were significantly correlated with S100A8/A9 in DM-ILD patients. S100A8/A9 was significantly correlated with high-resolution computed tomography (HRCT) (r = 0.1642, p = 0.0157) and lung function (DLCO%: r = − 0.2066, p = 0.0061, FVC%: r = − 0.2156, p = 0.0050). Moreover, logistic regression analysis revealed that S100A8/A9 levels were independently associated with ILD development in DM patients (p = 0.004). Conclusions Serum level of S100A8/A9 may be a valuable predictor for assessing the clinical severity of DM-ILD patients. Serum IL-4, IL-6 and IL-10 levels were highly correlated with S100A8/A9, so these cytokines may play a synergistic effect on the progression of DM-ILD.
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Affiliation(s)
- Yueyan Lou
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Yu Zheng
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Bijun Fan
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Liyan Zhang
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Feng Zhu
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaodong Wang
- Department of Rheumatology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Zhiwei Chen
- Department of Rheumatology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaoming Tan
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
| | - Qing Wei
- Department of Laboratory Medicine, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
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Epigenetic factors involved in the pathophysiology of inflammatory skin diseases. J Allergy Clin Immunol 2020; 145:1049-1060. [DOI: 10.1016/j.jaci.2019.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/23/2019] [Accepted: 10/01/2019] [Indexed: 12/11/2022]
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Ishizuka K, Fujii W, Azuma N, Mizobuchi H, Morimoto A, Sanjoba C, Matsumoto Y, Goto Y. Pathological roles of MRP14 in anemia and splenomegaly during experimental visceral leishmaniasis. PLoS Negl Trop Dis 2020; 14:e0008020. [PMID: 31961866 PMCID: PMC6994150 DOI: 10.1371/journal.pntd.0008020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/31/2020] [Accepted: 01/01/2020] [Indexed: 01/03/2023] Open
Abstract
Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL.
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Affiliation(s)
- Kanna Ishizuka
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Wataru Fujii
- Laboratory of Applied Genetics, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Natsuho Azuma
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Haruka Mizobuchi
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Ayako Morimoto
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Chizu Sanjoba
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshitsugu Matsumoto
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- * E-mail:
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Sreejit G, Flynn MC, Patil M, Krishnamurthy P, Murphy AJ, Nagareddy PR. S100 family proteins in inflammation and beyond. Adv Clin Chem 2020; 98:173-231. [PMID: 32564786 DOI: 10.1016/bs.acc.2020.02.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases. Strategies aimed at targeting S100-mediated signaling pathways hold a great potential in developing novel therapeutics for multiple diseases. In this chapter, we aim to summarize the current knowledge about the role of S100 family proteins in health and disease with a major focus on their role in inflammatory conditions.
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Affiliation(s)
| | - Michelle C Flynn
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Mallikarjun Patil
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Department of Immunology, Monash University, Melbourne, VIC, Australia
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Lou Y, Zheng Y, Fan B, Zhang L, Zhu F, Wang X, Chen Z, Tan X. Serum S100A12 levels are correlated with clinical severity in patients with dermatomyositis-associated interstitial lung disease. J Int Med Res 2019; 48:300060519887841. [PMID: 31865833 PMCID: PMC7607057 DOI: 10.1177/0300060519887841] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Objective S100A12 is an emerging inflammatory disease biomarker. Interstitial lung disease (ILD) is a common, severe complication of dermatomyositis (DM). This study was performed to investigate the association between S100A12 and disease activity and prognosis in patients with DM-associated ILD (i.e., DM-ILD). Methods Serum S100A12 levels were measured using enzyme-linked immunosorbent assays in patients with stable DM-ILD, patients with acute exacerbation of DM-ILD (AE DM-ILD), and healthy controls (HCs). The relationships of serum S100A12 levels with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, high-resolution computed tomography (HRCT) scores, and pulmonary functions were evaluated by multiple unpaired t-tests and Pearson correlation. Results Serum S100A12 levels were higher in patients with stable DM-ILD and those with AE DM-ILD than in HCs. Serum S100A12 levels in patients with stable DM-ILD and those with AE DM-ILD were positively correlated with CRP, ESR, and ferritin. S100A12 levels were positively correlated with HRCT scores in patients with stable DM-ILD and those with AE DM-ILD, while they were negatively correlated with predicted percentages of forced vital capacity and predicted percentages of carbon monoxide diffusing capacity in those patients. Conclusion Our findings demonstrate the usefulness of serum S100A12 levels for assessing clinical severity and prognosis of DM-ILD.
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Affiliation(s)
- Yueyan Lou
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Yu Zheng
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Bijun Fan
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Liyan Zhang
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Feng Zhu
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xiaodong Wang
- Department of Rheumatology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Zhiwei Chen
- Department of Rheumatology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xiaoming Tan
- Department of Pulmonology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
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Qiu X, Ping S, Kyle M, Longo J, Chin L, Zhao LR. S100 Calcium-Binding Protein A9 Knockout Contributes to Neuroprotection and Functional Improvement after Traumatic Brain Injury. J Neurotrauma 2019; 37:950-965. [PMID: 31621496 DOI: 10.1089/neu.2018.6170] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
S100 calcium-binding protein A9 (S100a9), a proinflammatory protein, has been shown to be involved in the development of neuroinflammatory disorders and neurodegenerative diseases. Upregulation of S100a9 in the brain during acute brain injury has been proposed to be associated with acute neuroinflammation. However, it remains unclear whether eliminating S100a9 expression will show beneficial outcomes after traumatic brain injury (TBI). Using S100a9 knockout mice, this study has demonstrated that S100a9 deletion ameliorates post-TBI anxiety, improves TBI-impaired motor and cognitive function, reduces lesion size, prevents perilesional neuron loss and neurodegeneration, diminishes neuroinflammation and TBI-induced neurogenesis, and enhances perilesional expression of neuroplasticity protein. These findings suggest that S100a9 plays a detrimental role in TBI. Genetic deletion of S100a9 enhances neuroprotection and improves functional outcome after TBI. This study sheds light on the pathological involvement of S100a9 in TBI, which would provide a new therapeutic target to minimize TBI-induced brain damage.
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Affiliation(s)
- Xuecheng Qiu
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York
| | - Suning Ping
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York
| | - Michele Kyle
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York
| | - John Longo
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York
| | - Lawrence Chin
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York
| | - Li-Ru Zhao
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York.,VA Health Care Upstate New York, Syracuse VA Medical Center, Syracuse, New York
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Zhou M, Li M, Liang X, Zhang Y, Huang H, Feng Y, Wang G, Liu T, Chen Z, Pei H, Chen Y. The Significance of Serum S100A9 and TNC Levels as Biomarkers in Colorectal Cancer. J Cancer 2019; 10:5315-5323. [PMID: 31632476 PMCID: PMC6775684 DOI: 10.7150/jca.31267] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 06/06/2019] [Indexed: 12/28/2022] Open
Abstract
Purpose: The aim of this study was to evaluate the diagnostic value of S100A9 and tenascin-c (TNC) levels as colorectal cancer (CRC) biomarkers in several ways, including through screening tests, differentiation tests, combination with existing biomarkers (CEA and CA19-9), and serum level measurements before and after surgery. Materials and Methods: In this case-control study, S100A9 and TNC serum levels were measured in 460 participants: 258 CRC patients, 99 patients with benign colonic disease (BCD) and 103 healthy donors (HD). Results: The serum levels of S100A9 were 22.32 (14.88-29.55) ng/ml, 10.02 (5.83-14.15) ng/ml and 10.05 (7.68-15.34) ng/ml in the CRC, BCD and HD groups, respectively. The serum levels of TNC were 4.30 (2.12-6.04) ng/ml, 1.60 (1.06-2.30) ng/ml and 2.00 (1.37-3.00) ng/ml in the CRC, BCD and HD groups, respectively. Significantly higher levels of both biomarkers (S100A9 and TNC) were found in CRC patients (both p<0.001). Both S100A9 and TNC levels were superior to CEA and CA19-9 levels as CRC diagnostic biomarkers; the combination of S100A9, TNC and CEA levels was an excellent biomarker with 79.8% sensitivity and 89.6% specificity. The serum levels of S100A9 and TNC in CRC patients were significantly lower after surgery than before surgery (p<0.01). Conclusion: S100A9 and TNC levels could serve as diagnostic biomarkers of colorectal cancer.
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Affiliation(s)
- Minze Zhou
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Maoyu Li
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xujun Liang
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ye Zhang
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Huichao Huang
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yilu Feng
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Guoqiang Wang
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ting Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhuchu Chen
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Haiping Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yongheng Chen
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, China
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Blastocyst activation engenders transcriptome reprogram affecting X-chromosome reactivation and inflammatory trigger of implantation. Proc Natl Acad Sci U S A 2019; 116:16621-16630. [PMID: 31346081 DOI: 10.1073/pnas.1900401116] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Implantation of the blastocyst into the uterus is the gateway for further embryonic development in mammals. Programming of blastocyst to an implantation-competent state known as blastocyst activation is the determining factor for implantation into the receptive uterus. However, it remains largely unclear how the blastocyst is globally programmed for implantation. Employing a delayed implantation mouse model, we show here that the blastocyst undergoes extensive programming essential for implantation. By analyzing the transcriptional profile of blastocysts with different implantation competency, we reveal the dynamic change in the biosynthesis, metabolism, and proliferation during blastocyst reactivation from diapause. We also demonstrate that reactivation of the X chromosome, one of the most important events during periimplantation of female embryonic development, is not completed even in blastocysts under conditions of dormancy, despite long term suspension in the uterus. Moreover, the mural trophectoderm (TE), but not the polar TE, differentiates to be more invasive through the weakened cell-cell tight junctions and extracellular matrices (ECMs). By analyzing the differentially expressed profile of secretory proteins, we further demonstrate that the blastocyst functions as a proinflammatory body to secrete proinflammatory signals, such as TNFα and S100A9, thereby triggering embryo-uterine attachment reaction during implantation. Collectively, our data systematically and comprehensively disclose the programming of blastocyst reactivation from diapause for implantation and uncover previously undefined roles of blastocyst during implantation.
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Heizmann CW. S100 proteins: Diagnostic and prognostic biomarkers in laboratory medicine. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1197-1206. [DOI: 10.1016/j.bbamcr.2018.10.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/12/2018] [Indexed: 01/04/2023]
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Heizmann CW. Ca 2+-Binding Proteins of the EF-Hand Superfamily: Diagnostic and Prognostic Biomarkers and Novel Therapeutic Targets. Methods Mol Biol 2019; 1929:157-186. [PMID: 30710273 DOI: 10.1007/978-1-4939-9030-6_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A multitude of Ca2+-sensor proteins containing the specific Ca2+-binding motif (helix-loop-helix, called EF-hand) are of major clinical relevance in a many human diseases. Measurements of troponin, the first intracellular Ca-sensor protein to be discovered, is nowadays the "gold standard" in the diagnosis of patients with acute coronary syndrome (ACS). Mutations have been identified in calmodulin and linked to inherited ventricular tachycardia and in patients affected by severe cardiac arrhythmias. Parvalbumin, when introduced into the diseased heart by gene therapy to increase contraction and relaxation speed, is considered to be a novel therapeutic strategy to combat heart failure. S100 proteins, the largest subgroup with the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation, and autoimmune pathologies. The intention of this review is to summarize the clinical importance of this protein family and their use as biomarkers and potential drug targets, which could help to improve the diagnosis of human diseases and identification of more selective therapeutic interventions.
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Affiliation(s)
- Claus W Heizmann
- Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zürich, Zürich, Switzerland.
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