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Zheng S, Xue T, Wang Q, Zhang P, Qi W, Xue C, Li X, Du H, Zhang P, Zao X, Ye Y. Chinese Medicine for the Treatment of Liver Cirrhosis: The Mechanism of Cellular Autophagy. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:409-433. [PMID: 40070295 DOI: 10.1142/s0192415x25500168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/08/2025]
Abstract
Liver cirrhosis is a critical stage in the progression of various chronic liver diseases, often leading to severe complications such as ascites, hepatic encephalopathy, and a high mortality rate, and it thus poses a serious threat to patient life. The activation of hepatic stellate cells is a central driver of disease progression. Cellular autophagy, a lysosome-mediated degradation process, plays a key role in maintaining cellular function and dynamic homeostasis. Research has shown that autophagy is closely associated with proteins like LC3, Beclin-1, P62, and mTOR, and is regulated through signaling pathways such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR. Additionally, the relationship between autophagy and apoptosis, as well as between autophagy and exosomes, has been further demonstrated. While modern medicine has made progress in treating cirrhosis, it still faces significant limitations. By contrast, numerous studies have demonstrated the efficacy of traditional Chinese medicine in preventing and treating liver cirrhosis by regulating autophagy, with fewer adverse effects. Chinese herbal monomers and formulations can modulate various autophagy-related signaling pathways, including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR, and influence key autophagy proteins such as LC3 and Beclin-1. This modulation inhibits hepatic stellate cell activation, reduces extracellular matrix deposition, and exerts anticirrhotic effects. Moreover, Chinese medicine appears to reduce adverse reactions in cirrhosis treatment and lower the risk of disease recurrence. This review explores the mechanisms of autophagy in the prevention and treatment of liver cirrhosis through Chinese medicine, offering new insights for the development of Chinese medicinal therapies for cirrhosis and their rational clinical application.
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Affiliation(s)
- Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing 100102, P. R. China
| | - Tianyu Xue
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, P. R. China
| | - Qiuyue Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing 100102, P. R. China
| | - Pingxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
| | - Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing 100102, P. R. China
| | - Chengyuan Xue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing 100102, P. R. China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
| | - Peng Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P. R. China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
| | - Yongan Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P. R. China
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Fang Y, Liu Y, Li D, Miu Y, Chen K, Zhou J, Xie L, Chen X, Wu J, Zhu Y, Lv L, Li W. Role of integrin α4 in the inhibition of fibrosis in activated hepatic stellate cells by Periplaneta americana extract. Front Pharmacol 2025; 16:1517491. [PMID: 40103586 PMCID: PMC11913867 DOI: 10.3389/fphar.2025.1517491] [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: 10/30/2024] [Accepted: 02/17/2025] [Indexed: 03/20/2025] Open
Abstract
This study aims to investigate the role of integrin α4 (ITGA4) in the inhibition of hepatic stellate cells (HSCs) fibrosis by Periplaneta americana extract (PAE), as well as to explore its molecular mechanisms. In vitro experiments utilized TGFβ-induced LX2 and HSC-T6 cells to examine the anti-fibrotic effects of PAE, particularly through ITGA4 overexpression, to elucidate its involvement in PAE-mediated inhibition via the PI3K-AKT signaling pathway. Cell viability was assessed using the CCK-8 method, and the IC50 for PAE was determined through statistical analysis. We evaluated cell proliferation using scratch and EDU assays, and migration capabilities using Transwell assays. Molecular mechanisms were investigated through western blot (WB), quantitative PCR (QPCR), and transcriptome analysis. Results indicate that PAE reduces hepatic fibrosis by curbing hepatic stellate cells (HSCs) proliferation, migration, collagen synthesis, inflammatory cytokine production, and epithelial-mesenchymal transition (EMT). Additionally, while PAE suppressed ITGA4's high expression in activated HSCs, ITGA4 overexpression counteracted PAE's effects on HSC proliferation, migration, and collagen synthesis. These findings demonstrate that PAE primarily mitigates fibrosis in activated HSCs by inhibiting ITGA4, thus delivering anti-fibrotic effects in the liver.
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Affiliation(s)
- Ying Fang
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Ye Liu
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Dingchun Li
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Yi Miu
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Kexuan Chen
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Jv Zhou
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Lijuan Xie
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Xinting Chen
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Jingyan Wu
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Lechun Lv
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, School of Rehabilitation, Kunming Medical University, Yunnan, China
| | - Wu Li
- Department of Infectious Disease, The First Affiliated Hospital of Kunming Medical University, Yunnan, China
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Luo Y, Zhang N, Ye J, Wang Z, Zhou X, Liu J, Cai J, Li C, Chen L. Unveiling lactylation modification: A new hope for cancer treatment. Biomed Pharmacother 2025; 184:117934. [PMID: 39986235 DOI: 10.1016/j.biopha.2025.117934] [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: 12/29/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025] Open
Abstract
This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.
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Affiliation(s)
- Yuxiang Luo
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Ning Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Zuao Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Xinchi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jipeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Chen Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China; Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi 330006, China; Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi 330006, China.
| | - Leifeng Chen
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Precision Oncology Medicine Center,The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People's Republic of China.
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Ge Y, Jiang L, Dong Q, Xu Y, Yam JWP, Zhong X. Exosome-mediated Crosstalk in the Tumor Immune Microenvironment: Critical Drivers of Hepatocellular Carcinoma Progression. J Clin Transl Hepatol 2025; 13:143-161. [PMID: 39917466 PMCID: PMC11797817 DOI: 10.14218/jcth.2024.00302] [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: 08/23/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.
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Affiliation(s)
- Yifei Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixue Jiang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Fang C, Zeng Z, Ye J, Ni B, Zou J, Zhang G. Progress of mesenchymal stem cells affecting extracellular matrix metabolism in the treatment of female stress urinary incontinence. Stem Cell Res Ther 2025; 16:95. [PMID: 40001265 PMCID: PMC11863768 DOI: 10.1186/s13287-025-04220-w] [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: 12/01/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Stress urinary incontinence (SUI) is a prevalent pelvic floor dysfunction in women post-pregnancy. Currently, conservative treatment options have low success rates, while surgical interventions often result in multiple complications. The altered state of the extracellular matrix (ECM) is a pivotal factor in the onset of various diseases and likely plays a significant role in the pathogenesis of SUI, particularly through changes in collagen and elastin levels. Recent advances in mesenchymal stem cells (MSCs) therapy have shown considerable promise in treating SUI by modulating ECM remodeling, thereby enhancing the supportive tissues of the female pelvic floor. MSCs exhibit substantial potential in enhancing urethral sphincter function, modulating connective tissue architecture, and stimulating fibroblast activity. They play a pivotal role in the reconstruction and functional recovery of the ECM by influencing various signaling pathways, including TGF-β/SMAD, JAK/STAT, Wnt/β-catenin, PI3K/AKT, and ERK/MAPK. We have reviewed the advancements in MSC-mediated ECM metabolism in SUI and, by integrating the functions of ECM in other diseases and how MSCs can ameliorate conditions through their impact on ECM metabolism, we have projected the future trajectory of SUI treatment development.
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Affiliation(s)
- Chunyun Fang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Zitao Zeng
- First Clinical College of Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Bin Ni
- Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Junrong Zou
- Department of Urology, Institute of Urology, First Affiliated Hospital of Gannan Medical University, Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, No. 128, Jinling Road, Zhanggong District, Ganzhou, Jiangxi, 341000, China
| | - Guoxi Zhang
- Department of Urology, Institute of Urology, First Affiliated Hospital of Gannan Medical University, Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, No. 128, Jinling Road, Zhanggong District, Ganzhou, Jiangxi, 341000, China.
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Zong R, Zheng Y, Yan Y, Sun W, Kong L, Huang Y, Liu Y, Jiang C, Ping J, Li C. Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling. Hepatol Int 2024; 18:1781-1791. [PMID: 39138757 DOI: 10.1007/s12072-024-10717-y] [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: 01/30/2024] [Accepted: 07/28/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND & AIMS Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis. METHODS Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide (TAA). Some mice were then given injection of UC-MSCs or UC-MSCs-derived exosomes (UC-MSCs-Exo) via the tail vein. Liver tissues were collected for histologic analysis. RESULTS We found that administration of UC-MSCs significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, and attenuated hepatic inflammation and fibrosis. Moreover, the therapeutic effect of UC-MSCs-derived exosomes was similar to that of UC-MSCs. Intriguingly, UC-MSCs-Exo treatment downregulated the expression of smoothened (SMO), a fundamental component of Hedgehog signaling which plays a critical role in fibrogenesis, and subsequently inhibited the activation of hepatic stellate cells, a central driver of fibrosis in experimental and human liver injury. Furthermore, the anti-inflammatory and anti-fibrotic effects of UCMSCs- Exo was reversed by the SMO agonist SAG treatment in mice. CONCLUSION Our findings suggest that UC-MSCs-Exo exert therapeutic effects on liver fibrosis, at least in part, through inhibiting the Hedgehog/SMO signaling pathway.
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Affiliation(s)
- Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yan Zheng
- Department of Pharmacy, Hubei Aerospace Hospital, Xiaogan, Hubei, China
| | - Yufei Yan
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Wenao Sun
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Liangyi Kong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yating Huang
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yujie Liu
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Chaochen Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jie Ping
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China.
- Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China.
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Yu Y, Li Y, Zhou L, Cheng X, Gong Z. Hepatic stellate cells promote hepatocellular carcinoma development by regulating histone lactylation: Novel insights from single-cell RNA sequencing and spatial transcriptomics analyses. Cancer Lett 2024; 604:217243. [PMID: 39260669 DOI: 10.1016/j.canlet.2024.217243] [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: 04/25/2024] [Revised: 08/23/2024] [Accepted: 09/06/2024] [Indexed: 09/13/2024]
Abstract
This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.
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Affiliation(s)
- Yifan Yu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
| | - Yongnan Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
| | - Long Zhou
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
| | - Xiaoli Cheng
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
| | - Zheng Gong
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
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Sekar V, VP V, Vijay V, BR A, Vijayan N, Perumal MK. Inhibition of hepatic stellate cell activation by nutraceuticals: an emphasis on mechanisms of action. JOURNAL OF FOOD SCIENCE AND TECHNOLOGY 2024; 61:2046-2056. [PMID: 39397845 PMCID: PMC11464960 DOI: 10.1007/s13197-024-06002-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 10/15/2024]
Abstract
Liver diseases emerge as a serious threat to humans worldwide due to increasing morbidity and mortality. Liver disease related deaths accounts for one third of all disease related death globally. A simple fatty liver if unattended advances further to liver fibrosis, cirrhosis and hepatocellular carcinoma. During liver fibrogenesis, hepatic stellate cells gets activated into myofibroblast like cells and exhibit proliferative and fibrogenic features. Targeting these activated hepatic stellate cells offer promising therapeutic approach towards liver fibrosis management. To date there is no Food and Drug Administration approved treatments for liver fibrosis. However, a large number of clinical trials are being conducted employing monoclonal antibodies, drugs, dietary supplements and herbal medicines. A vast number of research findings demonstrated nutraceuticals to be effective against experimental liver fibrosis both in vitro and in vivo. Nutraceuticals typically regulate key signaling pathways in activated hepatic stellate cells and exhibit anti-fibrotic effect. In this review, the mechanistic action of nutraceuticals targeting activated hepatic stellate cells were summarized to establish them as a possible therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Vasudevan Sekar
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
| | - Venkateish VP
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Vani Vijay
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Annapoorna BR
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Nivya Vijayan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
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Yang M, Li S, Luo R, Zhao Y, Sun Y, Li H, Cui Q, Wu J, Mao L. ADAM8 promotes alcoholic liver fibrosis through the MAPK signaling pathway. J Physiol Sci 2024; 74:52. [PMID: 39407108 PMCID: PMC11481351 DOI: 10.1186/s12576-024-00943-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024]
Abstract
The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF.
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Affiliation(s)
- Mengli Yang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Sanqiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
| | - Renli Luo
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yadi Zhao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yue Sun
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Haoyuan Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Qinyi Cui
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Junfei Wu
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Longfei Mao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
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10
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Gao R, Mao J. Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis. Noncoding RNA 2024; 10:44. [PMID: 39195573 DOI: 10.3390/ncrna10040044] [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: 05/22/2024] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Abstract
Liver fibrosis is a significant contributor to liver-related disease mortality on a global scale. Despite this, there remains a dearth of effective therapeutic interventions capable of reversing this condition. Consequently, it is imperative that we gain a comprehensive understanding of the underlying mechanisms driving liver fibrosis. In this regard, the activation of hepatic stellate cells (HSCs) is recognized as a pivotal factor in the development and progression of liver fibrosis. The role of noncoding RNAs (ncRNAs) in epigenetic regulation of HSCs transdifferentiation into myofibroblasts has been established, providing new insights into gene expression changes during HSCs activation. NcRNAs play a crucial role in mediating the epigenetics of HSCs, serving as novel regulators in the pathogenesis of liver fibrosis. As research on epigenetics expands, the connection between ncRNAs involved in HSCs activation and epigenetic mechanisms becomes more evident. These changes in gene regulation have attracted considerable attention from researchers in the field. Furthermore, epigenetics has contributed valuable insights to drug discovery and the identification of therapeutic targets for individuals suffering from liver fibrosis and cirrhosis. As such, this review offers a thorough discussion on the role of ncRNAs in the HSCs activation of liver fibrosis.
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Affiliation(s)
- Ruoyu Gao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jingwei Mao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
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11
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Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
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12
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Zhu Y, Gu J, Lu Y, Tao Q, Cao X, Zhu Y, Yang MQ, Liang X. IL-6 Released from Hepatic Stellate Cells Promotes Glycolysis and Migration of HCC Through the JAK1/vWF/TGFB1 Axis. J Hepatocell Carcinoma 2024; 11:1295-1310. [PMID: 38983936 PMCID: PMC11232958 DOI: 10.2147/jhc.s464880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 06/27/2024] [Indexed: 07/11/2024] Open
Abstract
Purpose The crosstalk between hepatocellular carcinoma (HCC) cells and hepatic stellate cells (HSCs) is one of the important mechanisms of liver cancer metastasis. The relationship between liver cancer metastasis and glycolysis has been extensively studied recently. However, the role of von Willebrand factor (vWF) mediated glycolysis mechanism in liver cancer metastasis is currently unknown. Methods Western blot was used to verify the expression of vWF in HCC cells. PAS staining, glycogen and L-lactate content assays were used to reflect cellular glycolysis levels. The ability of cell migration was explored by Wound-healing and Transwell assays. Besides, the effect of vWF on the progression of HCC in vivo was also studied using subcutaneous xenograft model. Results vWF derived from HCC cells promoted tumor migration by mediating glycolysis. Besides, vWF participated in the crosstalk between HCC cells and HSCs. HCC cells activated HSCs through vWF-mediated TGFB1 expression and secretion, and activated HSCs upregulated vWF expression in HCC cells through IL-6 secretion feedback. Further, in vitro and in vivo experiments also confirmed the importance of the JAK1/vWF/TGFB1 axis in regulating HSCs-derived IL-6 mediated HCC migration and growth. Conclusion In summary, this article demonstrated that IL-6 released from hepatic stellate cells enhanced glycolysis and migration ability of liver cancer cells by activating JAK1/vWF/TGFB1 axis which may also be a potential target for inhibiting liver cancer metastasis.
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Affiliation(s)
- Yifei Zhu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Jiayi Gu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yuxin Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Qianying Tao
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Xinliang Cao
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yanqing Zhu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Mu-Qing Yang
- Department of Hepatobiliary Surgical Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Xin Liang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
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13
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Very N, Boulet C, Gheeraert C, Berthier A, Johanns M, Bou Saleh M, Guille L, Bray F, Strub JM, Bobowski-Gerard M, Zummo FP, Vallez E, Molendi-Coste O, Woitrain E, Cianférani S, Montaigne D, Ntandja-Wandji LC, Dubuquoy L, Dubois-Chevalier J, Staels B, Lefebvre P, Eeckhoute J. O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts. Cell Death Dis 2024; 15:391. [PMID: 38830870 PMCID: PMC11148087 DOI: 10.1038/s41419-024-06773-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/05/2024]
Abstract
Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.
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Affiliation(s)
- Ninon Very
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Clémence Boulet
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Céline Gheeraert
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Alexandre Berthier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Manuel Johanns
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Mohamed Bou Saleh
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Loïc Guille
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Fabrice Bray
- Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, University of Lille, Villeneuve d'Ascq Cedex, France
| | - Jean-Marc Strub
- Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ. Strasbourg, IPHC, Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg, France
| | - Marie Bobowski-Gerard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Francesco P Zummo
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Emmanuelle Vallez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Olivier Molendi-Coste
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Eloise Woitrain
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sarah Cianférani
- Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ. Strasbourg, IPHC, Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg, France
| | - David Montaigne
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Line Carolle Ntandja-Wandji
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Laurent Dubuquoy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | | | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Jérôme Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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14
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Xiong F, Zhang Y, Li T, Tang Y, Song SY, Zhou Q, Wang Y. A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms. Front Pharmacol 2024; 15:1389179. [PMID: 38855739 PMCID: PMC11157233 DOI: 10.3389/fphar.2024.1389179] [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: 02/21/2024] [Accepted: 04/29/2024] [Indexed: 06/11/2024] Open
Abstract
Background Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential. Purpose This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis. Methods A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employed were "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis. Results This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effects on liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver. Conclusion The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential.
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Affiliation(s)
- Fei Xiong
- Department of Gastroenterology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Yichen Zhang
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People’s Hospital, Chengdu, China
| | - Yiping Tang
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Si-Yuan Song
- Baylor College of Medicine, Houston, TX, United States
| | - Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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15
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Alfattah MA, Correia CN, Browne JA, McGettigan PA, Pluta K, Carrington SD, MacHugh DE, Irwin JA. Transcriptomics analysis of the bovine endometrium during the perioestrus period. PLoS One 2024; 19:e0301005. [PMID: 38547106 PMCID: PMC10977793 DOI: 10.1371/journal.pone.0301005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 03/10/2024] [Indexed: 04/02/2024] Open
Abstract
During the oestrous cycle, the bovine endometrium undergoes morphological and functional changes, which are regulated by alterations in the levels of oestrogen and progesterone and consequent changes in gene expression. To clarify these changes before and after oestrus, RNA-seq was used to profile the transcriptome of oestrus-synchronized beef heifers. Endometrial samples were collected from 29 animals, which were slaughtered in six groups beginning 12 h after the withdrawal of intravaginal progesterone releasing devices until seven days post-oestrus onset (luteal phase). The groups represented proestrus, early oestrus, metoestrus and early dioestrus (luteal phase). Changes in gene expression were estimated relative to gene expression at oestrus. Ingenuity Pathway Analysis (IPA) was used to identify canonical pathways and functional processes of biological importance. A total of 5,845 differentially expressed genes (DEGs) were identified. The lowest number of DEGs was observed at the 12 h post-oestrus time point, whereas the greatest number was observed at Day 7 post-oestrus onset (luteal phase). A total of 2,748 DEGs at this time point did not overlap with any other time points. Prior to oestrus, Neurological disease and Organismal injury and abnormalities appeared among the top IPA diseases and functions categories, with upregulation of genes involved in neurogenesis. Lipid metabolism was upregulated before oestrus and downregulated at 48h post-oestrus, at which point an upregulation of immune-related pathways was observed. In contrast, in the luteal phase the Lipid metabolism and Small molecule biochemistry pathways were upregulated.
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Affiliation(s)
- Mohammed A. Alfattah
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
- King Faisal University, Al-Ahsa, Saudi Arabia
| | - Carolina N. Correia
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - John A. Browne
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - Paul A. McGettigan
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - Katarzyna Pluta
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - Stephen D. Carrington
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - David E. MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Jane A. Irwin
- UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin, Ireland
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16
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Ortega-Ribera M, Babuta M, Szabo G. Sinusoidal cell interactions—From soluble factors to exosomes. SINUSOIDAL CELLS IN LIVER DISEASES 2024:23-52. [DOI: 10.1016/b978-0-323-95262-0.00002-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Chi C, Liang X, Cui T, Gao X, Liu R, Yin C. SKIL/SnoN attenuates TGF-β1/SMAD signaling-dependent collagen synthesis in hepatic fibrosis. BIOMOLECULES & BIOMEDICINE 2023; 23:1014-1025. [PMID: 37389959 PMCID: PMC10655871 DOI: 10.17305/bb.2023.9000] [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: 03/10/2023] [Revised: 06/08/2023] [Accepted: 06/08/2023] [Indexed: 07/02/2023]
Abstract
The ski-related novel gene (SnoN), encoded by the SKIL gene, has been shown to negatively regulated transforming growth factor-β1 (TGF-β1) signaling pathway. However, the roles of SnoN in hepatic stellate cell (HSC) activation and hepatic fibrosis (HF) are still unclear. To evaluate the role of SnoN in HF, we combined bulk RNA sequencing analysis and single-cell RNA sequencing analysis to analyse patients with HF. The role of SKIL/SnoN was verified using liver samples from rat model transfected HSC-T6 and LX-2 cell lines. Immunohistochemistry, immunofluorescence, PCR, and western blotting techniques were used to demonstrate the expression of SnoN and its regulatory effects on TGF-β1 signaling in fibrotic liver tissues and cells. Furthermore, we constructed competitive endogenous RNA regulatory network and potential drug network associated with the SnoN gene. We identified SKIL gene as a differentially expressed gene in hepatic fibrosis. SnoN protein was found to be widely expressed in the cytoplasm of normal hepatic tissues, whereas it was almost absent in HF tissues. In the rat group subjected to bile duct ligation (BDL), SnoN protein expression decreased, while TGF-β1, collagen III, tissue inhibitor of metalloproteinase 1 (TIMP-1), and fibronectin levels increased. We observed the interaction of SnoN with p-SMAD2 and p-SMAD3 in the cytoplasm. Following SnoN overexpression, apoptosis of HSCs was promoted, and the expression of HF-associated proteins, including collagen I, collagen III, and TIMP-1, was reduced. Conversely, downregulation of SnoN inhibited HSC apoptosis, increased collagen III and TIMP-1 levels, and decreased matrix metalloproteinase 13 (MMP-13) expression. In conclusion, SnoN expression is downregulated in fibrotic livers, and could attenuate TGF-β1/SMADs signaling-dependent de-repression of collagen synthesis.
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Affiliation(s)
- Cheng Chi
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
- School of Nursing, Jining Medical University, Jining, Shandong, China
| | - Xifeng Liang
- School of Nursing, Jining Medical University, Jining, Shandong, China
- School of Nursing, Weifang Medical University, Weifang, Shandong, China
| | - Tianyu Cui
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Xiao Gao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Ruixia Liu
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Chenghong Yin
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
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18
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Wang K, Chen H, Qin S, Chen S, Zhang Q, Chen J, Di D, Su G, Yuan Y. Co-delivery of pirfenidone and siRNA in ZIF-based nanoparticles for dual inhibition of hepatic stellate cell activation in liver fibrotic therapy. Colloids Surf B Biointerfaces 2023; 231:113567. [PMID: 37797465 DOI: 10.1016/j.colsurfb.2023.113567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 09/07/2023] [Accepted: 09/26/2023] [Indexed: 10/07/2023]
Abstract
Hepatic fibrosis, as a destructive liver disease, occurs due to activated hepatic stellate cells (HSCs) producing excessive extracellular matrix deposition. If left untreated, it could further deteriorate into cirrhosis and hepatoma with high morbidity and mortality. Currently, to break the dilemma of poor targeting efficiency on HSCs and limited effect of monotherapy, it is urgent to explore a precise and efficient treatment against liver fibrosis. In the present work, a novel multifunctional nanoplatform based on vitamin A (VA) modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles was designed for co-delivery of chemical drug (Pirfenidone) and genetic drug (TGF-β1 siRNA) to achieve HSCs targeting mediated synergistic chemo-gene therapy against liver fibrosis. With the large specific surface area and acid-responsive degradation characteristics, ZIF-8 nanoparticles have great advantages to achieve high loading efficiency of Pirfenidone and enable acid-reactive drug release. After complexing siRNA, the prepared chemo-gene drug co-delivered nanocomplex (GP@ZIF-VL) proved excellent serum stability and effectively protected siRNA from degradation. Importantly, in vitro cell uptake and in vivo biodistribution demonstrated that VA functionalization markedly enhanced the delivery efficiency of GP@ZIF-VL nanocomplex into HSCs. As expected, GP@ZIF-VL significantly reduced extracellular matrix deposition and ameliorated hepatic fibrosis, as evidenced by decreased levels of liver enzymes in serum and a reduction in the hydroxyproline content in liver tissue. Therefore, GP@ZIF-VL nanocomplex displayed a bright future on the treatment of liver fibrosis with HSCs-targeting mediated chemo-gene synergetic therapy.
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Affiliation(s)
- Kaili Wang
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Hao Chen
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Si Qin
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Shuhui Chen
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Qian Zhang
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Jiali Chen
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Donghua Di
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China
| | - Guangyue Su
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
| | - Yue Yuan
- Shenyang Key Laboratory of Functional Drug Carrier Materials, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
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19
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Zhang L, Zhang Q, Teng D, Guo M, Tang K, Wang Z, Wei X, Lin L, Zhang X, Wang X, Huang D, Ren C, Yang Q, Zhang W, Gao Y, Chen W, Chang Y, Zhang H. FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301166. [PMID: 37566761 PMCID: PMC10558677 DOI: 10.1002/advs.202301166] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 07/20/2023] [Indexed: 08/13/2023]
Abstract
Most nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH-driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH-associated HCC. Furthermore, NASH-driven HCC mice models by feeding wildtype mice with high-fat/high-cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl4 ) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH-driven HCC mice models. Hepatocyte-specific FGF9 transgenic mice (FGF9Alb ) fed with a HFHC diet without CCl4 treatment exhibited an increased hepatic ECM and tumor burden. However, XAV-939 treatment blocked ECM accumulation and NASH-driven HCC in FGF9Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β-catenin dependent manner; and FGF9 exerts its effect on β-catenin stability via the ERK1/2-GSK-3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH-driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.
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Affiliation(s)
- Lei Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Key of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical University300070TianjinChina
| | - Qing Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Da Teng
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Manyu Guo
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Kechao Tang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Zhenglin Wang
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical University230022HefeiChina
| | - Xiang Wei
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Li Lin
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Xiaomin Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Xiuyun Wang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Dake Huang
- Synthetic Laboratory of School of Basic Medicine SciencesAnhui Medical University230032HefeiChina
| | - Cuiping Ren
- Department of Microbiology and ParasitologySchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Qingsong Yang
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Wenjun Zhang
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Yong Gao
- Science and Technology Innovation CenterGuangzhou University of Chinese Medicine510006GuangzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical University230022HefeiChina
| | - Yongsheng Chang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Key of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical University300070TianjinChina
| | - Huabing Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
- The Affiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
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20
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Godoy G, Bernardo C, Casagrande L, Sérgio M, Zanoni J, Perles J, Curi R, Bazotte R. Linseed oil attenuates fatty liver disease in mice fed a high-carbohydrate diet. Braz J Med Biol Res 2023; 56:e12927. [PMID: 37703111 PMCID: PMC10496762 DOI: 10.1590/1414-431x2023e12927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 07/27/2023] [Indexed: 09/15/2023] Open
Abstract
The impact of linseed oil as a lipid source on liver disease induced by a high-carbohydrate diet (HCD) was evaluated. Adult male Swiss mice received an HCD containing carbohydrates (72.1%), proteins (14.2%), and lipids (4.0%). The Control HCD group (HCD-C) received an HCD containing lard (3.6%) and soybean oil (0.4%) as lipid sources. The L10 and L100 groups received an HCD with 10 and 100% linseed oil as lipid sources, respectively. A group of mice were euthanized before receiving the diets (day 0) and the remaining groups after 56 days of receiving the diets (HCD-C, L10, and L-100 groups). Morphological and histopathological analyses, as well as collagen deposition were evaluated. Perivenous hepatocytes (PVH) of the HCD-C group were larger (P<0.05) than periportal hepatocytes (PPH) in the median lobe (ML) and left lobe (LL). There was a greater (P<0.05) deposition of type I collagen in PPH (vs PVH) and in the ML (vs LL). The ML exhibited a higher proportion of apoptotic bodies, inflammatory infiltrate, and hepatocellular ballooning. All these alterations (hepatocyte size, deposition of type I collagen, apoptotic bodies, inflammatory infiltrate, and hepatocellular ballooning) induced by HCD were prevented or attenuated in L10 and L100 groups. Another indicator of the beneficial effects of linseed oil was the lower (P<0.05) number of binucleated hepatocytes (HCD-C vs L10 or L100 group). In general, the L100 group had greater effects than the L10 group. In conclusion, linseed oil impedes or reduces the liver injury progression induced by an HCD.
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Affiliation(s)
- G. Godoy
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - C.C.O. Bernardo
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - L. Casagrande
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - M.L.M. Sérgio
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - J.N. Zanoni
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - J.V.C.M. Perles
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - R. Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, SP, Brasil
- Seção de Produção de Imunobiológicos, Centro Bioindustrial, Instituto Butantan, São Paulo, SP, Brasil
| | - R.B. Bazotte
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá, Maringá, PR, Brasil
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21
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Tang Z, Li X, Tian L, Sun Y, Zhu X, Liu F. Mesoporous polydopamine based biominetic nanodrug ameliorates liver fibrosis via antioxidation and TGF-β/SMADS pathway. Int J Biol Macromol 2023; 248:125906. [PMID: 37482153 DOI: 10.1016/j.ijbiomac.2023.125906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 05/12/2023] [Accepted: 07/09/2023] [Indexed: 07/25/2023]
Abstract
Early intervention of liver fibrosis can prevent its further irreversible progression. Both excess reactive oxygen species (ROS) and transforming growth factor beta(TGF-β)/drosophila mothers against decapentaplegic protein (SMADS) pathway balance disorder promote the progression of hepatic stellate cell (HSC) activation, but existing therapeutic strategies failed to focus on those two problems. A new biomimetic mesoporous polydopamine nandrug (MPO) was constructed for liver fibrosis therapy with multiple targets and reliable biosafety. The MPO was formed by mesoporous polydopamine (mPDA) which has the effect of ROS elimination and encapsulated with anti-fibrotic drug -oxymatrine (OMT) which can intervene liver fibrosis targeting TGF-β/SMADSpathway. Particularly, the nanodrug was completed by macrophage-derived exosome covering. The MPO was confirmed to possess a desired size distribution with negative zeta potential and exhibite strong ROS scavenger ability. Besides, in vitro studies, MPO showed efficient endocytosis and superior intracellular ROS scavenging without cytotoxicity; in vivo studies, MPO effectively cleared the excessive ROS in liver tissue and balanced the TGF-β/SMADS pathways, which in turn inhibited HSC activation and showed superior anti-liver fibrosis therapeutic efficiency with good biological safety. Taken together, this work showed highlights the great potential of the MPO for ameliorating liver fibrosis via ROS elimination and TGF-β/SMADS balancing.
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Affiliation(s)
- Zihui Tang
- Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China; State Key Laboratory of Systems Medicine for Cancer, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200090, China
| | - Xiaojuan Li
- Department of Gastroenterology, Minhang hospital of Fudan University, China
| | - Le Tian
- Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yuhao Sun
- Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xinyan Zhu
- Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
| | - Fei Liu
- Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
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22
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Sani F, Soufi Zomorrod M, Azarpira N, Soleimani M. The Effect of Mesenchymal Stem Cell-Derived Exosomes and miR17-5p Inhibitor on Multicellular Liver Fibrosis Microtissues. Stem Cells Int 2023; 2023:8836452. [PMID: 37576406 PMCID: PMC10421706 DOI: 10.1155/2023/8836452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 08/15/2023] Open
Abstract
Background Although several studies have been conducted on modeling human liver disease, it is still challenging to mimic nonalcoholic fatty liver disease in vitro. Here, we aimed to develop a fibrotic liver microtissue composed of hepatocytes, hepatic stellate, and endothelial cells. In addition, the therapeutic effects of umbilical cord mesenchymal stem cell-derived exosomes (UC-MSC-EXO) and anti-miR17-5p as new antifibrotic drugs were investigated. Methods To create an effective preclinical fibrosis model, multicellular liver microtissues (MLMs) consisting of HepG2, LX2, and HUVECs were cultured and supplemented with a mixture of palmitic acid and oleic acid for 96 hr. Then, MLMs were exposed to UC-MSC-EXO and anti-miR17-5p in different groups. The results of cell viability, reactive oxygen species (ROS) production, liver enzyme levels, inflammation, and histopathology were analyzed to assess the treatment efficacy. Furthermore, the expression of collagen I (COL I) and α-smooth muscle actin (α-SMA) as critical matrix components, transforming growth factor beta (TGF-β), and miR-17-5p were measured. Results Free fatty acid supplementation causes fibrosis in MLMs. Our results demonstrated that UC-MSC-EXO and anti-miR17-5p attenuated TGF-β1, interleukin-1β, and interleukin-6 in all experimental groups. According to the suppression of the TGF-β1 pathway, LX2 activation was inhibited, reducing extracellular matrix proteins, including COL I and α-SMA. Also, miR-17-5p expression was elevated in fibrosis conditions. Furthermore, we showed that our treatments decreased alanine aminotransferase and aspartate aminotransferase, and increased albumin levels in the culture supernatant. We also found that both MSC-EXO and MSC-EXO + anti-miR17-5p treatments could reduce ROS production. Conclusion Our findings indicated that anti-miR17-5p and MSC-EXO might be promising therapeutic options for treating liver fibrosis. Furthermore, EXO + anti-miR had the best effects on boosting the fibrotic markers. Therefore, we propose this novel MLM model to understand fibrosis mechanisms better and develop new drugs.
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Affiliation(s)
- Farnaz Sani
- Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mina Soufi Zomorrod
- Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street P.O. Box 7193711351, Shiraz, Iran
| | - Masoud Soleimani
- Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Ye B, Yu M, Yue M, Yin M, Zhang C, Wang Q, Ding X, Shen W, Zhao Z. Role of PDLIM1 in hepatic stellate cell activation and liver fibrosis progression. Sci Rep 2023; 13:10946. [PMID: 37414929 PMCID: PMC10326060 DOI: 10.1038/s41598-023-38144-3] [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: 02/14/2023] [Accepted: 07/04/2023] [Indexed: 07/08/2023] Open
Abstract
Liver fibrosis is caused by chronic hepatic injury and may lead to cirrhosis, and even hepatocellular carcinoma. When hepatic stellate cells (HSCs) are activated by liver injury, they transdifferentiate into myofibroblasts, which secrete extracellular matrix proteins that generate the fibrous scar. Therefore, it is extremely urgent to find safe and effective drugs for HSCs activation treatment to prevent liver against fibrosis. Here, we reported that PDZ and LIM domain protein 1 (PDLIM1), a highly conserved cytoskeleton organization regulator, was significantly up-regulated in fibrotic liver tissues and TGF-β-treated HSC-T6 cells. Through transcriptome analysis, we found that knockdown of PDLIM1 resulted in a significant downregulation of genes related to inflammation and immune-related pathways in HSC-T6 cells. Moreover, PDLIM1 knockdown significantly inhibited the activation of HSC-T6 cells and the trans-differentiation of HSC-T6 cells into myofibroblasts. Mechanistically, PDLIM1 is involved in the regulation of TGF-β-mediated signaling pathways in HSCs activation. Thus, targeting PDLIM1 may provide an alternative method to suppress HSCs activation during liver injury. CCCTC-binding factor (CTCF), a master regulator of genome architecture, is upregulated during HSCs activation. PDLIM1 knockdown also indirectly reduced CTCF protein expression, however, CTCF binding to chromatin was not significantly altered by CUT&Tag analysis. We speculate that CTCF may cooperate with PDLIM1 to activate HSCs in other ways. Our results suggest that PDLIM1 can accelerate the activation of HSCs and liver fibrosis progression and could be a potential biomarker for monitoring response to anti-fibrotic therapy.
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Affiliation(s)
- Bingyu Ye
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China.
| | - Mengli Yu
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Meijuan Yue
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Man Yin
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chunyan Zhang
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Qiwen Wang
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Xinru Ding
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Wenlong Shen
- Beijing Institute of Biotechnology, No. 20, Dongdajie Street, Fengtai District, Beijing, 100071, China.
| | - Zhihu Zhao
- Beijing Institute of Biotechnology, No. 20, Dongdajie Street, Fengtai District, Beijing, 100071, China.
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24
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Li T, Jiao J, Ke H, Ouyang W, Wang L, Pan J, Li X. Role of exosomes in the development of the immune microenvironment in hepatocellular carcinoma. Front Immunol 2023; 14:1200201. [PMID: 37457718 PMCID: PMC10339802 DOI: 10.3389/fimmu.2023.1200201] [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: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Despite numerous improved treatment methods used in recent years, hepatocellular carcinoma (HCC) is still a disease with a high mortality rate. Many recent studies have shown that immunotherapy has great potential for cancer treatment. Exosomes play a significant role in negatively regulating the immune system in HCC. Understanding how these exosomes play a role in innate and adaptive immunity in HCC can significantly improve the immunotherapeutic effects on HCC. Further, engineered exosomes can deliver different drugs and RNA molecules to regulate the immune microenvironment of HCC by regulating the aforementioned immune pathway, thereby significantly improving the mortality rate of HCC. This study aimed to declare the role of exosomes in the development of the immune microenvironment in HCC and list engineered exosomes that could be used for clinical transformation therapy. These findings might be beneficial for clinical patients.
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Affiliation(s)
- Tanghua Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiapeng Jiao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haoteng Ke
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenshan Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Luobin Wang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jin Pan
- The Department of Electronic Engineering, The Chinese University of Hong Kong, Hongkong, Hongkong SAR, China
| | - Xin Li
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
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25
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Zheng KX, Yuan SL, Dong M, Zhang HL, Jiang XX, Yan CL, Ye RC, Zhou HQ, Chen L, Jiang R, Cheng ZY, Zhang Z, Wang Q, Jin WZ, Xie W. Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type II receptor. World J Gastroenterol 2023; 29:3103-3118. [PMID: 37346154 PMCID: PMC10280794 DOI: 10.3748/wjg.v29.i20.3103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND The transforming growth factor β (TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type II receptor (TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.
AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.
METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.
RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.
CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
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Affiliation(s)
- Ke-Xin Zheng
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shou-Li Yuan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Meng Dong
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Han-Lin Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Xiao-Xiao Jiang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Chun-Long Yan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, Agriculture College of Yanbian University, Yanji 133002, Jilin Province, China
| | - Rong-Cai Ye
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Hui-Qiao Zhou
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Li Chen
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Rui Jiang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Zi-Yu Cheng
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Zhi Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wan-Zhu Jin
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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26
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Yin KL, Li M, Song PP, Duan YX, Ye WT, Tang W, Kokudo N, Gao Q, Liao R. Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases. J Clin Transl Hepatol 2023; 11:441-451. [PMID: 36643031 PMCID: PMC9817040 DOI: 10.14218/jcth.2022.00326] [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: 07/13/2022] [Revised: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSC-derived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSC-associated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.
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Affiliation(s)
- Kun-Li Yin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ming Li
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Pei-Pei Song
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Yu-Xin Duan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wen-Tao Ye
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Tang
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
- Correspondence to: Qiang Gao, Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, 180 Fenglin Road, Shanghai 200032, China. ORCID: https://orcid.org/0000-0002-6695-9906. ; Rui Liao, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, 1 Youyi Road, Chongqing 400016, China. ORCID: https://orcid.org/0000-0002-0057-2792. E-mail:
| | - Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Correspondence to: Qiang Gao, Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, 180 Fenglin Road, Shanghai 200032, China. ORCID: https://orcid.org/0000-0002-6695-9906. ; Rui Liao, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, 1 Youyi Road, Chongqing 400016, China. ORCID: https://orcid.org/0000-0002-0057-2792. E-mail:
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Goralska J, Razny U, Gruca A, Zdzienicka A, Micek A, Dembinska-Kiec A, Solnica B, Malczewska-Malec M. Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity. Biomolecules 2023; 13:biom13040675. [PMID: 37189422 DOI: 10.3390/biom13040675] [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: 02/20/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
There is growing interest in the non-invasive identification and monitoring of the outcome of liver damage in obese patients. Plasma cytokeratin-18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and have recently been proposed to independently predict the presence of non-alcoholic steatohepatitis (NASH). The aim of the study was to analyze the associations of CK-18 with obesity and related complications: insulin resistance, impaired lipid metabolism and the secretion of hepatokines, adipokines and pro-inflammatory cytokines. The study involved 151 overweight and obese patients (BMI 25-40), without diabetes, dyslipidemia or apparent liver disease. Liver function was assessed based on alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and the fatty liver index (FLI). CK-18 M30 plasma levels, FGF-21, FGF-19 and cytokines were determined by ELISA. CK-18 values >150 U/l were accompanied by high ALT, GGT and FLI, insulin resistance, postprandial hypertriglyceridemia, elevated FGF-21 and MCP-1 and decreased adiponectin. ALT activity was the strongest independent factor influencing high CK-18 plasma levels, even after an adjustment for age, sex and BMI [β coefficient (95%CI): 0.40 (0.19-0.61)]. In conclusion, the applied CK-18 cut-off point at 150 U/l allows to distinguish between two metabolic phenotypes in obesity.
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Affiliation(s)
- Joanna Goralska
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Urszula Razny
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Anna Gruca
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Anna Zdzienicka
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Agnieszka Micek
- Institute of Nursing and Midwifery, Jagiellonian University Medical College; Michałowskiego 12, 31-126 Krakow, Poland
| | - Aldona Dembinska-Kiec
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Bogdan Solnica
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
| | - Malgorzata Malczewska-Malec
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Skawinska 8, 31-066 Krakow, Poland
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Salem GEM, Azzam SM, Nasser MA, Malah TE, Abd El-Latief HM, Chavanich S, Khan RH, Anwar HM. Bacterial protease alleviate chronic liver fibrosis induced by thioacetamide through suppression of hepatic stellate cells consequently decrease its proliferative index. Int J Biol Macromol 2023; 239:124243. [PMID: 37011746 DOI: 10.1016/j.ijbiomac.2023.124243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/24/2023] [Accepted: 03/26/2023] [Indexed: 04/03/2023]
Abstract
In chronic liver diseases, liver fibrosis occurs due to excessive extracellular matrix (ECM) protein accumulation. Approximately 2 million deaths occur yearly due to liver disease, while cirrhosis is the 11th most common cause of death. Therefore, newer compounds or biomolecules must be synthesized to treat chronic liver diseases. In this aspect, the present study focuses on the assessment of the anti-inflammatory and antioxidant impact of Bacterial Protease (BP) produced by a new mutant strain of bacteria (Bacillus cereus S6-3/UM90) and 4,4'-(2,5-dimethoxy-1,4-phenylene) bis (1-(3-ethoxy phenyl)-1H-1,2,3-triazole) (DPET) in the treatment of early stage of liver fibrosis induced by thioacetamide (TAA). Sixty male rats were divided into six groups, ten rats each as follows: (1) Control group, (2) BP group, (3) TAA group, (4) TAA-Silymarin (S) group, (5) TAA-BP group, and (6) TAA-DPET group. Liver fibrosis significantly elevated liver function ALT, AST, and ALP, as well as anti-inflammatory interleukin 6 (IL-6) and VEGF. The oxidative stress parameters (MDA, SOD, and NO) were significantly increased with a marked reduction in GSH. Expression of MAPK and MCP-1 was unregulated in the TAA group, with downregulation of Nrf2 was observed. TAA caused histopathological alterations associated with hepatic vacuolation and fibrosis, increasing collagen fibers and high immuno-expression of VEGF. On the other hand, treatment with BP successfully improved the severe effects of TAA on the liver and restored histological architecture. Our study concluded the protective potentials of BP for attenuating liver fibrosis and could be used as adjuvant therapy for treating hepatic fibrosis.
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Cho YE, Kwon YS, Hwang S. Heterogeneous population of macrophages in the development of non-alcoholic fatty liver disease. LIVER RESEARCH 2023; 7:16-25. [PMID: 39959694 PMCID: PMC11791820 DOI: 10.1016/j.livres.2022.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/09/2022] [Accepted: 06/25/2022] [Indexed: 11/21/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by a spectrum of hepatic diseases, including fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation, necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets. Although fatty liver is benign and does not exert marked liver damage or inflammation, NAFLD progression involves inflammatory processes facilitated by immune cells. Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types, such as neutrophils, T cells, and natural killer cells. The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated; however, the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes, whose functions need to be comprehensively elucidated. The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development. In addition, the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.
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Affiliation(s)
- Ye Eun Cho
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Yong Seong Kwon
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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Paliwal VM, Kundu S, Kulhari U, Jala A, Ishteyaque S, Borkar RM, Mugale MN, Murty US, Sahu BD. Alternanthera brasiliana L. extract alleviates carbon tetrachloride-induced liver injury and fibrotic changes in mice: Role of matrix metalloproteinases and TGF-β/Smad axis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115992. [PMID: 36509261 DOI: 10.1016/j.jep.2022.115992] [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: 07/02/2022] [Revised: 11/20/2022] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alternanthera brasiliana L. is a flowering plant belonging to the family Amaranthaceae and is popularly known as "penicillin". It is used in folk medicine to treat infections, coughs, wound healing, and inflammatory diseases. AIM OF THE STUDY We investigated the effect of Alternanthera brasiliana L. leaves hydroalcoholic extract (AB) against oxidative stress, inflammation, and fibrotic changes in an experimental model of carbon tetrachloride (CCl4)-induced liver injury and fibrosis in mice. MATERIALS AND METHODS Thirty-six male Balb/C mice were randomized into five groups: normal control, AB control, CCl4 control, CCl4 + AB-200 mg/kg, and CCl4 + AB-400 mg/kg. In mice, liver injury was induced by intraperitoneal injection of CCl4 (20% in corn oil, 5 ml/kg body weight) thrice a week for six consecutive weeks. AB extract at two doses (200 mg/kg and 400 mg/kg body weight) was administered orally for six consecutive weeks. Liver injury-related serum markers (ALT, AST, ALP), antioxidants (GSH, GST, SOD, and vitamin C), pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18, ultrasonographic and histological alterations, proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), nuclear factor-κB (p65) (NF-κB), nod-like receptor protein 3 (NLRP3), and TGF-β/Smad signaling were accessed. LC-Q-TOF-MS/MS analysis of AB was performed. RESULTS AB treatment significantly decreased the CCl4-induced rise in serum ALT, AST, and ALP activities and improved the histological alterations. Compared with the CCl4-treated group, treatment with AB significantly restored the hepatic antioxidants and reduced the pro-inflammatory cytokines in the liver. The antioxidant activity of AB may be attributed to its terpenoid constituents, which was confirmed by LC-Q-TOF-MS/MS analysis. The CCl4-induced rise in expression of MMP-2 and MMP-9 and decrease in TIMP-1 were markedly restored in the AB-treated groups. Further findings revealed a significant reduction in the protein levels of phospho-NF-κB (p65), NLRP3, TGF-β, pSmad2/3, collagen I, and α-smooth muscle actin (α-SMA) in the AB treatment groups. CONCLUSIONS The hepatoprotective effect of AB may be attributed to the high content of terpenoid compounds and alleviates liver injury and associated fibrotic changes through modulating MMPs, NF-κB (p65), and the TGF-β/Smad axis.
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Affiliation(s)
- Vinay M Paliwal
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Sourav Kundu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Uttam Kulhari
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Aishwarya Jala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Sharmeen Ishteyaque
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Madhav Nilakanth Mugale
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Upadhyayula Suryanarayana Murty
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Bidya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India.
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Liu B, Wang J, Wang G, Jiang W, Li Z, Shi Y, Zhang J, Pei Q, Huang G, Wang L, Zhao S, Wu L, Zhang M, Wang W, Li X, Mou T, Zhang C, Ding Q. Hepatocyte-derived exosomes deliver H2AFJ to hepatic stellate cells and promote liver fibrosis via the MAPK/STMN1 axis activation. Int Immunopharmacol 2023; 115:109605. [PMID: 36608439 DOI: 10.1016/j.intimp.2022.109605] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 01/06/2023]
Abstract
Hepatic stellate cells (HSCs) activate and acquire proliferative features in response to liver injury. However, mechanisms involved in the activation of fibrotic HSCs remain uncharacterized. This study aims at elaborating the mechanistic basis by which exosomal H2AFJ derived from hepatocytes might affect the activation of HSCs and liver fibrosis. Bioinformatics analysis based on transcriptomic RNA-seq data was used to screen out the downstream regulatory genes and pathways of H2AFJ. Mouse hepatocytes AML-12 cells were stimulated with CCl4 to mimic an in vitro microenvironment of liver fibrosis, from which exosomes were isolated. Next, HSCs were co-cultured with hepatocyte-derived exosomes followed by detection of HSC migration and invasion in the presence of manipulated H2AFJ and STMN1 expression and MAPK pathway inhibitor. It was found that H2AFJ was highly expressed in hepatocyte-derived exosomes after CCl4 stimulation. Hepatocyte-derived exosomal H2AFJ promoted HSC migration and invasion. H2AFJ upregulated c-jun-mediated STMN1 by activating the MAPK signaling pathway. Furthermore, in vivo experiments verified that silencing of H2AFJ attenuated liver fibrosis in mice, while restoration of STMN1 negated its effect. Collectively, hepatocyte-derived exosomal H2AFJ aggravated liver fibrosis by activating the MAPK/STMN1 signaling pathway. This study provides a potential therapeutic target for alleviating liver fibrosis.
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Affiliation(s)
- Bin Liu
- Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Jinchao Wang
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Guangchuan Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Wanli Jiang
- First Clinical School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China
| | - Zhen Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Yongjun Shi
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Junyong Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Qingshan Pei
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Guangjun Huang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Lifen Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Shengqiang Zhao
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Lei Wu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Mingyan Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Wenwen Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Xiao Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Tong Mou
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China
| | - Qian Ding
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China.
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Li X, Yao Y, Wei L. Indirubin alleviates CCl 4-induced liver fibrosis by regulation of TGF-β-mediated signaling pathways. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1047-1052. [PMID: 37605732 PMCID: PMC10440143 DOI: 10.22038/ijbms.2023.70476.15319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/10/2023] [Indexed: 08/23/2023]
Abstract
Objectives Liver fibrosis is a common liver disease caused by chronic liver damage. However, there are currently no approved drugs available to treat it. Therefore, the therapeutic effect of indirubin on liver fibrosis was evaluated. This study investigated the protective effect and related molecular mechanism of indirubin against CCl4-induced liver fibrosis in mice. Materials and Methods We first detected the effect of indirubin on liver fibrosis in mice (n=8 per group, 32 mice total) by ELISA, HE, and Masson staining. Subsequently, the proliferation of activated HSCs was detected by MTT and EdU. Finally, the changes of related proteins and signaling pathways in mice treated with indirubin were investigated by qRT-PCR and Western blot. One-way ANOVA or two-tailed student's t-test was used for comparison between groups. Results Firstly, we found that indirubin (25 mg/kg) therapy could attenuate liver injury and significantly down-regulate α-SMA (P=0.0038) and collagen 1 (P=0.0057) in the liver using CCl4-induced liver fibrosis in mice. Secondly, we showed that indirubin (25 μM) could significantly inhibit hepatic stellate cell (HSC) trans-differentiation into myofibroblasts and proliferation (P=0.0063) in HSC-T6 cells treated by TGF-β. Finally, we showed that indirubin could greatly reduce the protein levels of p-Smad2/3, p38, p-ERK, and p-JNK in vivo and in vitro. Conclusion Our results suggested that indirubin alleviated liver fibrosis and HSC activation mainly through TGF-β-mediated signaling pathways in vivo and in vitro. In conclusion, our data showed that indirubin could be a promising clinical therapeutic drug for the prevention and treatment of liver fibrosis.
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Affiliation(s)
- Xiaoying Li
- College of Biology and Food Engineering, Huaihua University. Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, Hunan, 418000, China
| | - Yuanzhi Yao
- College of Biology and Food Engineering, Huaihua University. Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, Hunan, 418000, China
| | - Lin Wei
- College of Biology and Food Engineering, Huaihua University. Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, Hunan, 418000, China
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
- Daosheng Biology (Shenzhen) Co., Ltd, Shenzhen, 518107, China
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Ezhilarasan D, Najimi M. Intercellular communication among liver cells in the perisinusoidal space of the injured liver: Pathophysiology and therapeutic directions. J Cell Physiol 2023; 238:70-81. [PMID: 36409708 DOI: 10.1002/jcp.30915] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/25/2022] [Accepted: 11/03/2022] [Indexed: 11/22/2022]
Abstract
Hepatic stellate cells (HSCs) in the perisinusoidal space are surrounded by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and other resident immune cells. In the normal liver, HSCs communicate with these cells to maintain normal liver functions. However, after chronic liver injury, injured hepatocytes release several proinflammatory mediators, reactive oxygen species, and damage-associated molecular patterns into the perisinusoidal space. Consequently, such alteration activates quiescent HSCs to acquire a myofibroblast-like phenotype and express high amounts of transforming growth factor-β1, angiopoietins, vascular endothelial growth factors, interleukins 6 and 8, fibril forming collagens, laminin, and E-cadherin. These phenotypic and functional transdifferentiation lead to hepatic fibrosis with a typical abnormal extracellular matrix synthesis and disorganization of the perisinusoidal space of the injured liver. Those changes provide a favorable environment that regulates tumor cell proliferation, migration, adhesion, and survival in the perisinusoidal space. Such tumor cells by releasing transforming growth factor-β1 and other cytokines, will, in turn, activate and deeply interact with HSCs via a bidirectional loop. Furthermore, hepatocellular carcinoma-derived mediators convert HSCs and macrophages into protumorigenic cell populations. Thus, the perisinusoidal space serves as a critical hub for activating HSCs and their interactions with other cell types, which cause a variety of liver diseases such as hepatic inflammation, fibrosis, cirrhosis, and their complications, such as portal hypertension and hepatocellular carcinoma. Therefore, targeting the crosstalk between activated HSCs and tumor cells/immune cells in the tumor microenvironment may also support a promising therapeutic strategy.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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Godoy G, Antunes MM, Fernandes IDL, Manin LP, Zappielo C, Masi LN, Perles JVCM, Visentainer JV, Curi R, Bazotte RB. Linseed Oil Attenuates Liver Inflammation, Fatty Acid Accumulation, and Lipid Distribution in Periportal and Perivenous Hepatocytes Induced by a High-Carbohydrate Diet in Mice. J Med Food 2022; 25:1133-1145. [PMID: 36450115 DOI: 10.1089/jmf.2022.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
We evaluated whether linseed oil (LO) modulates the effects of a high-carbohydrate diet (HCD) on liver inflammation, fatty acid (FA) accumulation, and lipid distribution in periportal and perivenous hepatocytes. The control group (control high-carbohydrate diet [HCD-C]) received an HCD with lard and soybean oil as the lipid source. The L10 and L100 groups received the HCD with 10% and 100% of LO as the lipid source, respectively. The animals were killed by decapitation before (day 0) and after receiving the diets. Liver FA composition, inflammation, and fibrogenesis gene expression were evaluated. Also, the percentage of lipid-occupied area in periportal end perivenous hepatocytes were measured. The L100 group exhibited a higher (P < .05) liver amount of omega-3 polyunsaturated FA (n-3 PUFA) and lower (P < .05) amounts of saturated FA (SFA), monounsaturated FA (MUFA), and omega-6 polyunsaturated FA (n-6 PUFA) compared with L10 or HCD-C mice. On day 56, interleukin 10 and type IV collagen gene expression were significantly upregulated and downregulated, respectively in L100. Also, the L100 group showed lower (P < .05) FA accumulation (i.e., total FA, SFA, MUFA, and n-6 PUFA). Also, L10 and L100 presented lower (P < .05) percentage of high lipid-containing portion in periportal and perivenous hepatocytes. We concluded that LO attenuation of liver inflammation promoted by an HCD is associated with increased liver n-3 PUFA levels, so modulating FA composition, deposition, and distribution in periportal and perivenous hepatocytes.
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Affiliation(s)
- Guilherme Godoy
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná State, Brazil
| | - Marina Masetto Antunes
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná State, Brazil
| | - Ingrid de Lima Fernandes
- Postgraduate Program in Pharmaceutical Sciences, Department of Chemistry, State University of Maringá, Maringá, Paraná State, Brazil
| | - Luciana Pelissari Manin
- Postgraduate Program in Pharmaceutical Sciences, Department of Chemistry, State University of Maringá, Maringá, Paraná State, Brazil
| | - Caroline Zappielo
- Postgraduate Program in Pharmaceutical Sciences, Department of Chemistry, State University of Maringá, Maringá, Paraná State, Brazil
| | - Laureane Nunes Masi
- Interdisciplinary Postgraduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, São Paulo State, Brazil
| | - Juliana Vanessa Colombo Martins Perles
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná State, Brazil
| | - Jesuí Vergílio Visentainer
- Postgraduate Program in Pharmaceutical Sciences, Department of Chemistry, State University of Maringá, Maringá, Paraná State, Brazil
| | - Rui Curi
- Interdisciplinary Postgraduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, São Paulo State, Brazil
| | - Roberto Barbosa Bazotte
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná State, Brazil
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Kovner A, Zaparina O, Kapushchak Y, Minkova G, Mordvinov V, Pakharukova M. Jagged-1/Notch Pathway and Key Transient Markers Involved in Biliary Fibrosis during Opisthorchis felineus Infection. Trop Med Infect Dis 2022; 7:364. [PMID: 36355906 PMCID: PMC9697314 DOI: 10.3390/tropicalmed7110364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 12/20/2023] Open
Abstract
Chronic opisthorchiasis associated with Opisthorchis felineus infection is accompanied by severe fibrotic complications. It is of high practical significance to elucidate the mechanisms of hepatic fibrosis in chronic infection dynamics. The goal of the study is to investigate the temporal profile of key markers and the Jagged1/Notch signaling pathway in the implementation of fibrosis in a chronic O. felineus infection. For the first time, using histological methods and real-time PCR analysis, we demonstrated the activation of the Jagged1/Notch pathway in liver fibrogenesis, including the activation of the Hes1 and Hey1 target genes during experimental opisthorchiasis in Mesocricetus auratus. Cluster analysis followed by regression analysis of key markers during the infection showed that Jagged1 and Mmp9have the greatest contribution to the development of cholangiofibrosis and periductal fibrosis. Moreover, we detected a significant increase in the number of Jagged1-positive cells in the liver of chronic opisthorchiasis patients compared to that of the control group without infection. The results of the study are extremely informative both in terms of investigation both diverse fibrosis mechanisms as well as potential targets in complex antihelmintic therapy.
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Affiliation(s)
- Anna Kovner
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Oxana Zaparina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Yaroslav Kapushchak
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Galina Minkova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Viatcheslav Mordvinov
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Maria Pakharukova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
- Institute of Molecular Biology and Biophysics, Subdivision of FRC FTM, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630117, Russia
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Morsy MA, Abdel-Latif R, Hafez SMNA, Kandeel M, Abdel-Gaber SA. Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis-The Role of Drug Efflux Transporters. Pharmaceuticals (Basel) 2022; 15:ph15101296. [PMID: 36297408 PMCID: PMC9611069 DOI: 10.3390/ph15101296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/16/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.
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Affiliation(s)
- Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al Hofuf 31982, Al-Ahsa, Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
- Correspondence: ; Tel.: +966-5496-72245
| | - Rania Abdel-Latif
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
| | | | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Hofuf 31982, Al-Ahsa, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
| | - Seham A. Abdel-Gaber
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
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Guizhen Z, Guanchang J, Liwen L, Huifen W, Zhigang R, Ranran S, Zujiang Y. The tumor microenvironment of hepatocellular carcinoma and its targeting strategy by CAR-T cell immunotherapy. Front Endocrinol (Lausanne) 2022; 13:918869. [PMID: 36093115 PMCID: PMC9452721 DOI: 10.3389/fendo.2022.918869] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/05/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, which ranks sixth in cancer incidence and third in mortality. Although great strides have been made in novel therapy for HCC, such as immunotherapy, the prognosis remains less than satisfactory. Increasing evidence demonstrates that the tumor immune microenvironment (TME) exerts a significant role in the evolution of HCC and has a non-negligible impact on the efficacy of HCC treatment. In the past two decades, the success in hematological malignancies made by chimeric antigen receptor-modified T (CAR-T) cell therapy leveraging it holds great promise for cancer treatment. However, in the face of a hostile TME in solid tumors like HCC, the efficacy of CAR-T cells will be greatly compromised. Here, we provide an overview of TME features in HCC, discuss recent advances and challenges of CAR-T immunotherapy in HCC.
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Affiliation(s)
- Zhang Guizhen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ji Guanchang
- Department of Urology People’s Hospital of Puyang, Puyang, China
| | - Liu Liwen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wang Huifen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ren Zhigang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sun Ranran
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Zujiang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
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Duan N, Chen H, Pi L, Ali Y, Cao Q. Cis-4-[18F]fluoro-L-proline PET/CT molecular imaging quantifying liver collagenogenesis: No existing fibrotic deposition in experimental advanced-stage alcoholic liver fibrosis. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2022; 2:952943. [PMID: 39354960 PMCID: PMC11440931 DOI: 10.3389/fnume.2022.952943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/12/2022] [Indexed: 10/03/2024]
Abstract
Background and purpose Heavy alcohol drinking-induced alcoholic fatty liver, steatohepatitis, and early-stage alcoholic liver fibrosis may progress to advanced-stage alcoholic liver fibrosis (AALF)/cirrhosis. The lack of non-invasive imaging techniques for the diagnosising collagenogenesis in activated hepatic stellate cells (HSCs) can lead to incurable liver fibrosis at the early reversible stage. Proline has been known as the most abundant amino acid of collagen type 1 synthesized by activated HSC with the transportation of proline transporter. cis-4-[18F]fluoro-L-proline ([18F]proline) was reported as a useful tool to quantify collagenogenesis in experimental alcoholic steatohepatitis. This study aims to use [18F]proline micro PET as non-invasive imaging to quantify liver collagenogenesis in HSC of experimental AALF. Methods AALF model was set up by a modified Lieber-DeCarli liquid ethanol diet for 12 weeks along with intraperitoneal injection (IP) of CCl 4 (0.5 ml/kg) between the 5th and 12th weeks. Controls were fed an isocaloric liquid diet and IP. PBS. In vitro [3H]proline uptake by HSCs isolated from livers was quantified using a liquid scintillation counter. Collagen type 1 production in HSCs culture medium was assayed by ELISA. Ex vivo liver collagen type 1 and proline transporter protein were compared between AALF rats (n = 8) and mice (n = 8). [3H]Proline uptake specificity in ex vivo liver tissues was tested using unlabeled proline and transporter inhibitor benztropine at different doses. Liver H&E, trichrome stain, and blood biochemistry were tested in rats and mice. In vivo, at varying times after instillation, dynamic and static [18F]proline micro PET/CT were done to quantify tracer uptake in AALF mice (n = 3). Correlation among liver collagen, liver SUVmax, normalized liver-to-brain ratio, normalized liver-to-thigh ratio, and fluoro-proline-induced collagen levels in ex vivo liver tissues were analyzed. Results In vitro HSCs study showed significant higher [3H]proline uptake (23007.9 ± 5089.2 vs. 1075.4 ± 119.3 CPM/mg, p < 0.001) in HSCs isolated from AALF rats than controls and so was collagen type 1 production (24.3 ± 5.8 vs. 3.0 ± 0.62 mg/ml, p < 0.001) in HSCs culture medium. Highly positive correlation between [3H]proline uptake and collagen type 1 by HSCs of AALF rats was found (r value = 0.92, p < 0.01). Ex vivo liver tissue study showed no significant difference in collagen type 1 levels between AALF rats (14.83 ± 5.35 mg/g) and AALF mice (12.91 ± 3.62 mg/g, p > 0.05), so was proline transporter expression between AALF rats (7.76 ± 1.92-fold) and AALF mice (6.80 ± 0.97-fold). Unlabeled fluoro-proline induced generation of liver tissue collagen type 1 and [3H]proline uptake were specifically blocked by transporter inhibitor. In vivo [18F]proline micro PET/CT imaging showed higher SUVmax in liver (4.90 ± 0.91 vs. 1.63 ± 0.38, p < 0.01), higher normalized liver/brain ratio (12.54 ± 0.72 vs. 2.33 ± 0.41, p < 0.01), and higher normalized liver/thigh ratio (6.03 ± 0.78 vs. 1.09 ± 0.09, p < 0.01) in AALF mice than controls, which are all positively correlated with fluoro-proline-induced levels of collagen in liver tissue (r value ≥ 0.93, p < 0.01) in AALF mice, but not correlated with existing liver collagen. Liver histology showed increased collagen in the liver of AALF mice. Blood serum ALT and AST levels were remarkably higher in AALF mice than in controls, but there is no significant difference in blood fibrotic parameters HA, A2M, TGFβ1, and MMP1. Conclusions [18F]proline micro PET/CT might be useful to visualize collagenogenesis in activated HSC of experimental AALF but fails to quantify existing liver collagen in AALF mice. [18F]proline has the potential sensitivity to assess the activity and severity of liver fibrosis.
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Affiliation(s)
- Na Duan
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongxia Chen
- School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Liya Pi
- University of Maryland Medical Center, Tulane University, New Orleans, LA, United States
| | - Youssef Ali
- School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Qi Cao
- School of Medicine, University of Maryland, Baltimore, MD, United States
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Wu B, Tian X, Wang W, Zhu J, Lu Y, Du J, Xiao Y. Upregulation of cadherin-11 contributes to cholestatic liver fibrosis. Pediatr Investig 2022; 6:100-110. [PMID: 35774522 PMCID: PMC9218970 DOI: 10.1002/ped4.12317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/27/2022] [Indexed: 11/17/2022] Open
Abstract
Importance Cadherin-11 (CDH11), a cell-to-cell adhesion molecule, is implicated in the fibrotic process of several organs. Biliary atresia (BA) is a common cholestatic liver disease featuring cholestasis and progressive liver fibrosis in children. Cholestatic liver fibrosis may progress to liver cirrhosis and lacks effective therapeutic strategies. Currently, the role of CDH11 in cholestatic liver fibrosis remains unclear. Objective This study aimed to explore the functions of CDH11 in cholestatic liver fibrosis. Methods The expression of CDH11 in BA livers was evaluated by database analysis and immunostaining. Seven BA liver samples were used for immunostaining. The wild type (Wt) and CDH11 knockout (CDH11-/- ) mice were subjected to bile duct ligation (BDL) to induce cholestatic liver fibrosis. The serum biochemical analysis, liver histology, and western blotting were used to assess the extent of liver injury and fibrosis as well as activation of transforming growth factor-β (TGF-β)/Smad pathway. The effect of CDH11 on the activation of hepatic stellate cell line LX-2 cells was investigated. Results Analysis of public RNA-seq datasets showed that CDH11 expression levels were significantly increased in livers of BA, and CDH11 was correlated with liver fibrosis in BA. BDL-induced liver injury and liver fibrosis were attenuated in CDH11-/- mice compared to Wt mice. The protein expression levels of phosphorylated Smad2/3 were decreased in livers of CDH11-/- BDL mice compared to Wt BDL mice. CDH11 knockdown inhibited the activation of LX-2 cells. Interpretation CDH11 plays an important role in cholestatic liver fibrosis and may represent a potential therapeutic target for cholestatic liver disease, such as BA.
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Affiliation(s)
- Bo Wu
- Department of Pediatric Surgery, Xin Hua HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Xinbei Tian
- Department of Pediatric Surgery, Xin Hua HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Weipeng Wang
- Department of Pediatric Surgery, Xin Hua HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Jing Zhu
- Department of Pediatric Surgery, Xin Hua HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Ying Lu
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Jun Du
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
| | - Yongtao Xiao
- Department of Pediatric Surgery, Xin Hua HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Department of Pediatric Gastroenterology and NutritionShanghai Institute of Pediatric ResearchShanghaiChina
- Shanghai Key Laboratory of Pediatric Gastroenterology and NutritionShanghaiChina
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Zhang Y, Wu Y, Shen W, Wang B, Yuan X. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol Med Rep 2022; 25:208. [PMID: 35506449 PMCID: PMC9133963 DOI: 10.3892/mmr.2022.12724] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/19/2022] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is a common pathological process of chronic liver diseases, including viral hepatitis and alcoholic liver disease, and ultimately progresses to irreversible cirrhosis and cancer. Hepatic stellate cells (HSCs) are activated to produce amounts of collagens in response to liver injury, thus triggering the initiation and progression of fibrogenesis. Natural killer (NK) cells serve as the essential component of hepatic innate immunity and are considered to alleviate fibrosis by killing activated HSCs. Current antifibrotic interventions have improved fibrosis, but fail to halt its progression in the advanced stage. Clarifying the interaction between NK cells and HSCs will provide clues to the pathogenesis and potential therapies for advanced liver fibrosis.
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Affiliation(s)
- Yang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Yuan Wu
- The Graduate School, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Wenjuan Shen
- Department of Gynaecology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Bingyu Wang
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Xingxing Yuan
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
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Fu R, Zu SJ, Liu YJ, Li JC, Dang WZ, Liao LP, Liu LP, Chen PY, Huang HM, Wu KH, Zhou B, Pan Q, Luo C, Zhang YY, Li GM. Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis. Bioengineered 2022; 13:10914-10930. [PMID: 35499161 PMCID: PMC9278415 DOI: 10.1080/21655979.2022.2066756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl4-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.
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Affiliation(s)
- Rong Fu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Shi-Jia Zu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
| | - Yan-Jun Liu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Jia-Cheng Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Wen-Zhen Dang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Li-Ping Liao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Li-Ping Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Pan-Yu Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - He-Ming Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Kang-Hui Wu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Bing Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
- Research center, Zhoupu Hospital affiliated to Shanghai University of Medicine and Health Sciences, Shanghai, Zhouyuan District, China
| | - Cheng Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCAS, Hangzhou, Zhejiang, China
| | - Yuan-Yuan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Zuchongzhi District, Shanghai, China
- University of Chinese Academy of Sciences, Huairou District, Beijing, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCAS, Hangzhou, Zhejiang, China
| | - Guang-Ming Li
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, Yangpu District, China
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Pessoa J, Teixeira J. Cytoskeleton alterations in non-alcoholic fatty liver disease. Metabolism 2022; 128:155115. [PMID: 34974078 DOI: 10.1016/j.metabol.2021.155115] [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: 10/19/2021] [Revised: 12/08/2021] [Accepted: 12/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Due to its extremely high prevalence and severity, non-alcoholic fatty liver disease (NALFD) is a serious health and economic concern worldwide. Developing effective methods of diagnosis and therapy demands a deeper understanding of its molecular basis. One of the strategies in such an endeavor is the analysis of alterations in the morphology of liver cells. Such alterations, widely reported in NAFLD patients and disease models, are related to the cytoskeleton. Therefore, the fate of the cytoskeleton components is useful to uncover the molecular basis of NAFLD, to further design innovative approaches for its diagnosis and therapy. MAIN FINDINGS Several cytoskeleton proteins are up-regulated in liver cells of NAFLD patients. Under pathological conditions, keratin 18 is released from hepatocytes and its detection in the blood emerges as a non-invasive diagnosis tool. α-Smooth muscle actin is up-regulated in hepatic stellate cells and its down-regulation has been widely tested as a potential NALFD therapeutic approach. Other cytoskeleton proteins, such as vimentin, are also up-regulated. CONCLUSIONS NAFLD progression involves alterations in expression levels of proteins that build the liver cytoskeleton or associate with it. These findings provide a timely opportunity of developing novel approaches for NAFLD diagnosis and therapy.
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Affiliation(s)
- João Pessoa
- CNC - Center for Neuroscience and Cell Biology, CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
| | - José Teixeira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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Production of Bioactive Substances to Alleviates Hangover and Ethanol-Induced Liver Damage through Fermentation of Oenanthe javanica Using Lactiplantibacillus plantarum. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041175. [PMID: 35208964 PMCID: PMC8880744 DOI: 10.3390/molecules27041175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 11/22/2022]
Abstract
The purpose of this study is to evaluate the effect of the bioconversion products of Oenanthe javanica extract fermented by Lactiplantibacillus plantarum (OEFL) on relieving hangovers and improving liver function. In addition, the bioactive substance of the OEFL, which alleviates hangover and ethanol-induced liver damage, was identified and its bioactive property was verified through in vivo experiments. In major substances analysis using high-performance liquid chromatography, OEFL produced 9.5-fold higher p-coumaric acid than the O. Javanica extract (OE). In addition, considering that quinic acid, which is not present in the OE, was produced in the OEFL it was confirmed that chlorogenic acid was decomposed into quinic acid by bioconversion. In the in vivo experiment using Sprague-Dawley rats, the OEFL and p-coumaric acid diets reduced blood ethanol, acetaldehyde, GPT, and ALP concentrations, increasing blood albumin concentrations compared to ethanol-administered groups, demonstrating that OEFL and p-coumaric acid, the main substance in the OEFL, improved ethanol-induced liver damage. Furthermore, the OEFL and its main bioactive substance, p-coumaric acid, alleviated liver fibrosis by downregulating TGF-β, SMAD-2, SMAD-4, α-SMA, and upregulating MMP-1. Therefore, OEFL is expected to be used as a functional food or pharmaceutical material as it has been confirmed to effectively relieve hangovers, prevent liver damage, and delay liver fibrosis in ethanol-induced liver damages.
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Dorairaj V, Sulaiman SA, Abu N, Abdul Murad NA. Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis. Biomedicines 2021; 10:15. [PMID: 35052690 PMCID: PMC8773432 DOI: 10.3390/biomedicines10010015] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/14/2022] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form of steatosis, nonalcoholic steatohepatitis (NASH), which could progress to irreversible liver injury (fibrosis) and organ failure, and in some cases hepatocellular carcinoma (HCC). Although a liver biopsy remains the gold standard for accurate detection of this condition, it is unsuitable for clinical screening due to a higher risk of death. There is thus an increased need to find alternative techniques or tools for accurate diagnosis. Early detection for NASH matters for patients because NASH is the marker for severe disease progression. This review summarizes the current noninvasive tools for NAFLD diagnosis and their performance. We also discussed potential and newer alternative tools for diagnosing NAFLD.
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Affiliation(s)
| | - Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (V.D.); (N.A.); (N.A.A.M.)
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Abstract
Hepatic fibrosis is a reversible wound healing process following liver injury. Although this process is necessary for maintaining liver integrity, severe excessive extracellular matrix accumulation (ECM) could lead to permanent scar formation and destroy the liver structure. The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis. Previous studies show that most antifibrotic therapies focus on the apoptosis of HSCs and the prevention of HSC activation. Noncoding RNAs (ncRNAs) play a substantial role in HSC activation and are likely to be biomarkers or therapeutic targets for the treatment of hepatic fibrosis. This review summarizes and discusses the previously reported ncRNAs, including the microRNAs, long noncoding RNAs, and circular RNAs, highlighting their regulatory roles and interactions in the signaling pathways that regulate HSC activation in hepatic fibrosis.
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Is the Macrophage Phenotype Determinant for Fibrosis Development? Biomedicines 2021; 9:biomedicines9121747. [PMID: 34944564 PMCID: PMC8698841 DOI: 10.3390/biomedicines9121747] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/16/2022] Open
Abstract
Fibrosis is a pathophysiological process of wound repair that leads to the deposit of connective tissue in the extracellular matrix. This complication is mainly associated with different pathologies affecting several organs such as lung, liver, heart, kidney, and intestine. In this fibrotic process, macrophages play an important role since they can modulate fibrosis due to their high plasticity, being able to adopt different phenotypes depending on the microenvironment in which they are found. In this review, we will try to discuss whether the macrophage phenotype exerts a pivotal role in the fibrosis development in the most important fibrotic scenarios.
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