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Qi W, Zhao T, Liu M, Shi X, Yang Y, Huang Y, Li N, Ai K, Huang Q. Engineered tantalum sulfide nanosheets for effective acute liver injury treatment by regulating oxidative stress and inflammation. J Colloid Interface Sci 2025; 693:137596. [PMID: 40250115 DOI: 10.1016/j.jcis.2025.137596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/20/2025]
Abstract
INTRODUCTION Tantalum sulfide (TaS2), a two-dimensional layered material, shows significant promise for treating acute liver injury (ALI) due to its exceptional biocompatibility and potent reactive oxygen species (ROS) scavenging capacity. However, the clinical translation of TaS2-based therapy remains limited by challenges in optimizing its stability, bioavailability, and particle size to match the liver's complex architecture. OBJECTIVES This study investigated the mechanisms by which serum albumin (SA)-modified TaS2 nanosheets (S-TaS2) modulate oxidative stress, apoptosis, and inflammation to achieve therapeutic efficacy in ALI. METHODS S-TaS2 was synthesized via a top-down exfoliation strategy and comprehensively characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), ultraviolet-visible (UV-Vis) spectroscopy, and Zeta potential analysis. In vivo therapeutic performance was evaluated through liver function tests, Hematoxylin-Eosin staining (HE), Dihydroethidium (DHE) staining, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) staining, and ROS level assessments. Biodistribution, mitochondrial protection, and anti-inflammatory effects of S-TaS2 were assessed via in vivo fluorescence imaging, immunohistochemistry, western blotting, JC-1 and Mitochondrial Superoxide (MitoSOX) staining, Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI) apoptosis assays, enzyme-linked immunosorbent assays (ELISA), and other complementary techniques. RESULTS The exfoliation process successfully reduced TaS2 to monolayer nanosheets, yielding a nanoscale formulation with improved bioactivity. SA modification significantly enhanced aqueous stability and enabled targeted liver delivery. This targeting effect is attributed to two factors: the inherent liver affinity of SA and the optimal particle size of S-TaS2 (∼185 nm), which facilitates passage through hepatic sinusoids (50-200 nm) and, in pathological conditions such as ALI, through damaged vascular endothelium. In an acetaminophen (APAP)-induced ALI model, S-TaS2 preferentially accumulated in the injured liver, where it scavenged excessive ROS, mitigated mitochondrial dysfunction, and significantly preserved hepatocyte integrity. Notably, S-TaS2 also attenuated liver inflammation, reduced pro-inflammatory cytokine levels, and promoted tissue repair. Furthermore, it demonstrated adequate biosafety both in vitro and in vivo. CONCLUSIONS This study presents the first successful synthesis of S-TaS2, a liver-targeting nanotherapeutic engineered through SA modification and size optimization. S-TaS2 preferentially accumulates in damaged hepatic tissue and effectively combats ALI by suppressing oxidative stress and inflammation, while preventing their pathological amplification. These findings offer new therapeutic insights and a promising platform for future liver-targeted interventions.
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Affiliation(s)
- Weimin Qi
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Tianjiao Zhao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Min Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Xiaojing Shi
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Yongqi Yang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Yunying Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Niansheng Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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Jiang YC, Guo J, Liu SH, Dai X, Wang CY, Lian LH, Cui ZY, Nan JX, Wu YL. Vincamine ameliorates hepatic fibrosis via inhibiting S100A4-mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence. Br J Pharmacol 2025; 182:2447-2465. [PMID: 39940076 DOI: 10.1111/bph.17471] [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: 05/16/2024] [Revised: 01/07/2025] [Accepted: 01/12/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND AND PURPOSE Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis. EXPERIMENTAL APPROACH Hepatic stellate cells (HSCs), TGF-β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin. KEY RESULTS Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α-smooth muscle actin (α-SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on α-SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway. CONCLUSION AND IMPLICATIONS Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis.
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Affiliation(s)
- Yu-Chen Jiang
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Jia Guo
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Sai-Hu Liu
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Xu Dai
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Chen-Yu Wang
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Zhen-Yu Cui
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
- Jilin Vocational and Technical College, Longjing, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs); College of Pharmacy, Yanbian University, Yanji, China
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Zhong H, Liu C, Huang Z, Tan P, Chen H, Fu W. Crosstalk between Hepatic Stellate Cells and Hepatic Macrophages in Metabolic Dysfunction-Associated Steatohepatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:1040-1056. [PMID: 40414682 DOI: 10.1016/j.ajpath.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/29/2025] [Accepted: 02/19/2025] [Indexed: 05/27/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease is the most prevalent liver condition worldwide. Its more severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH), is accompanied by distinctive hepatocellular injury and inflammation with fibrosis. The involvement of chronic inflammation and accompanying immune cell activation in the maturation phases of MASH progression, mediated through hepatic stellate cells (HSCs), plays a central role. This review highlights the detailed molecular and cellular mechanisms of MASH, with special attention to the dynamic dialogue between HSCs and hepatic macrophages. This review will help narrow the existing gaps, with a summary of key roles HSCs and hepatic macrophages play within liver immunity to inflammation, discussing critical intercellular communication pathways as well as proposing new venues for research toward a better understanding of MASH pathobiology, which could pave ways toward breakthroughs in the clinical condition.
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Affiliation(s)
- Haoran Zhong
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chen Liu
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhiwei Huang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Tan
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Chen
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| | - Wenguang Fu
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [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: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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Chen L, Guillot A, Tacke F. Reviewing the function of macrophages in liver disease. Expert Rev Gastroenterol Hepatol 2025:1-17. [PMID: 40387555 DOI: 10.1080/17474124.2025.2508963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/10/2025] [Accepted: 05/08/2025] [Indexed: 05/20/2025]
Abstract
INTRODUCTION The liver is a central metabolic organ, but is also hosting a unique immune microenvironment to sustain homeostasis and proper defense measures against injury threats in healthy individuals. Liver macrophages, mostly represented by the tissue-resident Kupffer cells and bone marrow- or monocyte-derived macrophages, are intricately involved in various aspects of liver homeostasis and disease, including tissue injury, inflammation, fibrogenesis and repair mechanisms. AREAS COVERED We review recent findings on defining the liver macrophage landscape and their functions in liver diseases with the aim of highlighting potential targets for therapeutic interventions. A comprehensive literature search in PubMed and Google Scholar was conducted to identify relevant literature up to date. EXPERT OPINION Liver macrophages orchestrate key homeostatic and pathogenic processes in the liver. Thus, targeting liver macrophages represents an attractive strategy for drug development, e.g. to ameliorate liver inflammation, steatohepatitis or fibrosis. However, translation from fundamental research to therapies remains challenging due to the versatile nature of the liver macrophage compartment. Recent and major technical advances such as single-cell and spatially-resolved omics approaches deepened our understanding of macrophage biology at a molecular level. Yet, further studies are needed to identify suitable, etiology- and stage-dependent strategies for the treatment of liver diseases.
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Affiliation(s)
- Lanlan Chen
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité - Universitätsmedizin Berlin, Berlin, Germany
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité - Universitätsmedizin Berlin, Berlin, Germany
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Li R, Shu Y, Yan Y, Zhu J, Cheng Z, Zhang J, Zhu L, Qiao Y, Sun Q. Caveolin-1 Deficiency in Macrophages Alleviates Carbon Tetra-Chloride-Induced Acute Liver Injury in Mice. Int J Mol Sci 2025; 26:4903. [PMID: 40430042 DOI: 10.3390/ijms26104903] [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: 03/28/2025] [Revised: 05/08/2025] [Accepted: 05/11/2025] [Indexed: 05/29/2025] Open
Abstract
Bone marrow-derived macrophages (BMMs) exhibit dynamic behavior and functional capabilities in response to specific microenvironmental stimuli. Recent investigations have proved that BMMs play crucial roles in promoting necrotic lesion resolution. Despite substantial advancements in understanding their activation and interaction with injured livers, researchers face challenges to develop effective treatments based on manipulating BMMs function. Caveolin-1 (Cav-1) is the major structural protein on the plasma membrane. We previously reported that Cav-1 knockout (KO) mice exhibited less functional damage and necrosis in carbon tetrachloride (CCl4)-induced liver injury. We hypothesize that the activation and recruitment of BMMs are involved in the resolution of necrotic lesions in Cav-1 KO mice. Wild-type (WT) and Cav-1 KO mice were injected with CCl4 (10% v/v) to induce acute liver injury model. Blood samples and hepatic tissues were harvested for serum alanine transaminase (ALT) activity assessment, histopathological examination through hematoxylin-eosin (H&E) staining, and BMMs subpopulation analysis via flow cytometry. Then, primary BMMs were isolated and cultured to investigate the effect of Cav-1 on BMMs polarization, migration, and activation of STAT3 signal pathway. Validation of hepatic macrophage depletion was induced by administrating clodronate liposomes (CLs), and BMMs reconstitution was evaluated by EGFP labelled BMMs. Following this, hepatic macrophages were depleted by CLs, BMMs were isolated from Cav-1 KO, and WT mice were cultured and administrated to evaluate the protective role of Cav-1-deleted BMMs on the resolution of hepatocellular necrosis and apoptosis in acute liver injury. The BMMs ratio significantly increased from 2.12% (1D), 4.38% (1W), and 5.38% (2W) in oil control mice to 7.17%, 14.90%, and 19.30% in CCl4-treated mice (p < 0.01 or p < 0.001). Concurrently, Cav-1 positive BMMs exhibited a marked elevation from 6.41% at 1D to 24.90% by 2W (p = 0.0228). Cav-1 KO exerted protective effects by reducing serum ALT by 26% (p = 0.0265) and necrotic areas by 28% (p = 0.0220) and enhancing BMMs infiltration by 60% (p = 0.0059). In vitro, Cav-1 KO BMMs showed a decrease in CD206 fluorescence intensity (p < 0.001), a time-dependent upregulation of arginase-1 mRNA (p < 0.05 or p < 0.01), a 1.22-fold increase in phosphorylated STAT3 (p = 0.0036), and impaired wound healing from 12 to 24 h (p < 0.001). The macrophage-depleting action in livers by CL injection persists for a minimum of 48 h. Administrated EGFP+ BMMs emerged as the predominant population following CL injection for a duration of 48 h. Following clodronate liposome-mediated hepatic macrophage depletion, the adoptive transfer of Cav-1 KO BMMs demonstrated therapeutic efficacy in CCl4-induced acute liver injury. In CCl4-induced acute liver injury, the adoptive transfer of Cav-1 KO BMMs reduced necrosis by 12.8% (p = 0.0105), apoptosis by 25.2% (p = 0.0127), doubled macrophages infiltration (p = 0.0269), and suppressed CXCL9/10 mRNA expression (p = 0.0044 or p = 0.0385). BMMs play a key role in the resolution of liver necrotic lesions in CCl4-induced acute liver injury. Cav-1 depletion attenuates hepatocellular necrosis and apoptosis by accelerating BMMs recruitment and M2 polarization. Cav-1 in macrophages may represent a potential therapeutic target for acute liver injury.
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Affiliation(s)
- Ruirui Li
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yixue Shu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yulin Yan
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Junyi Zhu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Zilu Cheng
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Jie Zhang
- Laboratory Animal Center, Capital Medical University, Beijing 100069, China
| | - Liming Zhu
- Laboratory Animal Center, Capital Medical University, Beijing 100069, China
| | - Yanhua Qiao
- Laboratory Animal Center, Capital Medical University, Beijing 100069, China
| | - Quan Sun
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
- Laboratory Animal Center, Capital Medical University, Beijing 100069, China
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Li S, Liu J, Wu J, Zheng X. Immunological Mechanisms and Effects of Bacterial Infections in Acute-on-Chronic Liver Failure. Cells 2025; 14:718. [PMID: 40422221 DOI: 10.3390/cells14100718] [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: 04/09/2025] [Revised: 05/09/2025] [Accepted: 05/10/2025] [Indexed: 05/28/2025] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells-including monocytes, macrophages, and neutrophils-as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed.
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Affiliation(s)
- Sumeng Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
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Marei M, El-Nikhely N, Sheta E, Ragab H, Wahid A, Saeed H, Rostom SAF. Biochemical and Molecular Studies on the Role of Celecoxib and Some Related Bipyrazoles in Mitigating Induced Liver Injury in Experimental Animals. Drug Des Devel Ther 2025; 19:3857-3882. [PMID: 40391176 PMCID: PMC12087607 DOI: 10.2147/dddt.s512058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 05/01/2025] [Indexed: 05/21/2025] Open
Abstract
Introduction Liver fibrosis is a life-threatening disease that greatly impacts the morbidity and mortality of hepatic patients worldwide, resulting mainly as a consequence of hepatitis C, alcoholic and non-alcoholic fatty liver. COX-1 and COX-2 isozymes catalyze the synthesis of prostaglandins (PGs) and thromboxanes (TXs) from arachidonic acid causing inflammation. Owing to the scarcity of approved fibrolytic drugs available for human use, celecoxib (a selective COX-2 inhibitor) has been repurposed as a potential antifibrotic and fibrolytic agent in some chronic liver fibrosis models. Methods The present study aims to discover a non-invasive treatment for liver fibrosis through investigating the possible ability of three celecoxib-related bipyrazole compounds HR1-3 to reverse chemically induced liver fibrosis in rats using CCl4. This fibrolytic effect was verified by histopathological, immunohistochemical, biochemical and biomolecular assays. In addition, in silico computer-aided evaluation of the compounds' binding mode to certain molecular targets was performed, and the in silico physicochemical properties, drug likeness and pharmacokinetic parameters were predicted using web-based applications. Results The analogs HR1-3 could serve as novel therapeutic candidates for the mitigation of liver fibrosis that deserves further derivatizations and investigations. In particular, the fluorinated analog HR3 proved to be the most active member in this study when compared to celecoxib due to its distinguished histopathological and immunohistochemical investigation results, beside its antioxidant potential, as well as its reliable effects against some biomarkers, namely, MMP-9, TGF-β1, TIMP-1, IL-6 and TNF-α. Conclusion Based on the obtained results, the fluorinated analog HR3 could serve as a novel therapeutic candidate for the amelioration of liver fibrosis that deserves further derivatizations and investigations.
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Affiliation(s)
- Maram Marei
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21521, Egypt
| | - Nefertiti El-Nikhely
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21521, Egypt
| | - Eman Sheta
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, 21521, Egypt
| | - Hanan Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Hesham Saeed
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21521, Egypt
| | - Sherif A F Rostom
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
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Fan X, Tang Q, Xia N, Wang J, Zhao W, Jin M, Lu Q, Hu J, Zhang R, Zhang L, Jiang Z, Yu Q. Immune-endothelial cell crosstalk in hepatic endothelial injury of liver fibrotic mice. Eur J Pharmacol 2025; 1000:177730. [PMID: 40374060 DOI: 10.1016/j.ejphar.2025.177730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 05/09/2025] [Accepted: 05/13/2025] [Indexed: 05/17/2025]
Abstract
INTRODUCTION Liver fibrosis is a common pathological process in chronic liver disease, reflecting the advanced stage of the disease. Liver endothelial cells (ECs), especially liver sinusoidal endothelial cells (LSECs), are recognized as critical modulators of liver homeostasis and play essential roles in the recruitment and function of liver immune cells. In this study, we aimed to explore the mechanism of hepatic EC injury and the potential regulatory pathways of intercellular communication in liver fibrosis. METHODS In this study, C57BL/6 male mice were treated with CCl4 for 6 weeks to establish a liver fibrosis model. Masson staining and immunohistochemistry were performed to assess the extent of liver fibrosis. Hepatic endothelial injury was detected by using scanning electron microscopy (SEM) and PCR technology. Single-cell RNA sequencing (scRNA-seq) was performed to analyze phenotypic changes in nonparenchymal cells and dissect intercellular crosstalk. RESULTS A total of 24,534 cells were clustered into 10 main cell subsets. The LSEC fenestrae and surface receptor expression were reduced, and the expression of Cd34 was upregulated. Liver ECs exhibited dense cellular crosstalk with immune cells (macrophages, T and B cells). The analysis of intercellular signaling pathways revealed that immune cells targeted liver ECs through the Ptprc-Mrc1 and Sell-Podxl signaling pathways to maintain cellular interactions during liver fibrosis. CONCLUSION We revealed apparent damage and capillarization of liver ECs and demonstrated the cell-cell communications among liver immune cells and ECs during the development of liver fibrosis. The Ptprc-Mrc1 and Sell-Podxl signaling pathways exerted prominent roles in liver immune cell-EC interactions.
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Affiliation(s)
- Xue Fan
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Qianhui Tang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ninglin Xia
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Jiwei Wang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Wen Zhao
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ming Jin
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Qian Lu
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Jinyu Hu
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Rongmi Zhang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Zhenzhou Jiang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
| | - Qinwei Yu
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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10
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Wang J, Wang H, Yang W, Zhao D, Liu D, Tang L, Chen XP. GPNMB regulates the differentiation and transformation of monocyte-derived macrophages during MASLD. Int Immunopharmacol 2025; 154:114554. [PMID: 40186908 DOI: 10.1016/j.intimp.2025.114554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/22/2025] [Accepted: 03/23/2025] [Indexed: 04/07/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly concerning global health issue characterized by pronounced hepatic steatosis and liver fibrosis. Hepatic monocyte-derived macrophages (MDMs) are crucial in the pathogenesis of liver fibrosis under MASLD. Nevertheless, the precise functions of MDMs and the underlying mechanisms governing their differentiation remain inadequately elucidated. In this study, we revealed an orchestrator of this process: Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), one of the characteristic genes of MDMs. Notably, myeloid-specific Gpnmb-knockout contributed to the retention of resident Kupffer cells (KCs) and rerouted monocyte differentiation towards a monocyte-derived macrophage subset that occupies the Kupffer cell niche (MoKC subset, resembling resident KCs), thereby impeding the formation of hepatic lipid-associated macrophages (LAMs). This transition has a profound impact, manifested in significantly reduced steatosis and modestly decreased liver fibrosis in myeloid-specific Gpnmb-knockout mice. In conclusion, our research clarifies the complex interactions between Gpnmb and MDMs and underscores the therapeutic potential of targeting Gpnmb within MDMs to manage MASLD.
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Affiliation(s)
- Junqi Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.; State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China
| | - Huan Wang
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Wenting Yang
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Dianyuan Zhao
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Di Liu
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Li Tang
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China; Institute of Future Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, PR China..
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China.; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.; Furong Laboratory, Changsha, Hunan, China.
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11
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Xia LY, Yu NR, Huang SL, Qu H, Qin L, Zhao QS, Leng Y. Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice. Acta Pharmacol Sin 2025:10.1038/s41401-025-01569-9. [PMID: 40329004 DOI: 10.1038/s41401-025-01569-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025]
Abstract
Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf (P. cocos) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos, in a high-fat diet plus CCl4 induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mg·kg-1·d-1, i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5'-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.
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Affiliation(s)
- Ling-Yan Xia
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Nai-Rong Yu
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Su-Ling Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hui Qu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Li Qin
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Qin-Shi Zhao
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
| | - Ying Leng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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12
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Chen Z, Zhang J, Zhang L, Liu Y, Zhang T, Sang X, Xu Y, Lu X. Identification of PANoptosis related biomarkers to predict hepatic ischemia‒reperfusion injury after liver transplantation. Sci Rep 2025; 15:15437. [PMID: 40316717 PMCID: PMC12048552 DOI: 10.1038/s41598-025-99264-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/18/2025] [Indexed: 05/04/2025] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication following liver transplantation. Bioinformatic analysis was performed to elucidate the PANoptosis-related molecular mechanisms underlying HIRI. Comprehensive analysis of bulk and single-cell RNA sequencing data from human liver tissue before and after HIRI was performed. Differential expression analysis, weighted gene coexpression analysis, and protein interaction network analysis were used to identify candidate biomarkers. Multiple machine learning methods were utilized to screen for core biomarkers and construct a diagnostic predictive model. Functional and interaction analyses of the genes were also performed. Cellular clustering and annotation, pseudotemporal trajectory, and intercellular communication analyses of HIRI were conducted. Six PANoptosis-associated genes (CEBPB, HSPA1A, HSPA1B, IRF1, SERPINE1, and TNFAIP3) were identified as HIRI-related biomarkers. These biomarkers are regulated by NF-κB and miRNA-155. A nomogram for HIRI prediction based on these biomarkers was constructed and validated. In addition, the heterogeneity and dynamic changes in macrophage subpopulations during HIRI were revealed, highlighting the roles of Kupffer cells and monocyte-derived macrophages in modulating the hepatic microenvironment. The MIF and VISFATIN signaling pathways play important roles in the interaction between macrophages and other cells. These findings enhance our understanding of the mechanisms of PANoptosis in HIRI and provide a new basis and potential targets for prevention and treatment strategies for HIRI.
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Affiliation(s)
- Zhihong Chen
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Junwei Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Lei Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Yaoge Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Ting Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Yiyao Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
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13
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Ortuño-Costela MC, Pinzani M, Vallier L. Cell therapy for liver disorders: past, present and future. Nat Rev Gastroenterol Hepatol 2025; 22:329-342. [PMID: 40102584 DOI: 10.1038/s41575-025-01050-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2025] [Indexed: 03/20/2025]
Abstract
The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ's functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or 'liver' organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.
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Affiliation(s)
- M Carmen Ortuño-Costela
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Massimo Pinzani
- University College London Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
- University of Pittsburgh Medical Center-Mediterranean Institute for Transplantation and Highly Specialized Therapies (UPMC-ISMETT), Palermo, Italy
| | - Ludovic Vallier
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany.
- Max Planck Institute for Molecular Genetics, Berlin, Germany.
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14
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Makassy D, Williams K, Karwi QG. The Evolving Role of Macrophage Metabolic Reprogramming in Obesity. Can J Cardiol 2025:S0828-282X(25)00320-4. [PMID: 40311669 DOI: 10.1016/j.cjca.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 05/03/2025] Open
Abstract
Recent research has extensively explored the critical role of energy metabolism in shaping the inflammatory response and polarization of macrophages in obesity. This rapidly growing field emphasizes the need to understand the connection between metabolic processes that support macrophage polarization in obesity. Although most published research in this area has focused on glucose and fatty acids, how the flux through other metabolic pathways (such as ketone and amino acid oxidation) in macrophages is altered in obesity is not well defined. This review summarizes the main alterations in uptake, storage, and oxidation of oxidative substrates (glucose, fatty acids, ketone bodies, and amino acids) in macrophages and how these alterations are linked to macrophage polarization and contribution to augmented inflammatory markers in obesity. The review also discusses how oxidative substrates could modulate macrophage energy metabolism and inflammatory responses via feeding into other nonoxidative pathways (such as the pentose phosphate pathway, triacylglycerol synthesis/accumulation), via acting as signalling molecules, or via mediating post-translational modifications (such as O-GlcNAcylation or β-hydroxybutyrylation). The review also identifies several critical unanswered questions regarding the characteristics (functional and metabolic) of macrophages from different origins (adipose tissue, skeletal muscle, bone marrow) in obesity and how these characteristics contribute to early vs late phases of obesity. We also identified a number of new therapeutic targets that could be evaluated in future investigations. Targeting macrophage metabolism in obesity is an exciting and active area of research with significant potential to help identify new treatments to limit the detrimental effects of inflammation in obesity.
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Affiliation(s)
- Dorcus Makassy
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, Newfoundland and Labrador, Canada
| | - Kyra Williams
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, Newfoundland and Labrador, Canada
| | - Qutuba G Karwi
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, Newfoundland and Labrador, Canada.
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15
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Chen J, Zhang Y, Deng Z, Zhu Y, Xu C, Gao B, Wang W, Xiao J, Xiao Z, Zhang M, Tu K. Integrated cascade antioxidant nanozymes-Cu 5.4O@CNDs combat acute liver injury by regulating retinol metabolism. Theranostics 2025; 15:5592-5615. [PMID: 40365282 PMCID: PMC12068305 DOI: 10.7150/thno.106811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/27/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Acute liver failure (ALF) represents a critical medical condition marked by the abrupt onset of hepatocyte damage, commonly induced by etiological factors such as hepatic ischemia/reperfusion injury (HIRI) and drug-induced hepatotoxicity. Across various types of liver injury, oxidative stress, heightened inflammatory responses, and dysregulated hepatic retinol metabolism are pivotal contributors, particularly in the context of excessive reactive oxygen species (ROS). Methods: C-dots were combined with Cu5.4O USNPs to synthesize a cost-effective nanozyme, Cu5.4O@CNDs, which mimics the activity of cascade enzymes. The in vitro evaluation demonstrated the ROS scavenging and anti-inflammatory capacity of Cu5.4O@CNDs. The therapeutic potential of Cu5.4O@CNDs was evaluated in vivo using mouse models of hepatic ischemia/reperfusion injury and LPS/D-GalN induced hepatitis, with transcriptome analysis conducted to clarify the mechanism underlying hepatoprotection. Results: The Cu5.4O@CNDs demonstrated superoxide dismutase (SOD) and catalase (CAT) enzyme activities, as well as hydroxyl radical (·OH) scavenging capabilities, effectively mitigating ROS in vitro. Furthermore, the Cu5.4O@CNDs exhibited remarkable targeting efficacy towards inflammation cells induced by H2O2 and hepatic tissues in murine models of hepatitis, alongside exhibiting favorable biocompatibility in both in vitro and in vivo settings. Moreover, it has been demonstrated that Cu5.4O@CNDs effectively scavenged ROS, thereby enhancing cell survival in vitro. Additionally, Cu5.4O@CNDs exhibited significant therapeutic efficacy in mice models of HIRI and lipopolysaccharide-induced acute lung injury (LPS-ALI). This efficacy was achieved through the modulation of the ROS response and hepatic inflammatory network, as well as the amelioration of disruptions in hepatic retinol metabolism. Conclusions: In summary, this study demonstrates that Cu5.4O@CNDs exhibit significant potential for the treatment of various acute liver injury conditions, suggesting their promise as an intervention strategy for clinical application.
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Affiliation(s)
- Jiayu Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yujie Zhang
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zhichao Deng
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yuanyuan Zhu
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Chenxi Xu
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Bowen Gao
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Wenlong Wang
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Zhengtao Xiao
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Mingzhen Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
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16
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Sanchez Vasquez JD, Nkongolo S, Traum D, Sotov V, Kim SC, Mahamed D, Mehrotra A, Patel A, Chen DY, Fung S, Gaggar A, Feld JJ, Chang KM, Wallin JJ, Wang BX, Janssen HL, Gehring AJ. Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver. J Clin Invest 2025; 135:e175241. [PMID: 40231469 PMCID: PMC11996867 DOI: 10.1172/jci175241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/17/2025] [Indexed: 04/16/2025] Open
Abstract
Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immune-tolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of patients with chronic hepatitis B who had active liver inflammation and were starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA-Seq mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and were unique from macrophage found in healthy or cirrhotic liver. iMacs retained their core transcriptional signature after inflammation resolved, indicating inflammation-mediated remodeling of the macrophage population in the human liver that may affect progressive liver disease and immunotherapy.
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Affiliation(s)
- Juan Diego Sanchez Vasquez
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, and
- Schwartz Reisman Liver Research Centre, University Health Network, Toronto, Ontario, Canada
| | - Shirin Nkongolo
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF), partner site Heidelberg, Germany
| | - Daniel Traum
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Valentin Sotov
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Deeqa Mahamed
- Centre for Advanced Single Cell Analysis, The Hospital for Sick Children, Toronto, Canada
| | - Aman Mehrotra
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, and
| | | | | | - Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, and
| | - Anuj Gaggar
- Gilead Sciences, Foster City, California, USA
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, and
| | - Kyong-Mi Chang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | | | - Ben X. Wang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Harry L.A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Adam J. Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, and
- Schwartz Reisman Liver Research Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Canada
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17
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Hong J, Kim YH. Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum. J Control Release 2025; 380:433-456. [PMID: 39923856 DOI: 10.1016/j.jconrel.2025.02.008] [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: 09/30/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.
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Affiliation(s)
- Juhyeong Hong
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea
| | - Yong-Hee Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea; Cursus Bio Inc., Icure Tower, Gangnam-gu, Seoul 06170, Republic of Korea.
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18
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Liu H, Yin G, Franco Leonardi B, Lan T, Ait Ahmed Y, Berger H, Kohlhepp MS, Amiridze N, Martagón Calderón N, Frau C, Vallier L, Rezvani M, Tacke F, Guillot A. Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming. Gut 2025:gutjnl-2024-334425. [PMID: 40199572 DOI: 10.1136/gutjnl-2024-334425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/25/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown. OBJECTIVE We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury. DESIGN Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 -/- mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used. RESULTS Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell stress and Orm2 expression, but also tended to promote fibrogenic activation of hepatic stellate cells. Mechanistically, ORM2 effects were mediated by an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway. CONCLUSION This study reveals a paracrine communication circuit during ductular reaction, in which reactive cholangiocyte-derived ORM2 reprogrammes liver macrophages, participating in a pathogenic remodelling of the immune biliary niche.
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Affiliation(s)
- Hanyang Liu
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
- Cell Biology and Imaging Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Guo Yin
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Bianca Franco Leonardi
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Tian Lan
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yeni Ait Ahmed
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Marlene Sophia Kohlhepp
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Natalja Amiridze
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Natalia Martagón Calderón
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Carla Frau
- BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ludovic Vallier
- BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Max-Planck-Institute for Molecular Genetics, Berlin, Germany
| | - Milad Rezvani
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany
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Wang Y, Sanyal AJ, Hylemon P, Ren S. Discovery of a novel regulator, 3β-sulfate-5-cholestenoic acid, of lipid metabolism and inflammation. Am J Physiol Endocrinol Metab 2025; 328:E543-E554. [PMID: 40047198 DOI: 10.1152/ajpendo.00426.2024] [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: 10/23/2024] [Revised: 11/04/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025]
Abstract
Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS/MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following the addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also be derived from 27HC. In comparison, 25HC was converted to 25HC3S, which mostly remained in the cells and nuclei. The functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of proinflammatory cytokines induced by lipopolysaccharide in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.NEW & NOTEWORTHY This study identifies a novel oxysterol metabolite, 3β-sulfate-5-cholestenoic acid (3SCA), secreted by hepatocytes, which regulates lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings reveal previously unknown metabolic pathways of mitochondrial oxysterols and their roles in the progression and recovery of metabolic dysfunction-associated steatotic liver disease (MASLD), offering novel insights into potential therapeutic targets.
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Affiliation(s)
- Yaping Wang
- Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Center, Richmond, Virginia, United States
| | - Arun J Sanyal
- Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Center, Richmond, Virginia, United States
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, Virginia, United States
| | - Phillip Hylemon
- Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Center, Richmond, Virginia, United States
- Department of Microbiology, Virginia Commonwealth University/McGuire VA Medical Center, Richmond, Virginia, United States
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, Virginia, United States
| | - Shunlin Ren
- Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Center, Richmond, Virginia, United States
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20
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Kathuria S, Gupta A, Tracy AR, Luna Ramirez RI, Thulasingam SK, Zaghloul N, Ahmed M, Limesand SW. Systemic inflammatory responses to repeated and increasing endotoxin challenges in fetal sheep. Physiol Rep 2025; 13:e70316. [PMID: 40268878 PMCID: PMC12018166 DOI: 10.14814/phy2.70316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/28/2025] [Accepted: 03/28/2025] [Indexed: 04/25/2025] Open
Abstract
Repeated low-dose administration of lipopolysaccharide (LPS) attenuates subsequent fetal responses, which makes it challenging to investigate interventions to prolonged exposure. Our aim was to develop a fetal inflammatory response syndrome (FIRS) model that consistently and effectively elicits a marked physiological response to increasing LPS doses. Four intravenous LPS boluses (0.3, 1.5, 3, and 15 μg) were administered to fetal sheep over 5 days. Physiological responses were measured via blood gases, pH, lactate, and cortisol concentrations. Fetal peripheral blood mononuclear cells (PBMCs) were analyzed for transcriptomic changes and tissue cytokine expression postmortem. All LPS challenges increased lactate, cortisol, and pCO2 concentrations and decreased pH and pO2 levels at 3 and 5 hours. No interaction was found between day (increasing LPS doses) and hour (LPS response to each dose). PBMC numbers increase with LPS challenges. Transcriptional analysis on PBMCs identified several enriched gene clusters indicating upregulation of inflammatory gene signatures along with complement activation and NFκB signaling pathways. Expression of pro-inflammatory cytokines (TNFα, IL-6, or IL-1β) was measured in lung, heart, liver, placenta, and spleen. Physiological indices show both respiratory and metabolic acidosis with successive and increasing LPS challenges that demonstrate a robust systemic response despite tachyphylaxis to LPS in fetal sheep.
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Affiliation(s)
- Sanya Kathuria
- School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
| | - Akash Gupta
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of ArizonaTucsonArizonaUSA
| | - Ayna R. Tracy
- School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
| | - Rosa I. Luna Ramirez
- School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
| | - Senthil Kumar Thulasingam
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of ArizonaTucsonArizonaUSA
| | - Nahla Zaghloul
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of ArizonaTucsonArizonaUSA
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Mohamed Ahmed
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of ArizonaTucsonArizonaUSA
- Division of Neonatology, Department of Pediatrics, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Sean W. Limesand
- School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
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21
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Santol J, Rajcic D, Ortmayr G, Hoebinger C, Baranovskyi TP, Rumpf B, Schuler P, Probst J, Aiad M, Kern AE, Ammann M, Jankoschek AS, Weninger J, Gruenberger T, Starlinger P, Hendrikx T. Soluble TREM2 reflects liver fibrosis status and predicts postoperative liver dysfunction after liver surgery. JHEP Rep 2025; 7:101226. [PMID: 40124168 PMCID: PMC11929072 DOI: 10.1016/j.jhepr.2024.101226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 03/25/2025] Open
Abstract
Background & Aims Triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophages and systemic levels of soluble TREM2 (sTREM2) appear critical in the development of chronic liver disease (CLD) and seem relevant in its detection. The aim of this study was to examine sTREM2 as a marker for early CLD and its potential to predict posthepatectomy liver failure (PHLF) in patients undergoing partial hepatectomy. Methods sTREM2 was assessed in the plasma of 108 patients undergoing liver resection. Blood was drawn prior to surgery (preop) and on the first and fifth postoperative day. Results Preop sTREM2 levels were similar across different indications for resection (p = 0.091). Higher preop sTREM2 levels were associated with advanced hepatic fibrosis (p = 0.030) and PHLF (p = 0.007). Fibrosis-4 index (FIB-4) (p = 0.619) and model for end-stage liver disease (MELD) (p = 0.590) did not show a difference between patients grouped by their CLD. Comparing the AUC from receiver-operating characteristic analysis, sTREM2 (AUC = 0.708) outperformed FIB-4 (AUC = 0.529), MELD (AUC = 0.587), Child-Pugh grading (AUC = 0.570) and LiMAx (liver maximum capacity test) (AUC = 0.516) in predicting PHLF. Similarly, in uni- and multivariate analysis, only sTREM2 proved predictive for PHLF (p = 0.023). High-risk (p = 0.003) and low-risk (p = 0.011) cut-offs for systemic sTREM2 levels could identify patients at risk for adverse outcomes after surgery. Finally, high sTREM2 was associated with decreased overall survival after liver surgery (p <0.001). Conclusions Circulating sTREM2 shows sensitivity for early-stage, asymptomatic liver disease, irrespective of the underlying indication for liver surgery. Assessment of CLD via sTREM2 monitoring could improve early detection of CLD and improve outcomes after liver surgery. Impact and implications Soluble TREM2 (sTREM2) has previously been shown to correlate with the degree of chronic liver disease. We found that even in patients undergoing liver resection, who generally do not suffer from end-stage liver disease, sTREM2 reflects liver fibrosis status and predicts postoperative development of liver dysfunction. This is especially relevant for liver surgeons and patients, as postoperative liver dysfunction is the main reason for postoperative mortality. Our findings are also important for hepatologists, as early detection of liver fibrosis and cirrhosis is paramount for overall patient survival and we can show that even in a cohort with a median model for end-stage liver disease score of 6, sTREM2 is able to distinguish patients based on their liver fibrosis status.
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Affiliation(s)
- Jonas Santol
- Department of Surgery, HPB Center, Vienna Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Dragana Rajcic
- Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Constanze Hoebinger
- Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria
| | - Taras P. Baranovskyi
- Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria
| | - Benedikt Rumpf
- Hospital Barmherzige Schwestern, Department of Surgery, Vienna, Austria
| | - Pia Schuler
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Joel Probst
- Department of Surgery, HPB Center, Vienna Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Monika Aiad
- Medical University of Vienna, Vienna, Austria
| | | | - Markus Ammann
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Surgery, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | | | | | - Thomas Gruenberger
- Department of Surgery, HPB Center, Vienna Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Patrick Starlinger
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna Austria
| | - Tim Hendrikx
- Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria
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22
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Fernandez Alarcon J, Perez Schmidt P, Panini N, Caruso F, Violatto MB, Sukubo NG, Martinez‐Serra A, Ekalle‐Soppo CB, Morelli A, Moscatiello GY, Grasselli C, Corbelli A, Fiordaliso F, Kelk J, Petrosilli L, d'Orazio G, Mateu Ferrando R, Verdaguer Ferrer A, Fornaguera C, Lay L, Fumagalli S, Recchia S, Monopoli MP, Polito L, Bigini P, Sitia G. Functional Polarization of Liver Macrophages by Glyco Gold Nanoparticles. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407458. [PMID: 39950558 PMCID: PMC12021048 DOI: 10.1002/advs.202407458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/24/2024] [Indexed: 04/26/2025]
Abstract
Macrophages are crucial drivers of innate immunity. Reprogramming macrophages to a restorative phenotype in cancer or autoimmune diseases can stop their cancer-promoting activity or trigger anti-inflammatory immunity. Glycans have emerged as key components for immunity as they are involved in many pathophysiological disorders. Previous studies have demonstrated that supraphysiological amounts of mannose (Man) or sialic acid (Sia) can inhibit tumor growth and stimulate differentiation of regulatory T cells. Man is known to affect glucose metabolism in glycolysis by competing for the same intracellular transporters and affecting macrophage polarization, whereas Sia alters macrophage differentiation via signaling through Siglec-1. Herein, this work describes a macrophage targeting platform using gold nanoparticles (GNPs) functionalized with Man and Sia monosaccharides which exhibit high liver tropism. A single dose of glyco-GNPs can convert macrophages to a restorative phenotype in two completely different immune environments. Man promotes tumor-associated macrophages toward an antitumorigenic activity in a MC38 liver colorectal cancer model by secretion of TNF-α, IL -1β, and IL -6 in the tumor microenvironment. However, in a proinflammatory environment, as observed in a mouse model of autoimmune disease, primary biliary cholangitis, Man impairs the production of TNF-α, IL-1β, Arg1, and IL-6 cytokines. The results probe the dual role of Man in macrophage repolarization in response to the immune system. This study is a proof-of-concept that demonstrates that nanomedicine using specific glycans designed to target other immune cells such as myeloid cells, are a promising strategy not only against cancer but also against other pathologies such as autoimmune diseases.
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Affiliation(s)
- Jennifer Fernandez Alarcon
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
- Grup d'Enginyeria de Materials (GEMAT)Institut Químic de Sarrià (IQS)Universitat Ramon Llull (URL)Via Augusta 390Barcelona08017Spain
| | - Patricia Perez Schmidt
- Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”SCITEC‐CNR, Via G. Fantoli 16/15Milano20138Italy
| | - Nicolo Panini
- Department of OncologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Francesca Caruso
- Experimental Hepatology UnitDivision of Immunology, Transplantation and Infectious DiseasesIRCCS San Raffaele Scientific InstituteVia Olgettina 58Milano20132Italy
| | - Martina B. Violatto
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Naths Grazia Sukubo
- School of Medicine and SurgeryUniversity of Milano‐BicoccaPiazza dell'Ateneo Nuovo1Milano20126Italy
| | - Alberto Martinez‐Serra
- Department of ChemistryRoyal College of Surgeons of Ireland RCSISt Stephens Green 123DublinIreland
| | - Charlotte Blanche Ekalle‐Soppo
- Experimental Hepatology UnitDivision of Immunology, Transplantation and Infectious DiseasesIRCCS San Raffaele Scientific InstituteVia Olgettina 58Milano20132Italy
| | - Annalisa Morelli
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Giulia Yuri Moscatiello
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Chiara Grasselli
- Department of OncologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Alessandro Corbelli
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Fabio Fiordaliso
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Joe Kelk
- Department of NeurosciencesIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Laura Petrosilli
- Department of Organic ChemistryUniversity degli Studi di MilanoVia Golgi 19Milano20133Italy
| | - Giuseppe d'Orazio
- Department of Organic ChemistryUniversity degli Studi di MilanoVia Golgi 19Milano20133Italy
| | - Ruth Mateu Ferrando
- Department of Organic ChemistryUniversity degli Studi di MilanoVia Golgi 19Milano20133Italy
| | - Ariadna Verdaguer Ferrer
- Department of Analytical and Applied ChemistryInstitut Químic de Sarrià (IQS)Universitat Ramon Llull (URL)Via Augusta 390Barcelona08017Spain
| | - Cristina Fornaguera
- Grup d'Enginyeria de Materials (GEMAT)Institut Químic de Sarrià (IQS)Universitat Ramon Llull (URL)Via Augusta 390Barcelona08017Spain
| | - Luigi Lay
- Department of Organic ChemistryUniversity degli Studi di MilanoVia Golgi 19Milano20133Italy
| | - Stefano Fumagalli
- Department of NeurosciencesIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Sandro Recchia
- Department of Science and High TechnologyUniversity of InsubriaVia Valleggio 11Como22100Italy
| | - Marco P. Monopoli
- Department of ChemistryRoyal College of Surgeons of Ireland RCSISt Stephens Green 123DublinIreland
| | - Laura Polito
- Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”SCITEC‐CNR, Via G. Fantoli 16/15Milano20138Italy
| | - Paolo Bigini
- Department of Molecular Biochemistry and PharmacologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSVia Mario Negri 2Milano20156Italy
| | - Giovanni Sitia
- Experimental Hepatology UnitDivision of Immunology, Transplantation and Infectious DiseasesIRCCS San Raffaele Scientific InstituteVia Olgettina 58Milano20132Italy
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23
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Jiang B, Yang J, Huang Q, Li W, Peng Q, Gan H, Peng T, Yao L, Qi L. Schisandrin B downregulates exosomal fibronectin 1 expression to inhibit hepatocellular carcinoma growth. Front Pharmacol 2025; 16:1547685. [PMID: 40223922 PMCID: PMC11986357 DOI: 10.3389/fphar.2025.1547685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/10/2025] [Indexed: 04/15/2025] Open
Abstract
Introduction In recent years, natural compounds have attracted wide attention for the treatment of liver cancer due to their therapeutic potential and reduced toxicity. Among these, Schisandrin B (Sch B), a primary bioactive component derived from Schisandra chinensis, has shown notable antitumor activity; however, its specific mechanism remains unclear. Methods The effect of Sch B on the growth of hepatocellular carcinoma(HCC) cells were assessed using CCK-8 assay, colony formation assay and EdU assay, and apoptosis was detected by flow cytometry. The co-culture system of macrophages and HCC cells was established to detect the effect of Sch B on the cell viability and cell cycle changes of HCC cells in the co-culture system. Then, the migration of HCC cells in the co-culture system was studied using a subtoxic concentration of Sch B. Exosomes of the co-culture system with or without Sch B effect were collected for identification and protein spectrum analysis. The differential protein was analyzed by KEGG enrichment analysis and protein interaction network, which was verified by western blotting. Meanwhile, the expression changes of macrophage polarization markers were detected. Finally, the inhibitory effect of Sch B on HCC and the changes of FN1 were verified by in vivo experiments. Results Sch B inhibited HCC cell growth; moreover, it significantly suppressed HCC cell proliferation in the co-culture system and induced S-phase cell cycle arrest by downregulating CDK4, CDK2, and cyclin A2 while upregulating p27 Kip1. Additionally, Sch B inhibited the migration of HCC cells in the co-culture system.The differentially expressed protein fibronectin 1(FN1) in liver cancer patients was higher than that in healthy people. Moreover, after SchB treatment, the expression of FN1 protein in exosomes decreased and the macrophages exhibited M1 polarization. In vivo experiments also verified that Sch B inhibited HCC growth and downregulated the expression of FN1 protein in tumor tissues. Conclusion Sch B may inhibit the development of HCC by inhibiting the expression of exosomal FN1during interactions between macrophages and HCC cells.
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Affiliation(s)
- Baoyi Jiang
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
| | - Jie Yang
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
| | - Qingtian Huang
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
- Department of Pathology, The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guang Dong, China
| | - Wei Li
- Biological Sample Resource Centre, The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guang Dong, China
| | - Qian Peng
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
| | - Huoye Gan
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
| | - Tieli Peng
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
| | - Leyi Yao
- Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
| | - Ling Qi
- Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China
- Biological Sample Resource Centre, The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guang Dong, China
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24
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Bouma RG, Wang AZ, den Haan JMM. Exploring CD169 + Macrophages as Key Targets for Vaccination and Therapeutic Interventions. Vaccines (Basel) 2025; 13:330. [PMID: 40266235 PMCID: PMC11946325 DOI: 10.3390/vaccines13030330] [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: 02/20/2025] [Revised: 03/12/2025] [Accepted: 03/17/2025] [Indexed: 04/24/2025] Open
Abstract
CD169 is a sialic acid-binding immunoglobulin-like lectin (Siglec-1, sialoadhesin) that is expressed by subsets of tissue-resident macrophages and circulating monocytes. This receptor interacts with α2,3-linked Neu5Ac on glycoproteins as well as glycolipids present on the surface of immune cells and pathogens. CD169-expressing macrophages exert tissue-specific homeostatic functions, but they also have opposing effects on the immune response. CD169+ macrophages act as a pathogen filter, protect against infectious diseases, and enhance adaptive immunity, but at the same time pathogens also exploit them to enable further dissemination. In cancer, CD169+ macrophages in tumor-draining lymph nodes are correlated with better clinical outcomes. In inflammatory diseases, CD169 expression is upregulated on monocytes and on monocyte-derived macrophages and this correlates with the disease state. Given their role in promoting adaptive immunity, CD169+ macrophages are currently investigated as targets for vaccination strategies against cancer. In this review, we describe the studies investigating the importance of CD169 and CD169+ macrophages in several disease settings and the vaccination strategies currently under investigation.
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Affiliation(s)
- Rianne G. Bouma
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Cancer Immunology, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
| | - Aru Z. Wang
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Cancer Immunology, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
| | - Joke M. M. den Haan
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Cancer Immunology, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
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25
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Livingstone EJ, Cartwright JA, Campana L, Lewis PJS, Dwyer BJ, Aird R, Man TY, Vermeren M, Rossi AG, Boulter L, Forbes SJ. Semaphorin 7a is protective through immune modulation during acetaminophen-induced liver injury. J Inflamm (Lond) 2025; 22:13. [PMID: 40114253 PMCID: PMC11927371 DOI: 10.1186/s12950-025-00429-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/13/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND AND AIM Acetaminophen (APAP) induced acute liver injury (ALI), the leading cause acute liver failure in the western world, has limited treatment options. APAP toxicity results in massive hepatic necrosis and secondary infiltrating monocytes and neutrophils, which contribute to pathogenesis. Semaphorin 7a (Sema7a), a chemoattractant and modulator of monocytes and neutrophils, is a potential therapeutic target in other conditions, but its role in APAP-ALI is unexplored. METHODS Wild-type (WT) and Sema7a knockout (KO) mice were examined during APAP-ALI. Serum liver function tests, histological analysis and cellular localisation of Sema7a and its receptors, Plexin C1 and Integrin β1, were examined. Serum cytokines were quantified, tissue macrophages and neutrophils were localised, and in vivo phenotype, including phagocytosis, was assessed by immunohistochemistry and flow cytometry. RESULTS Sema7a was expressed by HNF4α + peri-necrotic hepatocytes circumferentially during APAP-ALI injury phases, and serum concentrations were increased, and correlated with hepatic injury. Sema7a KO mice had increased circulating inflammatory cytokines and significantly less hepatic F4/80 + macrophages, a cell type required for hepatic repair. Sema7a KO mice had higher necrotic area neutrophils, and increased neutrophil chemoattractant CXCL1. Without Sema7a expression, mice displayed increased necrosis and liver injury markers compared to Sema7a WT mice. Without peri-necrotic hepatocyte Sema7a expression, we also identified increased cell death and hepatic cellular stress outside of necrosis. CONCLUSION We have identified a novel protective role of Sema7a during injury phases of APAP-ALI. Without peri-necrotic hepatocyte Sema7a expression and secretion, there is increased inflammation, time specific worsened hepatic necrosis and increased hepatic cell stress and death outside of the necrotic zone.
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Affiliation(s)
- Eilidh J Livingstone
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Jennifer A Cartwright
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
- The Royal (Dick) School of Veterinary Studiesand Theaq , Roslin Institute, University of Edinburgh, Edinburgh, UK.
| | - Lara Campana
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Philip J Starkey Lewis
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Benjamin J Dwyer
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Rhona Aird
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Tak Yung Man
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Matthieu Vermeren
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Adriano Giorgio Rossi
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Stuart John Forbes
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
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Ran R, Uslu M, Siddiqui MF, Brubaker DK, Trapecar M. Single-Cell Analysis Reveals Tissue-Specific T Cell Adaptation and Clonal Distribution Across the Human Gut-Liver-Blood Axis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.11.642626. [PMID: 40161783 PMCID: PMC11952442 DOI: 10.1101/2025.03.11.642626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Understanding T cell clonal relationships and tissue-specific adaptations is crucial for deciphering human immune responses, particularly within the gut-liver axis. We performed paired single-cell RNA and T cell receptor sequencing on matched colon (epithelium, lamina propria), liver, and blood T cells from the same human donors. This approach tracked clones across sites and assessed microenvironmental impacts on T cell phenotype. While some clones were shared between blood and tissues, colonic intraepithelial lymphocytes (IELs) exhibited limited overlap with lamina propria T cells, suggesting a largely resident population. Furthermore, tissue-resident memory T cells (TRM) in the colon and liver displayed distinct transcriptional profiles. Notably, our analysis suggested that factors enriched in the liver microenvironment may influence the phenotype of colon lamina propria TRM. This integrated single-cell analysis maps T cell clonal distribution and adaptation across the gut-liver-blood axis, highlighting a potential liver role in shaping colonic immunity.
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Affiliation(s)
- Ran Ran
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Merve Uslu
- Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
| | - Mohd Farhan Siddiqui
- Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
| | - Douglas K. Brubaker
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH
- The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH
| | - Martin Trapecar
- Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
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Nakamura T, Masuda A, Nakano D, Amano K, Sano T, Nakano M, Kawaguchi T. Pathogenic Mechanisms of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Associated Hepatocellular Carcinoma. Cells 2025; 14:428. [PMID: 40136677 PMCID: PMC11941585 DOI: 10.3390/cells14060428] [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: 12/19/2024] [Revised: 02/25/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths worldwide. The etiology of HCC has now dramatically changed from viral hepatitis to metabolic dysfunction-associated steatotic liver disease (MASLD). The main pathogenesis of MASLD-related HCC is the hepatic lipid accumulation of hepatocytes, which causes chronic inflammation and the subsequent progression of hepatic fibrosis. Chronic hepatic inflammation generates oxidative stress and DNA damage in hepatocytes, which contribute to genomic instability, resulting in the development of HCC. Several metabolic and molecular pathways are also linked to chronic inflammation and HCC in MASLD. In particular, the MAPK and PI3K-Akt-mTOR pathways are upregulated in MASLD, promoting the survival and proliferation of HCC cells. In addition, MASLD has been reported to enhance the development of HCC in patients with chronic viral hepatitis infection. Although there is no approved medication for MASLD besides resmetirom in the USA, there are some preventive strategies for the onset and progression of HCC. Sodium-glucose cotransporter-2 (SGLT2) inhibitor, a class of medications, has been reported to exert anti-tumor effects on HCC by regulating metabolic reprogramming. Moreover, CD34-positive cell transplantation improves hepatic fibrosis by promoting intrahepatic angiogenesis and supplying various growth factors. Furthermore, exercise improves MASLD through an increase in energy consumption as well as changes in chemokines and myokines. In this review, we summarize the recent progress made in the pathogenic mechanisms of MASLD-associated HCC. Furthermore, we introduced new therapeutic strategies for preventing the development of HCC based on the pathogenesis of MASLD.
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Affiliation(s)
- Toru Nakamura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume 830-0011, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
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Zhang X, Zhang J, Xun G, Gao Y, Zhao J, Fu Y, Su S, Kong D, Wang Q, Wang X. Alleviation effect of macrophage depletion on hepatotoxicity of triptolide: A new insight based on metabolomics and proteomics. JOURNAL OF ETHNOPHARMACOLOGY 2025; 343:119485. [PMID: 39947369 DOI: 10.1016/j.jep.2025.119485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 12/14/2024] [Accepted: 02/10/2025] [Indexed: 02/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Triptolide (TP) is an abietane-type diterpenoid isolated from the traditional Chinese herb Tripterygium wilfordii Hook. F, which is used to relieve rheumatism, alleviate joint pain and swelling, and promote blood circulation for more than 600 years in China. The most common preparations containing TP from Tripterygium wilfordii Hook F, which are Tripterygium tablets and Tripterygium glycoside tablets, are widely used in clinical for treating rheumatoid arthritis and other autoimmune diseases at present. However, the clinical application is hindered by severe systemic toxicity induced by TP, especially hepatotoxicity. It is crucial to discover potent and specific detoxification strategy for TP. AIM OF STUDY According to our previous study, TP-induced hepatotoxicity is primarily related to macrophages. This study aimed to investigate the alleviation effects of macrophage depletion on the TP-induced liver injury in mice and to explore the related mechanisms by integration of metabolomics and proteomics. MATERIALS AND METHODS Mice were treated with clodronate liposomes to deplete macrophage before administration of triptolide. The alleviation effects were evaluated by biochemical analysis of serum and histopathology observation of the hepatic tissues. Metabolomics and proteomics were carried out to explore the mechanism of macrophage depletion on triptolide-induced liver injury. The levels of mRNA and protein of TLR4- MyD88-NF-κB axis were further detected. RESULTS The altered levels of biochemistry indicators, including aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), and γ-glutamyltranspeptidase (GGT) were significantly recovered, and histopathological liver injury also showed restoring tendency in mice with macrophage depletion compared to mice with TP-treatment. The inflammation indicator interleukin-6 (IL-6) and interleukin-1β (IL-1β) were recovered significantly after depletion of macrophage. Results of metabolomics and proteomics demonstrated that macrophage depletion exerted protective effects on triptolide-induced liver injury by regulating 85 metabolites and 202 proteins. Joint analysis of multi-omics data suggested macrophage depletion could regulate lipid metabolism and maintain inflammatory homeostasis. The increased expression of NF-κB, TLR4, and MyD88 were decreased after depletion of macrophage. CONCLUSION TP-induced hepatotoxicity is mainly associated with dysfunction of macrophages and imbalance of inflammatory homeostasis. The findings of this study may help facilitate the development of novel therapeutic strategies.
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Affiliation(s)
- Xiaoguang Zhang
- Core Facilities and Centers, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Jia Zhang
- School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Ge Xun
- School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Yanhua Gao
- School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, PR China
| | - Jie Zhao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Yan Fu
- Core Facilities and Centers, Hebei Medical University, Shijiazhuang, Hebei, PR China; School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Suwen Su
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Dezhi Kong
- Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Qiao Wang
- School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China.
| | - Xu Wang
- School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei, PR China.
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Airola C, Varca S, Del Gaudio A, Pizzolante F. The Covert Side of Ascites in Cirrhosis: Cellular and Molecular Aspects. Biomedicines 2025; 13:680. [PMID: 40149656 PMCID: PMC11940454 DOI: 10.3390/biomedicines13030680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/25/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin-angiotensin-aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. Inflammation, mediated by cytokines (interleukin-1, interleukin-4, interleukin-6, tumor necrosis factor-α), chemokines (chemokine ligand 21, C-X-C motif chemokine ligand 12), and reactive oxygen species (ROS), plays a pivotal role. Besides pro-inflammatory cytokines, hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and smooth muscle cells (SMCs) contribute to the process through their activation and altered functions. Once activated, these cell types can worsen ascites accumulationthrough extracellular matrix (ECM) deposition and paracrine signals. Besides this, macrophages, both resident and infiltrating, through their plasticity, participate in this complex crosstalk by promoting inflammation and dysregulating lymphatic system reabsorption. Indeed, the lymphatic system and lymphangiogenesis, essential for fluid reabsorption, is dysregulated in cirrhosis, exacerbating ascites. The gut microbiota and intestinal barrier alterations which occur in cirrhosis and portal hypertension also play a role by inducing inflammation, creating a vicious circle which worsens portal hypertension and fluid accumulation. This review aims to gather these aspects of ascites pathophysiology which are usually less considered and to date have not been addressed using specific therapy. Nonetheless, it emphasizes the need for further research to understand the complex interactions among these mechanisms, ultimately leading to targeted interventions in specific molecular pathways, aiming towards the development of new therapeutic strategies.
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Affiliation(s)
- Carlo Airola
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Simone Varca
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Angelo Del Gaudio
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Fabrizio Pizzolante
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
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Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y, Liu Z, Xia Z, Zhang H, Cheng Q. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther 2025; 10:93. [PMID: 40055311 PMCID: PMC11889221 DOI: 10.1038/s41392-025-02124-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/01/2024] [Accepted: 12/15/2024] [Indexed: 05/04/2025] Open
Abstract
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
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Affiliation(s)
- Fan Guan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruixuan Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyao Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yao Xie
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, China.
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Ghosh C, Kundu T, Pathak T, Saini S, Das N, Saini S, Sircar D, Kumar P, Roy P. Indian lychee honey ameliorates hepatic glucose uptake by regulating the ChREBP/Glut4 axis under insulin-resistant conditions. Food Funct 2025; 16:2031-2056. [PMID: 39963045 DOI: 10.1039/d4fo03900a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed in vitro in palmitic acid-induced insulin-resistant HepG2 cells. Various assays, such as FACS, GCMS, qRT-PCR, immunoblot and ChIP-qPCR, were performed to establish the anti-hyperglycaemic role of LyH in vitro. The in vitro results were subsequently confirmed in vivo using a high-fat diet-induced diabetic C57BL/6 mice model. The in vivo study was supported by several experiments, such as examining blood parameters, histopathology, double-immunohistochemistry and ELISA. Finally, the finding was validated by comparing it with a couple of GEO datasets from the NCBI database. This study found that LyH is an excellent choice for regulating blood sugar levels under diabetic conditions without significant harmful side effects. Moreover, LyH showed excellent hepatic glucose uptake activity in an insulin-independent manner. This activity is mainly governed by sugars as its main ingredient. LyH treatment also regulates hepatic lipid homeostasis by maintaining a balance between saturated and unsaturated fatty acids in insulin-resistant HepG2 cells. Further, sugar, when supplemented individually, caused severe inflammation, which was validated through histopathology, ELISA and IHC. Collectively, the findings of this study indicate that Indian LyH provides a better food matrix (the right proportion of sugars and different bioactive compounds), which significantly improves hyperglycemia and inflammation under diabetic conditions by regulating the hepatic ChREBP/Glut4 axis.
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Affiliation(s)
- Chandrachur Ghosh
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Tathagata Kundu
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Tiyasa Pathak
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Saakshi Saini
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Neeladrisingha Das
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Surendra Saini
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
| | - Debabrata Sircar
- Plant Molecular Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India
| | - Prabhat Kumar
- National Bee Board, DA & FW, Ministry of Agriculture and Farmers Welfare, B Wing, 2nd Floor, Janpath Bhawan, Janpath, New Delhi - 110 001, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
- Center for Indian Knowledge Systems, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India
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Entsie P, Amoafo EB, Kang Y, Gustad T, Dorsam GP, Frey MR, Liverani E. Sex-specific activation of platelet purinergic signaling is key in local cytokine release and phagocytosis in the peritoneal cavity in intra-abdominal sepsis. Am J Physiol Cell Physiol 2025; 328:C791-C805. [PMID: 39854048 DOI: 10.1152/ajpcell.00116.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/07/2024] [Accepted: 01/17/2025] [Indexed: 01/26/2025]
Abstract
Intra-abdominal sepsis is a life-threatening complex syndrome caused by microbes in the gut microbiota invading the peritoneal cavity. It is one of the major complications of intra-abdominal surgery. To date, only supportive therapies are available. No studies have investigated the progression of intra-abdominal sepsis in the peritoneal cavity. Our group has shown that platelets play an essential role during sepsis, and blocking purinergic signaling in platelets through P2Y1 and P2Y12 antagonism significantly lowered inflammatory levels and improved survival in a murine model of sepsis. Here, we tested whether antagonizing purinergic signaling in platelets in the peritoneal cavity can reduce the local release of cytokines and modulate platelet interaction with the immune system. We used cecal ligation and puncture (CLP) to induce sepsis followed by intraperitoneal administration of MRS2279 (P2Y1 antagonist) or ticagrelor (P2Y12 antagonist) in male and female mice. The peritoneal cavity fluid (PCF) was collected 4 or 24 h post-CLP and analyzed for cell recruitment, platelet markers, cytokines, and platelet immune cell interactions. Platelet markers were increased 24 h after CLP, although the total platelet count in the peritoneal cavity was lower than the blood. Blocking P2Y12 or P2Y1 improved bacterial clearance in the PCF in a sex-dependent manner. The influx of immune cells in the peritoneal cavity was altered by blocking P2Y12 or P2Y1 sex-dependently. Blocking P2Y1 and P2Y12 receptors can enhance the phagocytic activity in the peritoneal cavity in a sex- and time-related manner, and platelets significantly contribute to the development and progression of sepsis in the peritoneal cavity.NEW & NOTEWORTHY Intra-abdominal sepsis is a challenging complication postabdominal surgery caused by perforations of the gastrointestinal tract where microbes invade the peritoneal cavity. This leads to local cytokine release and immune cell dysfunction. Our data identify platelets as key players in mediating inflammation in intra-abdominal sepsis. We have shown that blocking purinergic signaling in the peritoneal cavity reduced cytokine release and cell-cell interactions differently in males and females, hence a sex-specific strategy to improve intra-abdominal sepsis.
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Affiliation(s)
- Philomena Entsie
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota, United States
| | - Emmanuel Boadi Amoafo
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota, United States
| | - Ying Kang
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota, United States
| | - Thomas Gustad
- Department of Microbiological Sciences, College of Agriculture, Food Systems and Natural Resources, North Dakota State University, Fargo, North Dakota, United States
| | - Glenn P Dorsam
- Department of Microbiological Sciences, College of Agriculture, Food Systems and Natural Resources, North Dakota State University, Fargo, North Dakota, United States
| | - Mark R Frey
- Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
| | - Elisabetta Liverani
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota, United States
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Park JS, Ma YQ, Wang F, Ma H, Sui G, Rustamov N, Han M, Son Y, Park CW, Han SB, Hong JT, Jeong LS, Lee J, Roh YS. A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution. Metabolism 2025; 164:156114. [PMID: 39732364 DOI: 10.1016/j.metabol.2024.156114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD. APPROACH & RESULTS A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4'-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects. CONCLUSIONS This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.
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Affiliation(s)
- Jeong-Su Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Yuan-Qiang Ma
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Feng Wang
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Hwan Ma
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Guoyan Sui
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Nodir Rustamov
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Minyeong Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Yejin Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Chun-Woong Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea
| | - Lak Shin Jeong
- Research and Development Center, Future Medicine Co., Ltd, Seongnam, South Korea; College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Jin Lee
- Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Yoon Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, South Korea.
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Chen S, Ma T, Hu M, Li R, Lu D, Jin Y, Zhang M, Huang Y, Li Y, Liu T, Liu W. Common immunotoxicity mechanisms of hepatotoxicity induced by raw Polygonum multiflorum and Polygonum multiflorum praeparata: Inhibition of M2 macrophage polarization. Toxicon 2025; 257:108293. [PMID: 39999927 DOI: 10.1016/j.toxicon.2025.108293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/17/2025] [Accepted: 02/22/2025] [Indexed: 02/27/2025]
Abstract
Macrophage polarization has been linked to hepatotoxicity induced by raw Polygonum multiflorum (RPM) and Polygonum multiflorum praeparata (PMP), but the regulatory mechanisms behind this remain unclear. This study aims to investigate the regulatory effects of RPM and PMP on M2 macrophages and the potential mechanisms. Sprague-Dawley rats were exposed to RPM and PMP under lipopolysaccharide (LPS) stimulation. RAW264.7 cells induced with IL-4 were treated with RPM and PMP. Under LPS stimulation, both RPM and PMP increased serum enzyme levels and pro-inflammatory factor levels and induced histopathological injury. M1 macrophage infiltration and M1 gene expression in the liver increased, whereas M2 macrophage infiltration and M2 gene expression decreased. RPM and PMP inhibited M2 gene expression and reduced green fluorescence intensity. RNA sequencing and metabolomics revealed that RPM regulated sphingolipid signaling and Janus kinase/signal transducer and activator of transcription signaling pathways, while PMP influenced arginine and proline metabolism, arginine biosynthesis, and cholesterol metabolism pathways. RPM and PMP orchestrate distinct signaling pathways, thereby inhibiting M2 macrophage polarization and inducing hepatotoxicity. This study not only elucidates the pathophysiology underlying RPM- and PMP-induced hepatotoxicity, but also provides insights for the development of new therapeutic interventions.
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Affiliation(s)
- Shuaishuai Chen
- Guizhou Institute of Precision Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550009, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China; School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China
| | - Taotao Ma
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China; School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China
| | - Minmin Hu
- School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China
| | - Ruixi Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China
| | - Dingyan Lu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China
| | - Yang Jin
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China
| | - Mingliang Zhang
- Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450003, China
| | - Yong Huang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China
| | - Yongjun Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China; School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China.
| | - Ting Liu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China; School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China.
| | - Wen Liu
- Guizhou Institute of Precision Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550009, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Guizhou Medical University, Guian New Area, 561113, China; School of Pharmacy, Guizhou Medical University, Guian New Area, 561113, China.
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Zimmermann A, Scheffschick A, Hänsel R, Borchardt H, Liu JL, Ehnert S, Schicht G, Seidemann L, Aigner A, Schiffmann S, Nüssler A, Seehofer D, Damm G. A new human autologous hepatocyte/macrophage co-culture system that mimics drug-induced liver injury-like inflammation. Arch Toxicol 2025; 99:1167-1185. [PMID: 39710784 PMCID: PMC11821741 DOI: 10.1007/s00204-024-03943-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/11/2024] [Indexed: 12/24/2024]
Abstract
The development of in vitro hepatocyte cell culture systems is crucial for investigating drug-induced liver injury (DILI). One prerequisite for monitoring DILI related immunologic reactions is the extension of primary human hepatocyte (PHH) cultures towards the inclusion of macrophages. Therefore, we developed and characterized an autologous co-culture system of PHH and primary human hepatic macrophages (hepM) (CoC1). We compared CoC1 with a co-culture of the same PHH batch + M0 macrophages derived from THP1 cells (CoC2) in order to represent a donor independent macrophage reaction. Then, we treated the mono- and co-cultures with drugs that cause DILI-menadione (MEN, 1 or 10 µM, 3 h), diclofenac (DIC, 0.5 or 5 mM, 6 h), or acetaminophen (APAP, 0.5 or 5 mM, 6 h)-and assessed culture stability, cell activity, macrophage differentiation, cytokine production and cell viability. Without drug treatment, CoC1 was the most stable over a culture time of up to 60 h. Cytokine array analysis revealed a proinflammatory profile of PHH mono-cultures due to isolation stress but showed different influences of hepM and M0 on the cytokine profile in the co-cultures. MEN, DIC and APAP treatment led to donor-dependent signs of cell stress and toxicity. HepM can either promote or reduce the DILI effects donor dependently in CoC1. CoC2 are slightly less sensitive than CoC1 in representing DILI. In summary, we present a new autologous co-culture system that can mimic DILI in a donor-dependent manner. This cellular system could be useful for new drug testing strategies and reducing animal testing.
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Affiliation(s)
- Andrea Zimmermann
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany
| | - Andrea Scheffschick
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany
| | - René Hänsel
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Leipzig University, Leipzig, Germany
| | - Hannes Borchardt
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Jia Li Liu
- Department of General, Visceral- and Transplantation Surgery, Charité - University Medicine Berlin, Berlin, Germany
| | - Sabrina Ehnert
- Department of Traumatology, BG Trauma Center, University of Tübingen, Tübingen, Germany
| | - Gerda Schicht
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany
| | - Lena Seidemann
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Susanne Schiffmann
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt Am Main, Germany
| | - Andreas Nüssler
- Department of Traumatology, BG Trauma Center, University of Tübingen, Tübingen, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany
- Department of General, Visceral- and Transplantation Surgery, Charité - University Medicine Berlin, Berlin, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic and Polyclinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany.
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Germany.
- Department of General, Visceral- and Transplantation Surgery, Charité - University Medicine Berlin, Berlin, Germany.
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Lu J, Wu H, Wu S, Wang S, Fan H, Ruan H, Qiao J, Caiyin Q, Wen M. Salmonella: Infection mechanism and control strategies. Microbiol Res 2025; 292:128013. [PMID: 39675139 DOI: 10.1016/j.micres.2024.128013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
Salmonella is a foodborne pathogen that predominantly resides in the intestinal tract of humans and animals. Infections caused by Salmonella can lead to various illnesses, including gastroenteritis, bacteremia, septicemia, and focal infections, with severe cases potentially resulting in host mortality. The mechanisms by which Salmonella invades host cells and disseminates throughout the body are partly understood, but there are still many scientific questions to be solved. This review aims to synthesize existing research on the interactions between Salmonella and hosts, detailing a comprehensive infection mechanism from adhesion and invasion to intracellular propagation and systemic spread. Overuse of antibiotics contributes to the emergence of drug-resistant Salmonella strains. An in-depth analysis of the mechanism of Salmonella infection will provide a theoretical basis for the development of novel Salmonella control strategies. These innovative control strategies include antibiotic adjuvants, small molecules, phages, attenuated vaccines, and probiotic therapies, which show huge potential in controlling Salmonella infection.
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Affiliation(s)
- Juane Lu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Hao Wu
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing 312300, China; School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Shengbo Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing 312300, China
| | - Shengli Wang
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing 312300, China
| | - Hongfei Fan
- Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300072, China
| | - Haihua Ruan
- Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300072, China
| | - Jianjun Qiao
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing 312300, China; Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Qinggele Caiyin
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China.
| | - Mingzhang Wen
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing 312300, China; Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, China.
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Sasaki K, Rooge S, Gunewardena S, Hintz JA, Ghosh P, Pulido Ruiz IA, Yuquimpo K, Schonfeld M, Mehta H, Stevenson HL, Saldarriaga OA, Arroyave E, Tikhanovich I, Wozniak AL, Weinman SA. Kupffer cell diversity maintains liver function in alcohol-associated liver disease. Hepatology 2025; 81:870-887. [PMID: 38687563 PMCID: PMC11616785 DOI: 10.1097/hep.0000000000000918] [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: 09/12/2023] [Accepted: 04/12/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIMS Liver macrophages are heterogeneous and play an important role in alcohol-associated liver disease (ALD) but there is limited understanding of the functions of specific macrophage subsets in the disease. We used a Western diet alcohol (WDA) mouse model of ALD to examine the hepatic myeloid cell compartment by single cell RNAseq and targeted KC ablation to understand the diversity and function of liver macrophages in ALD. APPROACH AND RESULTS In the WDA liver, KCs and infiltrating monocytes/macrophages each represented about 50% of the myeloid pool. Five major KC clusters all expressed genes associated with receptor-mediated endocytosis and lipid metabolism, but most were predicted to be noninflammatory and antifibrotic with 1 minor KC cluster having a proinflammatory and extracellular matrix degradation gene signature. Infiltrating monocyte/macrophage clusters, in contrast, were predicted to be proinflammatory and profibrotic. In vivo, diphtheria toxin-based selective KC ablation during alcohol exposure resulted in a liver failure phenotype with increases in PT/INR and bilirubin, loss of differentiated hepatocyte gene expression, and an increase in expression of hepatocyte progenitor markers such as EpCAM, CK7, and Igf2bp3. Gene set enrichment analysis of whole-liver RNAseq from the KC-ablated WDA mice showed a similar pattern as seen in human alcoholic hepatitis. CONCLUSIONS In this ALD model, KCs are anti-inflammatory and are critical for the maintenance of hepatocyte differentiation. Infiltrating monocytes/macrophages are largely proinflammatory and contribute more to liver fibrosis. Future targeting of specific macrophage subsets may provide new approaches to the treatment of liver failure and fibrosis in ALD.
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Affiliation(s)
- Kyo Sasaki
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sheetalnath Rooge
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Janice Averilla Hintz
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Priyanka Ghosh
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | | | - Kyle Yuquimpo
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Heer Mehta
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Esteban Arroyave
- Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ann L Wozniak
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
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Pudgerd A, Pluangnooch P, Soontrapa K, Saedan S, Vanichviriyakit R, Sridurongrit S. Macrophage expression of constitutively active TβRI alleviates hepatic injury in a mouse model of concanavalin A-induced autoimmune hepatitis. Heliyon 2025; 11:e42691. [PMID: 40040984 PMCID: PMC11876931 DOI: 10.1016/j.heliyon.2025.e42691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 03/06/2025] Open
Abstract
Transforming growth factor-β (Tgf-β) contributes to the development of liver diseases through its regulation of various cell types. While Tgf-β signaling to hepatic stellate cells (HSCs) and hepatocytes was shown to mediate hepatic damage, the effect of Tgf-β on other cells in liver is yet to be clearly defined. Herein we identified a regulatory function of macrophage Tgf-β signaling in liver injury. We found that transgenic mice expressing constitutively active Tgf-β receptor type I (TβRI CA ) under the control of Fsp1-Cre (TβRI CA /Fsp1-Cre mice) were less susceptible to concanavalin A (conA)-induced autoimmune hepatitis. Liver tissue examination showed a decrease of necrotic area in conA-treated TβRI CA /Fsp1-Cre liver compared to those of wild-type mice. Blood test revealed that serum aminotransferases were significantly reduced in conA-treated TβRI CA /Fsp1-Cre mice as compared to those of wild-type mice. Immunohistochemistry for CD3 and myeloperoxidase demonstrated that there was a decreased accumulation of T cells and neutrophils, respectively, whereas ELISA showed that IL-4, IL-5, IL-10, IL-12 and IFN-γ was increased in livers of conA-treated TβRI CA /Fsp1-Cre mice. Alternatively activated macrophage (M2) polarization was significantly elevated in livers of conA-treated TβRI CA /Fsp1-Cre mice as indicated by enhanced hepatic expression of CCR2 and CD206 as well as increased numbers of liver macrophages expressing M2 subtype marker, CD163. qPCR analysis indicated an increased expression of TβRI CA , Arg1, Ym1, CD206, Snail1, Foxo1 and IRF4 as well as a decreased expression of MHC class II and CD1d in liver macrophages that were isolated from TβRI CA /Fsp1-Cre mice. Moreover, flow cytometry analysis showed a lower number of NKT cells in livers of conA-treated TβRI CA /Fsp1-Cre mice when compared to those of wild-type mice. In conclusion, Fsp1-Cre-mediated expression of TβRI CA lead to a decreased conA-induced liver injury that was associated with enhanced M2 macrophage polarization and reduced NKT cell recruitment.
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Affiliation(s)
- Arnon Pudgerd
- Division of Anatomy, School of Medical Science, University of Phayao, Phayao, 56000, Thailand
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (Centex Shrimp), Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand
| | - Panwadee Pluangnooch
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Kitipong Soontrapa
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Sukanya Saedan
- Division of Anatomy, School of Medical Science, University of Phayao, Phayao, 56000, Thailand
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (Centex Shrimp), Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand
| | - Rapeepun Vanichviriyakit
- Division of Anatomy, School of Medical Science, University of Phayao, Phayao, 56000, Thailand
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (Centex Shrimp), Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand
| | - Somyoth Sridurongrit
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
- Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Bangkok, 10400, Thailand
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Yang J, Gui Y, Zheng Y, He H, Chen L, Li T, Liu H, Wang D, Yuan D, Yuan C. Total saponins from Panax japonicus reduced lipid deposition and inflammation in hepatocyte via PHD2 and hepatic macrophage-derived exosomal miR-463-5p. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119376. [PMID: 39842748 DOI: 10.1016/j.jep.2025.119376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/21/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax japonicus (T. Nees) C.A. Mey. (PJ) is a traditional Chinese herbal medicine revered as the "King of Herbs" in Tujia and Hmong medical practices. Clinically, it is primarily used to treat weakness and fatigue, wound bleeding, arthritis, hyperlipidemia, and fatty liver. It is rich in saponins, and the total saponins from PJ (TSPJ), possess immunomodulatory, antioxidant, and lipid-lowering effects. These properties hold significant potential in managing liver-related metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). AIM OF STUDY Evaluate the therapeutic effects of TSPJ on lipid metabolism disorders in a NASH model and explore the possible underlying mechanisms. MATERIALS AND METHODS To model NASH, C57BL/6J mice were fed a high-fat diet (HFD) and RAW264.7 cells were stimulated with lipopolysaccharide (LPS) and palmitic acid (PA). The animal and cell models were also treated with TSPJ, and the changes in inflammation and lipid metabolism were measured. Additional models were created by transfecting lentiviral vectors to cause miR-463-5p knockdown in the C57BL/6J mouse and the RAW264.7 cells. RESULTS In the HFD-induced mice, TSPJ reduced the body weight and liver weight, lowered the serum levels of TG, T-CHO, ALT, and AST, and reduced the hepatic lipid droplet formation and vacuolization. In the RAW264.7 cells, TSPJ upregulated the M2 markers and downregulated the M1 markers. TSPJ also significantly increased the expression of miR-463-5p in the exosomes derived from the RAW264.7 cells or the primary mouse hepatic macrophages, and miR-463-5p suppressed the expression of PHD2 in hepatocytes to improve lipid metabolism. However, when the exosome secretion inhibitor GW4869 was applied, TSPJ became less effective in alleviating the lipid deposition and inflammation in hepatocytes. CONCLUSIONS TSPJ significantly upregulated the expression of miR-463-5p in the exosomes of hepatic macrophages to thus downregulate PHD2 expression in hepatocytes and improve hepatic lipid metabolism.
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Affiliation(s)
- Jingjie Yang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Yibei Gui
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Ying Zheng
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Haodong He
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Lihan Chen
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Tongtong Li
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Haoran Liu
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Dongshuo Wang
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Ding Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China.
| | - Chengfu Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China; College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
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40
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Sun Y, Bi Y, Wang X, Liu S, Wang L. VIM model: a novel model to depict the spatial heterogeneity of the radiation microenvironment. Int J Med Sci 2025; 22:1477-1484. [PMID: 40084253 PMCID: PMC11898854 DOI: 10.7150/ijms.104046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 02/06/2025] [Indexed: 03/16/2025] Open
Abstract
Radiation-induced disease (RID) is the most important factor limiting the radiotherapy dose for malignant tumors, especially for patients with organ insufficiency or chronic inflammation. In this paper, it studied the changes in the microenvironment after radiation exposure from the perspectives of molecular biology, cell biology and histopathology, and first proposed a novel model of the radiation microenvironment to depict radiation-induced spatial heterogeneity. The radiation microenvironment was divided into the VIM model: vascular microenvironment, inflammatory microenvironment, and metabolic microenvironment according to the special cell functions, molecular expressions and pathological structures after radiation. The structural functions of each microenvironment were explored to provide the new theoretical basis for molecular target prediction, radiation damage assessment, prevention and treatment of radiation-induced disease, and using radiation-induced liver injury as a template to depict the VIM model.
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Affiliation(s)
- Yinan Sun
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ying Bi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaohui Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shunfang Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lu Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Kim S, Kim YK, Kim S, Choi YS, Lee I, Joo H, Kim J, Kwon M, Park S, Jo MK, Choi Y, D'Souza T, Jung JW, Zakhem E, Lenzini S, Woo J, Choi H, Park J, Park SY, Kim GB, Nam GH, Kim IS. Dual-mode action of scalable, high-quality engineered stem cell-derived SIRPα-extracellular vesicles for treating acute liver failure. Nat Commun 2025; 16:1903. [PMID: 39988725 PMCID: PMC11847939 DOI: 10.1038/s41467-025-57133-w] [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: 07/07/2024] [Accepted: 02/06/2025] [Indexed: 02/25/2025] Open
Abstract
Acute liver failure (ALF) is a life-threatening condition caused by rapid hepatocyte death and impaired liver regeneration. Here we show that extracellular vesicles engineered to express Signal Regulatory Protein Alpha (SIRP-EVs), produced via a scalable 3D bioreactor process with high yield and purity, exhibit significant therapeutic potential by targeting damaged cells and promoting tissue repair. SIRP-EVs block CD47, a crucial inhibitory signal on necroptotic cells, to enhance macrophage-mediated clearance of dying hepatocytes. They also deliver regenerative cargo from mesenchymal stem cells, reprogramming macrophages to support liver regeneration. In male animal models, SIRP-EVs significantly reduce liver injury markers and improve survival, demonstrating their dual-function therapeutic efficacy. By integrating the resolution of necroptosis with regenerative macrophage reprogramming, SIRP-EVs represent a promising platform for restoring liver function. These findings support the development of EV-based in vivo macrophage reprogramming therapies for ALF and other inflammation-driven diseases, paving the way for the clinical application of engineered EV therapeutics.
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Grants
- This research was funded by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (Grant Number: RS-2017-NR022964).
- This research was supported by SHIFTBIO INC., Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare (Grant Number: 23C0111L1), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: RS-2023-KH136648), and a grant of the BIG3 Project, funded by the Ministry of SMEs and Startups, Republic of Korea (Grant Number: RS-2022-TI022422).
- This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: RS-2023-KH136648; RS-2023-KH140007).
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Affiliation(s)
| | | | | | | | - Inkyu Lee
- SHIFTBIO INC, Seoul, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | - Hyemin Joo
- SHIFTBIO INC, Seoul, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | | | - Minjeong Kwon
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seryoung Park
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Min Kyoung Jo
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
| | | | | | | | | | | | - Jiwan Woo
- Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
| | - Hongyoon Choi
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Portrai, Inc, Seoul, Republic of Korea
| | | | - Seung-Yoon Park
- Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju, Republic of Korea
| | | | - Gi-Hoon Nam
- SHIFTBIO INC, Seoul, Republic of Korea.
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
| | - In-San Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
- Chemical and Biological Integrative Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
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Biswas T, Lal BB, Sood V, Kale P, Khillan V, Khanna R, Alam S. Bacterial and Fungal Infections in Pediatric Acute Liver Failure and Their Impact on Clinical Outcomes. Pediatr Infect Dis J 2025:00006454-990000000-01225. [PMID: 39970318 DOI: 10.1097/inf.0000000000004762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
OBJECTIVES The current study aimed to explore the prevalence, predictors and outcomes of infections in pediatric acute liver failure (PALF). METHODS Data were retrieved from a prospectively maintained database of patients admitted with PALF between January 2012 and June 2024. "Sepsis" was defined as the presence of systemic inflammatory response syndrome with suspected or proven infection. Patients with positive bacterial and/or fungal cultures were labeled as "culture-positive sepsis." Outcome variables included native liver survival (NLS) and overall survival (OS) at day 28. RESULTS A total of 422 patients of PALF were included in the study of whom 195 (46.21%) fulfilled the criteria of sepsis and 71 (16.8%) had culture-positive sepsis. Bronchoalveolar fluid (37/81, 45.7%) was the commonest site of culture positivity followed by blood (29, 35.8%). More than 80% of cultures grew Gram-negative organisms with a high prevalence of carbapenem (77.1%) and multidrug (60%) resistance. These organisms were sensitive to colistin and newer beta-lactam combinations. Intensive care unit (ICU) stay, mechanical ventilation, grade 3-4 hepatic encephalopathy and use of extracorporeal liver support systems were associated with culture-positive sepsis. Patients with culture-negative sepsis had lower NLS and OS, whereas patients with culture-positive sepsis had outcomes comparable with patients without sepsis. However, culture-positive severe sepsis patients had significantly lowered NLS (33.3%) and OS (42.9%) at day 28. CONCLUSION There is a high prevalence of carbapenem and multidrug-resistant sepsis in PALF. ICU stay and use of extracorporeal support are factors independently associated with sepsis. While culture-positive sepsis did not significantly affect survival, patients with severe sepsis had lower NLS and OS.
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Affiliation(s)
| | | | | | - Pratibha Kale
- Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikas Khillan
- Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Seema Alam
- From the Department of Pediatric Hepatology
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Kuklin A, Slabber CF, Tortola L, Kwan CL, Liebisch G, Kondylis V, Mair F, Kopf M, Weber A, Werner S. An Nrf2-NF-κB Crosstalk Controls Hepatocyte Proliferation in the Normal and Injured Liver. Cell Mol Gastroenterol Hepatol 2025; 19:101480. [PMID: 39970988 DOI: 10.1016/j.jcmgh.2025.101480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND & AIMS The liver has remarkable regenerative and detoxification capacities, which require the Nrf2 and NF-κB transcription factors. Although their individual functions in hepatocytes are well characterized, knowledge about their crosstalk in the adult liver is limited. METHODS We performed AAV8-Cre inducible, hepatocyte-specific knockout of Nrf2, the NF-κB subunit p65, or both genes to determine the individual and combined roles of these transcription factors in the intact liver of male adult mice and after acute CCl4 injury. Mice were characterized using histologic and immunohistochemical stainings, serum and liver bile acid analysis, flow cytometry, and RNA sequencing. To distinguish between cell-autonomous and non-cell-autonomous mechanisms, we generated and analyzed knockout and knockdown AML12 liver cells. Clodronate liposome-mediated macrophage depletion was used to determine the role of these immune cells in hepatocyte proliferation after CCl4 injection. RESULTS Loss of p65 alone or p65 in combination with Nrf2 caused spontaneous liver inflammation and necrosis. Gene expression profiling identified individual and common target genes of both transcription factors, including genes involved in the control of cell proliferation. Consistent with the expression of these genes, hepatocyte proliferation was reduced by Nrf2 deficiency under homeostatic conditions and after CCl4 injury, which was rescued by additional loss of p65. The increased hepatocyte proliferation in the double-knockout mice was non-cell-autonomous and correlated with macrophage accumulation in the liver. Depletion of macrophages in these mice suppressed hepatocyte proliferation after CCl4 treatment. CONCLUSIONS These results reveal a crosstalk between Nrf2 and p65 in the control of hepatocyte proliferation and point to a key role of macrophages in this effect.
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Affiliation(s)
- Andrii Kuklin
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
| | | | - Luigi Tortola
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Chan Lap Kwan
- Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
| | - Vangelis Kondylis
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany
| | - Florian Mair
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Manfred Kopf
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Sabine Werner
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
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Zhang JJ, Zhang JX, Feng QY, Shi LQ, Guo X, Sun HM, Song J. Eriocitrin ameliorates hepatic fibrosis and inflammation: The involvement of PPARα-mediated NLRP1/NLRC4 inflammasome signaling cascades. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119119. [PMID: 39557108 DOI: 10.1016/j.jep.2024.119119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Citri Reticulatae Pericarpium (Chenpi) is a traditional Chinese medicine and recorded to have hepatoprotective therapeutic and condition value. Eriocitrin (ER) a natural compound isolated from Citri Reticulatae Pericarpium may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY The current study investigates the hepatoprotective effect and potential mechanism of ER against hepatic fibrosis. MATERIALS AND METHODS The hepatic fibrosis mouse model was constructed by intraperitoneally injecting thioacetamide (TAA) for five weeks. Hepatic stellate cells (HSCs) were treated with transforming growth factor-β (TGF-β). Meanwhile, lipopolysaccharide/adenosine triphosphate (LPS/ATP) was given to excite the normal mouse bone marrow-derived macrophages (BMDMs), and thus the cells could acquire the conditioned medium. Moreover, LX-2 cells were administrated with PPARα knockdown vector (siRNA-PPARα). RESULTS RNA sequencing studies revealed that in mice induced by TAA, the PPARα/NOD-like receptor/neutrophil extracellular traps (NETs) significantly influence ER-based hepatic protection. In TAA-induced mice, ER could up-regulate PPARα and down-regulate NLRP1/NLRC4 and the development of NETs. Our findings indicated that ER significantly up-regulated PPARα, inhibited NLRP1/NLRC4 inflammasome in HSCs. Deficiency of PPARα in the activated LX-2 weakened the regulatory effect of ER on inhibiting the NLRP1/NLRC4 inflammasome. In addition, ER might hinder the activation of BMDMs and also obstruct IL-1β and IL-6 passage in the extracellular space. CONCLUSIONS The results indicated that ER decreased inflammation by controlling the PPARα-NLRP1/NLRC4 signaling pathway and inhibiting fibril formation. Collectively, our results underscore the therapeutic potential of ER in addressing hepatic fibrosis.
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Affiliation(s)
- Jin-Jin Zhang
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China
| | - Jia-Xin Zhang
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China
| | - Qi-Yuan Feng
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China
| | - Li-Qiang Shi
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China
| | - Xin Guo
- School of Pharmacy and Medicine, Tonghua Normal University, Tonghua, Jilin Province, 134001, China.
| | - Hai-Ming Sun
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China.
| | - Jian Song
- College of Pharmacy, Beihua University, Jilin, Jilin Province, 132013, China.
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45
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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [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: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Boltnarova B, Durinova A, Jandova L, Micuda S, Kucera O, Pavkova I, Machacek M, Nemeckova I, Vojta M, Dusek J, Krutakova M, Nachtigal P, Pavek P, Holas O. Dexamethasone Acetate-Loaded PLGA Nanospheres Targeting Liver Macrophages. Macromol Biosci 2025; 25:e2400411. [PMID: 39611304 PMCID: PMC11827543 DOI: 10.1002/mabi.202400411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/14/2024] [Indexed: 11/30/2024]
Abstract
Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.
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Affiliation(s)
- Barbora Boltnarova
- Department of Pharmaceutical TechnologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Anna Durinova
- Department of Pharmacology and ToxicologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Lenka Jandova
- Department of PharmacologyFaculty of Medicine in Hradec KraloveCharles UniversitySimkova 870Hradec Kralove50003Czech Republic
| | - Stanislav Micuda
- Department of PharmacologyFaculty of Medicine in Hradec KraloveCharles UniversitySimkova 870Hradec Kralove50003Czech Republic
| | - Otto Kucera
- Department of PhysiologyFaculty of Medicine in Hradec KraloveCharles UniversitySimkova 870Hradec Kralove50003Czech Republic
| | - Ivona Pavkova
- Department of Molecular Pathology and BiologyMilitary Faculty of MedicineUniversity of DefenceTrebesska 1575Hradec Kralove50001Czech Republic
| | - Miloslav Machacek
- Department of Biochemical SciencesFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Ivana Nemeckova
- Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Marek Vojta
- Department of PhysicsFaculty of ScienceUniversity of Hradec KraloveRokitanskeho 62Hradec Kralove50003Czech Republic
| | - Jan Dusek
- Department of Pharmacology and ToxicologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
- Department of PhysiologyFaculty of Medicine in Hradec KraloveCharles UniversitySimkova 870Hradec Kralove50003Czech Republic
| | - Maria Krutakova
- Department of Pharmacology and ToxicologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Petr Nachtigal
- Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Petr Pavek
- Department of Pharmacology and ToxicologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
| | - Ondrej Holas
- Department of Pharmaceutical TechnologyFaculty of Pharmacy in Hradec KraloveCharles UniversityAkademika Heyrovskeho 1203Hradec Kralove50005Czech Republic
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Sepehrinia M, Khanmohammadi S, Rezaei N, Kuchay MS. Dietary inflammatory potential and metabolic (dysfunction)-associated steatotic liver disease and its complications: A comprehensive review. Clin Nutr ESPEN 2025; 65:162-171. [PMID: 39608495 DOI: 10.1016/j.clnesp.2024.11.032] [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: 07/08/2024] [Revised: 09/30/2024] [Accepted: 11/20/2024] [Indexed: 11/30/2024]
Abstract
Metabolic (dysfunction)-associated steatotic liver disease (MASLD) represents a spectrum of liver pathologies linked to metabolic syndrome components. Inflammation emerges as a pivotal player in MASLD pathogenesis, initiating and perpetuating hepatic injury. Diet, a modifiable risk factor, influences inflammation levels and MASLD progression. This review synthesizes existing evidence on the association between pro-inflammatory diets, assessed via the Dietary Inflammatory Index (DII) and Empirical Dietary Inflammatory Potential (EDIP), and MASLD. Evidence suggests a significant association between higher DII/EDIP scores and MASLD risk, with studies revealing a positive correlation between inflammatory diet intake and MASLD occurrence, particularly in males. However, inconsistencies exist regarding the influence of body mass index (BMI) on this association and criticisms regarding adjustment for BMI and reliance on surrogate markers necessitate cautious interpretation. Limited data suggest a potential link between dietary inflammatory potential and advanced liver fibrosis and heightened risk of hepatocellular carcinoma (HCC) with increased DII/EDIP scores, albeit requiring further confirmation through gold-standard assessment methods. Dietary-induced inflammation exacerbates MASLD pathogenesis through multiple pathways, including insulin resistance, adipose tissue dysfunction, gut microbiota alterations, and oxidative stress, culminating in hepatic steatosis, inflammation, and fibrosis. Further research utilizing robust methodologies is imperative to confirm these findings and elucidate underlying mechanisms, thus informing targeted dietary interventions for MASLD management.
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Affiliation(s)
- Matin Sepehrinia
- Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute (WHO Collaborating Center), Shahid Beheshti University of Medical Sciences, Tehran, Iran; Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran.
| | - Shaghayegh Khanmohammadi
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran, Iran; University of Medical Sciences, Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta The Medicity, Gurugram 122001, Haryana, India.
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Zhang H, Gao M, Wang H, Zhang J, Wang L, Dong G, Ma Q, Li C, Dai J, Li Z, Yan F, Xiong H. Atractylenolide I prevents acute liver failure in mouse by regulating M1 macrophage polarization. Sci Rep 2025; 15:4015. [PMID: 39893238 PMCID: PMC11787394 DOI: 10.1038/s41598-025-86977-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] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/15/2025] [Indexed: 02/04/2025] Open
Abstract
Acute liver failure (ALF) is a life-threatening clinical syndrome with a substantial risk of mortality. A murine model of lipopolysaccharide (LPS)- and D-galactosamine (D-GalN)-induced ALF is widely used to investigate the underlying mechanisms and potential therapeutic drugs for human liver failure. Atractylenolide I (ATR-I) is an active component of the Atractylodes macrocephala rhizome and possesses various pharmacological activities, including anti-tumor, anti-inflammatory, and anti-oxidant properties. Given the key role of oxidative stress and inflammation in ALF pathogenesis, this study investigates the protective effects of ATR-I on LPS/D-GalN-induced ALF in mice. The results suggest that ATR-I pretreatment significantly ameliorates ALF, as evidenced by decreased serum aminotransferase levels and prolonged mice survival. Additionally, ATR-I pretreatment inhibits oxidative stress. Furthermore, the ATR-I pretreatment markedly suppresses M1 macrophage activation in hepatic mononuclear cells. In vitro experiments with bone marrow-derived macrophages indicate that ATR-I regulates macrophage polarization through the mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling pathways. Collectively, ATR-I pretreatment protects mice from LPS/D-GalN-induced ALF partially by regulating M1 macrophage polarization.
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Affiliation(s)
- Hui Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Min Gao
- Clinical Laboratory, Jining First People's Hospital, Jining, Shandong, China
| | - Haiyan Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Junfeng Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Lin Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Qun Ma
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Chunxia Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Jun Dai
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Zhihua Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Fenglian Yan
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China.
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China.
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China.
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China.
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Zhang X, Huang N, Mu Y, Chen H, Zhu M, Zhang S, Liu P, Zhang H, Deng H, Feng K, Shang Q, Liu X, Zhang C, Shi M, Yang L, Sun J, Kong G, Geng J, Lu S, Li Z. Mechanical Force-Induced cGAS Activation in Carcinoma Cells Facilitates Splenocytes into Liver to Drive Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2401127. [PMID: 39737867 PMCID: PMC11848607 DOI: 10.1002/advs.202401127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 11/27/2024] [Indexed: 01/01/2025]
Abstract
Liver metastasis is the main cause of cancer-related mortality. During the metastasis process, circulating carcinoma cells hardly pass through narrow capillaries, leading to nuclear deformation. However, the effects of nuclear deformation and its underlying mechanisms on metastasis need further study. Here, it is shown that mechanical force-induced nuclear deformation exacerbates liver metastasis by activating the cGAS-STING pathway, which promotes splenocyte infiltration in the liver. Mechanical force results in nuclear deformation and rupture of the nuclear envelope with inevitable DNA leakage. Cytoplasmic DNA triggers the activation of cGAS-STING pathway, enhancing the production of IL6, TNFα, and CCL2. Additionally, splenocyte recruitment by the proinflammatory cytokines support carcinoma cell survival and colonization in the liver. Importantly, both intervening activity of cGAS and blocking of splenocyte migration to the liver efficiently ameliorate liver metastasis. Overall, these findings reveal a mechanism by which mechanical force-induced nuclear deformation exacerbates liver metastasis by regulating splenocyte infiltration into the liver and support targeting cGAS and blocking splenocyte recruitment as candidate therapeutic approaches for liver metastasis.
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Song Z, Wu J, Jiang T, He R, Wen H. The protective effect of the vagus nerve-α7nAChR-IL-22 pathway on acute liver injury. Cytokine 2025; 186:156840. [PMID: 39705885 DOI: 10.1016/j.cyto.2024.156840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/14/2024] [Accepted: 12/14/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Acute liver injury is a common pathological feature of various clinical diseases, and prolonged liver damage can lead to fibrosis and even liver failure. Studies have reported that the vagus nerve can repair liver injury through the regulation of the cholinergic anti-inflammatory pathway. However, there is limited research on the regulation of interleukin-22 and its role in liver injury. This study aimed to investigate the regulatory effect of vagus nerve receptor α7nAChR on interleukin-22 and whether this regulatory axis can protect against liver injury. METHODS Rats and the human liver cell line L-02 were treated with carbon tetrachloride to simulate acute liver injury. The experimental groups were divided as follows: control group, model group, model + PNU282987 group, model + MLA group, and MLA group. After the intervention, blood samples, liver tissues, and cells were collected to assess liver function (AST, ALT), inflammation (TNF-α, IL-6,), α7nAChR and interleukin-22 concentrations, apoptosis levels (Bax, BCL-2), and proliferation markers (Ki-67, PCNA) using quantitative real time PCR, Western blot, immunohistochemistry and ELISA. RESULTS The results indicated that carbon tetrachloride intervention led to compensatory increases in interleukin-22 while inhibition of α7nAChR decreased interleukin-22 concentrations and exacerbated the injury marked by high levels of AST, ALT and TNF-α,IL-6. Exogenous administration of a vagus nerve agonist alleviated liver injury and was accompanied by an increase in interleukin-22 levels. In rescue experiments, simultaneous inhibition of vagus nerve receptors and administration of exogenous interleukin-22 reduced liver injury and significantly enhanced liver regeneration. Conversely, activation of vagus nerve receptors while inhibiting interleukin-22 aggravated liver injury. CONCLUSION This study confirms that vagus nerve receptor α7nAChR can promote liver regeneration and protect against carbon tetrachloride-induced liver injury by regulating interleukin-22.
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Affiliation(s)
- Zhihao Song
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jing Wu
- Department of Liver Transplantation & Laparoscopic Surgery, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tiemin Jiang
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Rongdong He
- Department of Liver Transplantation & Laparoscopic Surgery, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hao Wen
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China; State Key Laboratory of Pathogenesis, Prevention, Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China.
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