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Mak KM, Shekhar AC, Ding SY. Neutrophil extracellular traps mediate pathophysiology of hepatic cells during liver injury. Anat Rec (Hoboken) 2025. [PMID: 40219700 DOI: 10.1002/ar.25673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
Neutrophil extracellular traps (NETs) are web-like, bactericidal structures produced by neutrophils and are composed principally of extracellular DNA, histones, elastase, and myeloperoxidase, among other components. NET formation is an innate immune response that is beneficial for pathogen killing and clearance. However, excessive NET formation and clearance defects can lead to inflammation and induce damage to host organs. NETs are also implicated in the development of noninfectious inflammatory disorders, such as liver injury in chronic liver diseases. The liver parenchyma contains hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. Each of these cells possesses unique structures and functions, and their interactions with NETs result in pathophysiological changes contributing to liver injury. This review updates the findings related to the modes of action and molecular mechanisms by which NETs modulate the pathophysiology of various hepatic cells and potentiate liver injury. The article also reviews the roles of NETs in hepatic ischemia reperfusion injury, hepatocellular carcinoma pathogenesis, and cancer metastasis. Last, we examine data to determine whether NETs induce crosstalk among various hepatic cells during liver injury and to identify future research directions.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aditya C Shekhar
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Selena Y Ding
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
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MESH Headings
- Humans
- Liver Cirrhosis/genetics
- Liver Cirrhosis/pathology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/virology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Epigenesis, Genetic
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/pathology
- Hepatitis B virus/genetics
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- Animals
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
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Zhou Z, Feng Y, Jiang M, Yao Z, Wang J, Pan F, Feng R, Zhao C, Ma Y, Zhou J, Sun L, Sun X, Zhan C, He X, Jiang K, Yu J, Yan Z. Ionizable polymeric micelles (IPMs) for efficient siRNA delivery. Nat Commun 2025; 16:360. [PMID: 39753560 PMCID: PMC11699125 DOI: 10.1038/s41467-024-55721-w] [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: 04/11/2024] [Accepted: 12/19/2024] [Indexed: 01/06/2025] Open
Abstract
Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.
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Affiliation(s)
- Ziyu Zhou
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
- School of Pharmacy, East China Normal University, Shanghai, PR China
| | - Yu Feng
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
| | - Mingzhou Jiang
- Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, PR China
| | - Zijun Yao
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
| | - Jing Wang
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
| | - Feng Pan
- Ministry of Education & Department of Pharmacy, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Shanghai Fudan University, Shanghai, PR China
| | - Rulan Feng
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
| | - Chong Zhao
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
| | - Yinyu Ma
- Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, PR China
| | - Jinge Zhou
- Institute of Biomedical Engineering, Kunming Medical University, Kunming, PR China
| | - Lei Sun
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China
- Department of NanoEngineering, Chemical Engineering Program, University of California San Diego, La Jolla, CA, USA
| | - Xiaotian Sun
- Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, PR China
| | - Changyou Zhan
- Ministry of Education & Department of Pharmacy, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Shanghai Fudan University, Shanghai, PR China
- Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, PR China
| | - Xiao He
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
- Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
| | - Kuan Jiang
- Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, PR China.
- Eye Institute and Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, PR China.
| | - Jiahui Yu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
| | - Zhiqiang Yan
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
- Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
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Wang L, Dong Z, Zhang Y, Peng L. Emerging Roles of High-mobility Group Box-1 in Liver Disease. J Clin Transl Hepatol 2024; 12:1043-1056. [PMID: 39649031 PMCID: PMC11622203 DOI: 10.14218/jcth.2024.00317] [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: 08/30/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 12/10/2024] Open
Abstract
High-mobility group box-1 (HMGB1) is an architectural chromosomal protein with various roles depending on its cellular localization. Extracellular HMGB1 functions as a prototypical damage-associated molecular pattern that triggers inflammation and adaptive immune responses, mediated by specific cell surface receptors, including receptors for advanced glycation end products and toll-like receptors. Post-translational modifications of HMGB1 significantly impact various cellular processes that contribute to the pathogenesis of liver diseases. Recent studies have highlighted the close relationship between HMGB1 and the pathogenesis of acute liver injuries, including acetaminophen-induced liver injury, hepatic ischemia-reperfusion injury, and acute liver failure. In chronic liver diseases, HMGB1 plays a role in nonalcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, and hepatocellular carcinoma. Targeting HMGB1 as a therapeutic approach, either by inhibiting its release or blocking its extracellular function, is a promising strategy for treating liver diseases. This review aimed to summarize the available evidence on HMGB1's role in liver disease, focusing on its multifaceted signaling pathways, impact on disease progression, and the translation of these findings into clinical interventions.
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Affiliation(s)
- Lu Wang
- Department of Diagnostics, Second School of Clinical Medicine, Binzhou Medical University, Yantai, Shandong, China
| | - Zhiwei Dong
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yeqiong Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Liu J, Li H, Chen H, Xiao X, Jin Z, Paerhati P, Bao W, Cui C, Zhu J, Yuan Y. An anti-RAGE chimeric antibody alleviates CCl 4-induced liver fibrosis via RAGE/NF-kB pathway in mice. Biomed Pharmacother 2024; 181:117737. [PMID: 39657505 DOI: 10.1016/j.biopha.2024.117737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 11/23/2024] [Accepted: 12/03/2024] [Indexed: 12/12/2024] Open
Abstract
Liver fibrosis is a progressive condition characterized by excessive deposition of extracellular matrix components, leading to organ dysfunction. Chronic inflammation and activation of hepatic stellate cells (HSCs) are two dominant events in all stages of fibrosis development. The receptor for advanced glycation end products (RAGE) pathway is involved in modulating liver injury and fibrosis, and preventing it, or deletion of Ager gene can protect the liver against fibrosis progression. To investigate functions and mechanism of chimeric anti-RAGE monoclonal antibody against liver fibrosis, murine-derived monoclonal anti-RAGE antibodies were used to construct murine-human chimeric antibodies. The properties of the chimeric antibody were characterized, and the biological functions of antibody A5 or its evolved humanized molecule, huA5, were investigated in cell or animal model. The data showed that blocking the RAGE pathway with huA5 robustly reduced liver injury and fibrosis. Furthermore, huA5 significantly suppressed the activation of HSCs and inhibited expression of fibrosis-associated genes, including COL1A1,TIMP1, and ACTA2. huA5 also interfered with RAGE downstream signal transduction and down-regulate both ERK and NF-κB phosphorylation, inhibited the RAGE/NF-kB pathway, leading to reduced expression of pro-inflammatory cytokines and profibrotic markers. Finally, RAGE silencing significantly decreased the expression of activation-related genes in HSCs, inhibiting HSCs proliferation and migration. These results clearly revealed that the anti-RAGE chimeric antibody exerted antifibrotic efficacy in vitro and attenuated liver fibrosis in vivo. HuA5 can be further developed as a lead molecule of drug to treat patients with liver fibrosis.
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Affiliation(s)
- Jing Liu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Huiyi Li
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Hui Chen
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Xinyi Xiao
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Zhedong Jin
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Pameila Paerhati
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Wenxin Bao
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Caixia Cui
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Jianwei Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Yunsheng Yuan
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
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Li X, Wang S, Zhang D, Feng Y, Liu Y, Yu W, Cui L, Harkany T, Verkhratsky A, Xia M, Li B. The periaxonal space as a conduit for cerebrospinal fluid flow to peripheral organs. Proc Natl Acad Sci U S A 2024; 121:e2400024121. [PMID: 39485799 PMCID: PMC11551422 DOI: 10.1073/pnas.2400024121] [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: 01/12/2024] [Accepted: 09/20/2024] [Indexed: 11/03/2024] Open
Abstract
Mechanisms controlling the movement of the cerebrospinal fluid (CSF) toward peripheral nerves are poorly characterized. We found that, in addition to the foramina Magendie and Luschka for CSF flow toward the subarachnoid space and glymphatic system, CSF outflow could also occur along periaxonal spaces (termed "PAS pathway") from the spinal cord to peripheral organs, such as the liver and pancreas. When interrogating the latter route, we found that serotonin, acting through 5-HT2B receptors expressed in ependymocytes that line the central canal, triggered Ca2+ signals to induce polymerization of F-actin, a cytoskeletal protein, to reduce the volume of ependymal cells. This paralleled an increased rate of PAS-mediated CSF redistribution toward peripheral organs. In the liver, CSF was received by hepatic stellate cells. CSF efflux toward peripheral organs through the PAS pathway represents a mechanism dynamically connecting the nervous system with the periphery. Our findings are compatible with the traditional theory of CSF efflux into the glymphatic system to clear metabolic waste from the cerebral parenchyma. Thus, we extend the knowledge of CSF flow and expand the understanding of connectivity between the CNS and peripheral organs.
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Affiliation(s)
- Xinyu Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Siman Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Dianjun Zhang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Yuliang Feng
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Yingyu Liu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Weiyang Yu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Lulu Cui
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Tibor Harkany
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna1090, Austria
- Department of Neuroscience, Biomedicum, Karolinska Institutet, Solna17165, Sweden
| | - Alexei Verkhratsky
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Faculty of Biology, Medicine and Health, The University of Manchester, ManchesterM13 9PL, United Kingdom
- Department of Neurosciences, University of the Basque Country, Leioa48940, Bizkaia, Spain
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, VilniusLT-01102, Lithuania
| | - Maosheng Xia
- Department of Orthopaedics, The First Hospital, China Medical University, Shenyang110002, China
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
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Yang Y, Wang X. Nano-drug delivery systems (NDDS) in metabolic dysfunction-associated steatotic liver disease (MASLD): current status, prospects and challenges. Front Pharmacol 2024; 15:1419384. [PMID: 39166109 PMCID: PMC11333238 DOI: 10.3389/fphar.2024.1419384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/24/2024] [Indexed: 08/22/2024] Open
Abstract
About one-third of the global population suffers from metabolic dysfunction-associated steatotic liver disease (MASLD), but specific treatments for MASLD have long been lacking, primarily due to the unclear etiology of the disease. In addition to lifestyle modifications and weight loss surgery, pharmacotherapy is the most common treatment among MASLD patients, and these drugs typically target the pathogenic factors of MASLD. However, bioavailability, efficacy, and side effects all limit the maximum therapeutic potential of the drugs. With the development of nanomedicine, recent years have seen attempts to combine MASLD pharmacotherapy with nanomaterials, such as liposomes, polymer nanoparticles, micelles, and cocrystals, which effectively improves the water solubility and targeting of the drugs, thereby enhancing therapeutic efficacy and reducing toxic side effects, offering new perspectives and futures for the treatment of MASLD.
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Affiliation(s)
| | - Xiaojing Wang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui, China
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Liu XY, Zhang W, Ma BF, Sun MM, Shang QH. Advances in Research on the Effectiveness and Mechanism of Active Ingredients from Traditional Chinese Medicine in Regulating Hepatic Stellate Cells Autophagy Against Hepatic Fibrosis. Drug Des Devel Ther 2024; 18:2715-2727. [PMID: 38974122 PMCID: PMC11227309 DOI: 10.2147/dddt.s467480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/10/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.
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Affiliation(s)
- Xin-Yu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| | - Bao-Feng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, Shandong, 271100, People’s Republic of China
| | - Mi-Mi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Tai’an, Shandong, 271000, People’s Republic of China
| | - Qing-Hua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
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9
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Abdelgalil MH, Elhammamy RH, Ragab HM, Sheta E, Wahid A. The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition. Biol Res 2024; 57:32. [PMID: 38797855 PMCID: PMC11129499 DOI: 10.1186/s40659-024-00510-4] [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: 01/04/2024] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS AND RESULTS Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities. CONCLUSION Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.
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Affiliation(s)
- Mohamed Hussein Abdelgalil
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Reem H Elhammamy
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Hanan M Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Eman Sheta
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
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Xie Z, Li Y, Xiao P, Ke S. GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:219-229. [PMID: 37207965 DOI: 10.1016/j.gastrohep.2023.05.005] [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: 12/07/2022] [Revised: 04/16/2023] [Accepted: 05/10/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. METHODS ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-β1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. RESULTS CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3'-UTR. The promotion of GATA3 to TGF-β1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. CONCLUSIONS This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF.
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Affiliation(s)
- Zhengyuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
| | - Yangyang Li
- Medical College of Nanchang University, Nanchang 330006, China
| | - Peiguang Xiao
- Medical College of Nanchang University, Nanchang 330006, China
| | - Shanmiao Ke
- Medical College of Nanchang University, Nanchang 330006, China
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11
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Wang S, Ding Q, Xiu A, Xia Y, Wang G, Zhang C. Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis. J Cell Mol Med 2024; 28:e18047. [PMID: 37970991 PMCID: PMC10826435 DOI: 10.1111/jcmm.18047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/25/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.
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Affiliation(s)
- Sining Wang
- Department of GastroenterologyShandong Provincial Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Qian Ding
- Department of GastroenterologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
| | - Aiyuan Xiu
- Department of GastroenterologyShandong Provincial Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Yifu Xia
- Department of GastroenterologyShandong Provincial Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Guangchuan Wang
- Department of GastroenterologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
| | - Chunqing Zhang
- Department of GastroenterologyShandong Provincial Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
- Department of GastroenterologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
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12
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Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
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Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
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13
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Li Q, Lin Y, Liang G, Xiao N, Zhang H, Yang X, Yang J, Liu A. Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases. Int J Mol Sci 2023; 24:16880. [PMID: 38069199 PMCID: PMC10706096 DOI: 10.3390/ijms242316880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases.
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Affiliation(s)
| | | | | | | | | | | | | | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430100, China; (Q.L.); (Y.L.); (G.L.); (N.X.); (H.Z.); (X.Y.); (J.Y.)
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14
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Fu J, Deng W, Ge J, Fu S, Li P, Wu H, Wang J, Gao Y, Gao H, Wu T. Sirtuin 1 alleviates alcoholic liver disease by inhibiting HMGB1 acetylation and translocation. PeerJ 2023; 11:e16480. [PMID: 38034869 PMCID: PMC10688304 DOI: 10.7717/peerj.16480] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023] Open
Abstract
Background Alcoholic liver disease (ALD) encompasses a spectrum of liver disorders resulting from prolonged alcohol consumption and is influenced by factors such as oxidative stress, inflammation, and apoptosis. High Mobility Group Box 1 (HMGB1) plays a pivotal role in ALD due to its involvement in inflammation and immune responses. Another key factor, Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is known for its roles in cellular stress responses and metabolic regulation. Despite individual studies on HMGB1 and SIRT1 in ALD, their specific molecular interactions and combined effects on disease advancement remain incompletely understood. Methods Alcohol-induced liver injury (ALI) models were established using HepG2 cells and male C57BL/6 mice. HMGB1 and SIRT1 expressions were assessed at the mRNA and protein levels usingreverse transcription-quantitative polymerase chain reaction, western blot, and immunofluorescence staining. The physical interaction between HMGB1 and SIRT1 was investigated using co-immunoprecipitation and immunofluorescence co-expression analyses. Cellular viability was evaluated using the CCK-8 assay. Results In patients with clinical ALI, HMGB1 mRNA levels were elevated, while SIRT1 expression was reduced, indicating a negative correlation between the two. ALI models were successfully established in cells and mice, as evidenced by increased markers of cellular and liver damage. HMGB1 acetylation and translocation were observed in both ALI cells and mouse models. Treatment with the SIRT1 agonist, SRT1720, reversed the upregulation of HMGB1 acetylation, nuclear translocation, and release in the ethyl alcohol (EtOH) group. Furthermore, SIRT1 significantly attenuated ALI. Importantly, in vivo binding was confirmed between SIRT1 and HMGB1. Conclusions SIRT1 alleviates HMGB1 acetylation and translocation, thereby ameliorating ALI.
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Affiliation(s)
- Juan Fu
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Wei Deng
- Department of Oral and Maxillofacial Surgery, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jun Ge
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shengqi Fu
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Panpan Li
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Huazhi Wu
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jiao Wang
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yi Gao
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Hui Gao
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Tao Wu
- Department of Infectious Diseases, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
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15
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Jiang LF, Yang M, Meng HW, Jia PC, Du CL, Liu JY, Lv XW, Cheng-Huang, Li J. The effect of hepatic stellate cell derived-IL-11 on hepatocyte injury in hepatic fibrosis. Life Sci 2023; 330:121974. [PMID: 37495078 DOI: 10.1016/j.lfs.2023.121974] [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: 04/16/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 07/28/2023]
Abstract
AIMS This study aimed to elucidate the role of Interleukin-11 (IL-11) in hepatic fibrosis (HF) and its potential as a therapeutic target for HF treatment. MATERIALS AND METHODS We investigated IL-11 expression in patients with varying degrees of liver injury through ELISA and immunohistochemistry. A CCl4-induced HF mouse model was constructed to study IL-11 expression and cell apoptosis using Western blotting (WB) and other techniques. The expression of IL-11 was silenced using rAAV8 in the mouse model. In vitro stimulation of hepatic stellate cells (LX-2) with TGF-β1, and of LO-2 cells with exogenous IL-11, were performed. Cell supernatants of TGF-β1-stimulated LX-2 were used to culture LO-2 cells, with apoptosis monitored via flow cytometry and WB. KEY FINDINGS Increased IL-11 levels were observed in patients and the HF mouse model, with silencing reducing IL-11 expression. In vitro experiments revealed increased endogenous IL-11 in TGF-β1-stimulated LX-2 cells and an increase in apoptotic index, IL11RA, and gp130 in IL-11-stimulated LO-2 cells. Cell apoptosis was reduced in the siRNA/IL11, siRNA/IL11RA, and anti-IL11 groups. WB and immunohistochemistry results showed upregulated p-JNK, p-ERK, and p-P53 expressions in the CCl4-induced HF mouse model and IL-11-treated LO-2 cells. SIGNIFICANCE Our findings suggest IL-11 enhances LX-2 cell activation and proliferation, and promotes LO-2 cell apoptosis through JNK/ERK signaling pathways. This suggests that targeting IL-11 secretion may serve as a potential therapeutic strategy for HF, providing a foundation for its clinical application in HF treatment.
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Affiliation(s)
- Ling-Feng Jiang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ming Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hong-Wu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Chang-Lin Du
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jin-Yu Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Cheng-Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
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16
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Siapoush S, Rezaei R, Alavifard H, Hatami B, Zali MR, Vosough M, Lorzadeh S, Łos MJ, Baghaei K, Ghavami S. Therapeutic implications of targeting autophagy and TGF-β crosstalk for the treatment of liver fibrosis. Life Sci 2023; 329:121894. [PMID: 37380126 DOI: 10.1016/j.lfs.2023.121894] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/19/2023] [Accepted: 06/25/2023] [Indexed: 06/30/2023]
Abstract
Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis.
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Affiliation(s)
- Samaneh Siapoush
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramazan Rezaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland; Autophagy Research Center, Department of Biochemistry; Shiraz University of Medical Sciences, Shiraz, Iran; LinkoCare Life Sciences AB, Linkoping, Sweden
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.
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17
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Pei Q, Yi Q, Tang L. Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities. Int J Mol Sci 2023; 24:ijms24119671. [PMID: 37298621 DOI: 10.3390/ijms24119671] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis.
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Affiliation(s)
- Qiying Pei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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18
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Abstract
The understanding of the mechanisms of liver fibrosis has been dominated by models in which chronic hepatocellular injury is the initiating step as is seen with viral infections. The increased prevalence of the metabolic syndrome, and the increases in liver fibrosis due to metabolic syndrome driven non-alcoholic steatohepatitis (NASH), has made it a priority to understand how this type of liver fibrosis is similar to, and different from, pure hepatocellular injury driven liver fibrosis. Both types of liver fibrosis have the transformation of the hepatic stellate cell (HSC) into a myofibroblast as a key step. In metabolic syndrome, there is little evidence that metabolite changes such as high levels of glucose and free fatty acids are directly inducing HSC transdifferentiation, however, metabolite changes may lead to reductions in immunomodulatory and hepatoprotective molecules such as lipoxins, resolvins and Interleukin (IL)-22. Cells of the innate immune system are known to be important intermediaries between hepatocellular damage and HSC transdifferentiation, primarily by producing cytokines such as transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF). Resident and infiltrating macrophages are the dominant innate immune cells, but others (dendritic cells, neutrophils, natural killer T cells and mucosal-associated invariant T cells) also have important roles in inducing and resolving liver fibrosis. CD8+ and CD4+ T cells of the adaptive immune system have been identified to have greater profibrotic roles than previously realised by inducing hepatocyte death (auto-aggressive CD8+T) cells and cytokines producing (TH17 producing CD4+T) cells. Finally, the cellular networks present in NASH fibrosis are being identified and suggest that once fibrosis has developed cell-to-cell communication is dominated by myofibroblasts autocrine signalling followed by communication with cholangiocytes and endothelial cells, with myofibroblast-hepatocyte, and myofibroblast-macrophage signalling having minor roles. Such information is essential to the development of antifibrotic strategies for different stages of fibrosis.
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Affiliation(s)
- Wajahat Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
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19
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Efremova NA, Greshnyakova VA, Goryacheva LG. Modern concepts on pathogenetic mechanisms of liver fibrosis. JOURNAL INFECTOLOGY 2023; 15:16-24. [DOI: 10.22625/2072-6732-2023-15-1-16-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- N. A. Efremova
- Pediatric Research and Clinical Center for Infectious Diseases
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You H, Wang X, Ma L, Zhang F, Zhang H, Wang Y, Pan X, Zheng K, Kong F, Tang R. Insights into the impact of hepatitis B virus on hepatic stellate cell activation. Cell Commun Signal 2023; 21:70. [PMID: 37041599 PMCID: PMC10088164 DOI: 10.1186/s12964-023-01091-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/26/2023] [Indexed: 04/13/2023] Open
Abstract
During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-β and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. Video abstract.
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Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xing Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lihong Ma
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Huanyang Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yuxin Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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21
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Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway. J Mol Med (Berl) 2022; 100:1787-1799. [PMID: 36371595 DOI: 10.1007/s00109-022-02270-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 10/27/2022] [Accepted: 11/02/2022] [Indexed: 11/13/2022]
Abstract
The histidine-rich calcium-binding protein (HRC) is a regulator of Ca2 + homeostasis and it plays a significant role in liver fibrosis. Pyroptosis, a specific inflammatory cell death, can lead to hepatic stellate cells (HSCs) activation and liver fibrosis. However, the role of HRC in pyroptosis has not been explored. In this study, we demonstrated that HRC, mainly located in the hepatocyte, was over expressed in fibrotic liver tissues. We further found that enforced expression of HRC in hepatocytes induced pyroptosis and HMGB1 release, and subsequently led to HSCs activation by NLRP3/caspase-1 pathway. In addition, the proliferation and migration of HSCs were also enhanced by HRC overexpression in hepatocytes. Furthermore, NLRP3 inhibitor MCC950 and caspase-1 inhibitor VX-765 alleviated hepatic HRC-mediated hepatocytes pyroptosis and HSCs activation. This study demonstrated that hepatic HRC promoted HSCs activation by inducing hepatocyte pyroptosis, which suggests that HRC may be a promising therapeutic target to prevent liver fibrosis.
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22
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Yang B, Lu L, Zhou D, Fan W, Barbier-Torres L, Steggerda J, Yang H, Yang X. Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Front Endocrinol (Lausanne) 2022; 13:1007944. [PMID: 36267567 PMCID: PMC9578007 DOI: 10.3389/fendo.2022.1007944] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/05/2022] [Indexed: 11/29/2022] Open
Abstract
Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH.
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Affiliation(s)
- Bing Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liqing Lu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Dongmei Zhou
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Fan
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Lucía Barbier-Torres
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Justin Steggerda
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Heping Yang
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Xi Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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23
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Mei C, Yang Y, Dong P, Song L, Zhou Y, Xu Y, Yu C. Deficiency of PKCλ/ι alleviates the liver pathologic impairment of Schistosoma japonicum infection by thwarting Th2 response. Parasit Vectors 2022; 15:154. [PMID: 35505421 PMCID: PMC9066985 DOI: 10.1186/s13071-022-05283-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 04/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The activation of immune response driven by the eggs of Schistosoma japonicum and the subsequent secretions is the culprit behind granulomatous inflammation and liver fibrosis. Evidence suggests that PKCλ/ι participates in a variety of physiological and pathological processes, including the regulation of metabolism, growth, proliferation and differentiation of cells. However, the role of PKCλ/ι in liver disease caused by Schistosoma japonicum remains unclear. METHODS In the present study, we observe the pathological changes of egg-induced granulomatous inflammation and fibrosis in the liver of mice infected by Schistosoma japonicum by using conditional PKCλ/ι-knockout mice and wild-type control. Immune cytokines and fibrogenic factors were analyzed by performing flow cytometry and real-time fluorescence quantitative PCR. RESULTS The results of H&E and Masson staining show that the degree of granulomatous lesions and fibrosis in the liver of the infected PKCλ/ι-knockout mice was significantly reduced compared with those of the infected wild-type mice. The mean area of single granuloma and hepatic fibrosis in the PKCλ/ι-knockout mice was significantly lower than that of the wild-type mice (85,295.10 ± 5399.30 μm2 vs. 1,433,702.04 ± 16,294.01 μm2, P < 0.001; 93,778.20 ± 8949.05 μm2 vs. 163,103.01 ± 11,103.20 μm2, P < 0.001), respectively. Serological analysis showed that the ALT content was significantly reduced in the infected knockout mice compared with infected wild-type mice. RT-PCR analysis showed that IL-4 content in knockout mice was significantly increased after Schistosoma japonicum infection, yet the increase was less than that in infected wild-type mice (P < 0.05). PKCλ/ι deficiency led to reduced expression of fibrosis-related factors, including TGF-β1, Col-1, Col-3, α-SMA and liver DAMP factor HMGB1. Flow cytometry analysis showed that the increasing percentage of Th2 cells, which mainly secrete IL-4 cytokines in spleen cells, was significantly lower in PKCλ/ι-deficient mice compared with wild-type mice after infection (P < 0.05). CONCLUSIONS Our data demonstrate that PKCλ/ι deficiency alleviating granulomatous inflammation and fibrosis in the liver of mice with S. japonicum infection by downregulating Th2 immune response is the potential molecular mechanism behind the role of PKCλ/ι in schistosomiasis.
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Affiliation(s)
- Congjin Mei
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Yingying Yang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Panpan Dong
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Lijun Song
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Yonghua Zhou
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Yongliang Xu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China.,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Chuanxin Yu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, 117 Meiyuan Yangxiang, Wuxi, 214064, Jiangsu, China. .,Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu, China.
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24
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Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022; 10:3662-3676. [PMID: 35647163 PMCID: PMC9100727 DOI: 10.12998/wjcc.v10.i12.3662] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The "Initiation" phase of hepatic stellate cells activation overlaps and continues with the "Perpetuation" phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
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25
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Miao H, Ouyang H, Guo Q, Wei M, Lu B, Kai G, Ji L. Chlorogenic acid alleviated liver fibrosis in methionine and choline deficient diet-induced nonalcoholic steatohepatitis in mice and its mechanism. J Nutr Biochem 2022; 106:109020. [PMID: 35472433 DOI: 10.1016/j.jnutbio.2022.109020] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 01/22/2022] [Accepted: 03/21/2022] [Indexed: 01/19/2023]
Abstract
Nonalcoholic steatohepatitis (NASH), one of the most common chronic liver diseases, is a progressive form of nonalcoholic fatty liver disease (NAFLD) accompanied by the development of liver fibrosis. Chlorogenic acid (CGA) is a natural polyphenolic compound. This study aims to observe the CGA-provided alleviation on liver fibrosis in methionine and choline deficient (MCD) diet-induced NASH in mice and to elucidate its engaged mechanism. CGA attenuated hepatocellular injury, decreased the elevated hepatic lipids accumulation and attenuated liver fibrosis by reducing hepatic collagen deposition in mice fed with MCD diet. CGA abrogated the activation of hepatic stellate cells (HSCs) and promoted mitochondrial biogenesis both in vivo and in vitro. Moreover, the CGA-provided inhibition on HSCs activation in vitro was obviously disappeared after the application of peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PGC1α) siRNA. CGA reduced the enhanced hepatic extracellular matrix (ECM) expression and the elevated serum high-mobility group box 1 (HMGB1) content in mice fed with MCD diet. CGA decreased the HMGB1-induced ECM production in both human liver sinusoidal endothelial cells (LSECs) and human umbilical vein endothelial cells (HUVECs). CGA also weakly promoted mitochondrial biogenesis in both LSECs and HUVECs incubated with HMGB1. Hence, CGA ameliorated hepatic fibrosis in mice fed with MCD diet through inhibiting HSCs activation via promoting mitochondrial biogenesis and reducing the HMGB1-initiated ECM production in hepatic vascular endothelial cells.
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Affiliation(s)
- Hui Miao
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao Ouyang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qian Guo
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guoyin Kai
- Laboratory of Medicinal Plant Biotechnology, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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26
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Chen D, Chen J, Chen Y, Chen F, Wang X, Huang Y. Interleukin-10 regulates starvation-induced autophagy through the STAT3-mTOR-p70s6k axis in hepatic stellate cells. Exp Biol Med (Maywood) 2022; 247:832-841. [PMID: 35196893 DOI: 10.1177/15353702221080435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The degree of activation of hepatic stellate cells (HSCs) is closely related to the level of autophagy in HSCs. We previously showed that interleukin-10 (IL-10) strongly inhibits HSC activation in rat fibrotic liver. However, little is known about the effect of IL-10 on HSC autophagy. For investigation of the effect of IL-10 on starvation-induced autophagy in immortal rat hepatic stellate cells (HSC-T6) and the molecular mechanism, HSC-T6 cells were incubated with serum-free DMEM for different periods and treated with IL-10 at different concentrations. Transmission electron microscopy (TEM), analysis of autophagic flux and Western blotting (WB) assays were used to observe changes in autophagosome morphology and number and autophagy-related protein expression in HSC-T6 cells and to evaluate the regulatory effect of IL-10 on starvation-induced autophagy. Cryptotanshinone (CPT) and rapamycin (Rapa) were used to block activation of the signal transducer and activator of transcription 3 (STAT3) and mTOR signaling pathways, respectively. STAT3-mTOR-p70s6k signaling pathway proteins were analyzed by WB to assess the signaling pathway by which IL-10 regulates autophagy. WB showed an increased LC3II/I ratio, increased Beclin1 expression, and decreased p62 expression in HSC-T6 cells starved for 3 h (p < 0.05). IL-10 inhibited the increases in the LC3II/I ratio and Beclin1 expression and upregulated p62 expression (p < 0.05), and the optimal IL-10 concentration was 20 ng/mL. TEM and double-labeled immunofluorescence analysis showed that IL-10 inhibited autophagosome formation and autophagic flux, as indicated by the decreased numbers of double-membrane autophagosomes and yellow autophagic puncta. Further examination of signaling pathway molecules showed that phosphorylation of the mTOR, STAT3, and p70s6k proteins was significantly decreased during starvation-induced autophagy, but IL-10 could increase mTOR, STAT3, and p70s6k protein phosphorylation (p < 0.05). Blocking either the mTOR or STAT3 pathway reversed the inhibitory effect of IL-10 on starvation-induced autophagy in HSC-T6 cells (p < 0.05). IL-10 suppresses starvation-induced autophagosome formation through activation of the STAT3-mTOR-p70s6k axis in HSC-T6 cells.
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Affiliation(s)
- Dongmei Chen
- Department of Clinical Nutrition, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Jiabing Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.,Fujian Institute of Digestive Diseases, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yizhen Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.,Fujian Institute of Digestive Diseases, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Fenglin Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.,Fujian Institute of Digestive Diseases, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Xiaozhong Wang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.,Fujian Institute of Digestive Diseases, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yuehong Huang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.,Fujian Institute of Digestive Diseases, Fujian Medical University Union Hospital, Fuzhou 350001, China
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27
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Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis. J Control Release 2022; 343:175-186. [DOI: 10.1016/j.jconrel.2022.01.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/12/2021] [Accepted: 01/23/2022] [Indexed: 12/12/2022]
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28
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Li M, Yang L. Autophagy in the liver. AUTOPHAGY IN HEALTH AND DISEASE 2022:161-179. [DOI: 10.1016/b978-0-12-822003-0.00014-0] [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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29
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Li J, Deng X, Wang S, Jiang Q, Xu K. Resolvin D1 attenuates CCl4 Induced Liver Fibrosis by Inhibiting Autophagy-Mediated HSC activation via AKT/mTOR Pathway. Front Pharmacol 2021; 12:792414. [PMID: 34987404 PMCID: PMC8721195 DOI: 10.3389/fphar.2021.792414] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/22/2021] [Indexed: 01/30/2023] Open
Abstract
Resolvin D1 (RvD1) was previously reported to relieve inflammation and liver damage in several liver diseases, but its potential role in liver fibrosis remains elusive. The aim of our study was to investigate the effects and underlying mechanisms of RvD1 in hepatic autophagy in liver fibrosis. In vivo, male C57BL/6 mice were intraperitoneally injected with 20% carbon tetrachloride (CCl4, 5 ml/kg) twice weekly for 6 weeks to establish liver fibrosis model. RvD1 (100 ng or 300 ng/mouse) was added daily in the last 2 weeks of the modeling period. In vitro, lipopolysaccharide (LPS)-activated LX-2 cells were co-treated with increasing concentrations (2.5-10 nM) of RvD1. The degree of liver injury was measured by detecting serum AST and ALT contents and H&E staining. Hepatic fibrosis was assessed by masson's trichrome staining and metavir scoring. The qRT-PCR, western blot, immunohistochemistry, and immunofluorescence were applied to liver tissues or LPS-activated LX-2 cells to explore the protective effects of RvD1 in liver fibrosis. Our findings reported that RvD1 significantly attenuated CCl4 induced liver injury and fibrosis by decreasing plasma AST and ALT levels, reducing collagen I and α-SMA accumulation and other pro-fibrotic genes (CTGF, TIMP-1 and Vimentin) expressions in mouse liver, restoring damaged histological architecture and improving hepatic fibrosis scores. In vitro, RvD1 also repressed the LPS induced LX-2 cells activation and proliferation. These significant improvements mainly attributed to the inhibiting effect of RvD1 on autophagy in the process of hepatic stellate cell (HSC) activation, as demonstrated by decreased ratio of LC3-II/I and elevated p62 after RvD1 treatment. In addition, using AZD5363 (an AKT inhibitor that activates autophagy) and AZD8055 (an mTOR inhibitor, another autophagy activator), we further verified that RvD1 suppressed autophagy-mediated HSC activation and alleviated CCl4 induced liver fibrosis partly through AKT/mTOR pathway. Overall, these results demonstrate that RvD1 treatment is expected to become a novel therapeutic strategy against liver fibrosis.
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Affiliation(s)
- Jiahuan Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoling Deng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuhan Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianqian Jiang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Keshu Xu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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30
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Chen H, Li G, Zhang J, Zheng T, Chen Q, Zhang Y, Yang F, Wang C, Nie H, Zheng B, Gong Q. Sodium butyrate ameliorates Schistosoma japonicum-induced liver fibrosis by inhibiting HMGB1 expression. Exp Parasitol 2021; 231:108171. [PMID: 34736899 DOI: 10.1016/j.exppara.2021.108171] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/16/2021] [Accepted: 10/31/2021] [Indexed: 11/25/2022]
Abstract
Schistosomiasis is a prevalent zoonotic parasitic disease caused by schistosomes. Its main threat to human health is hepatic granuloma and fibrosis due to worm eggs. Praziquantel remains the first choice for the treatment of schistosomiasis but has limited benefit in treating liver fibrosis. Therefore, the need to develop effective drugs for treating schistosomiasis-induced hepatic fibrosis is urgent. High-mobility group box 1 protein (HMGB1) is a potential immune mediator that is highly associated with the development of some fibrotic diseases and may be involved in the liver pathology of schistosomiasis. We speculated that HMGB1 inhibitors could have an anti-fibrotic effect. Sodium butyrate (SB), a potent inhibitor of HMGB1, has shown anti-inflammatory activity in some animal disease models. In this study, we evaluated the effects of SB on a murine schistosomiasis model. Mice were percutaneously infected with 20 ± 2 cercariae of Schistosoma japonicum. SB (500 mg/kg/day) was administered every 3 days for the entire experiment period. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology, HMGB1 expression, and the levels of interferon gamma (IFN-γ), transforming growth factor-β1 (TGF-β1), and interleukin-6 (IL-6) in serum were analyzed. SB reduced hepatic granuloma and fibrosis of schistosomiasis, reflected by the decreased levels of ALT and AST in serum and the reduced expression of pro-inflammatory and fibrogenic cytokines (IFN-γ, TGF-β1, and IL-6). The protective effect could be attributable to the inhibition of the expression of HMGB1 and release by SB.
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Affiliation(s)
- Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Gang Li
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Department of Gastroenterology, Jingmen Second People's Hospital, Jingmen, Hubei Province, 448000, PR China
| | - Jianqiang Zhang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Ting Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Qianglin Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Yanxiang Zhang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Fei Yang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Chao Wang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China.
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China; Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, PR China.
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31
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Li W, Sun Y, Wang Z. Allicin Improves Hepatic Fibrosis by Regulating Notch 1 Pathway. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aim: To discuss effects and mechanisms of allicin in hepatic fibrosis by vivo study. Materials and methods: Dividing 45 rats into 5 groups. Evaluating pathology and fibrosis by HE and Masson staining, measuring α-SMA, Collage III, Notch 1, p-AKT and p-mTOR
protein expression by IHC assay and WB assay; LC 3B protein expression were evaluated by Immunofluorescence. Liver function were measured by Elisa assay. Results: With Allicin supplement, rats’ liver function, pathological and Collagen volume fraction were significantly improved
with doses-dependent in liver tissues (P < 0.05, respectively); α-SMA, Collage III, Notch 1, p-AKT and p-mTOR protein expression were significantly suppressed with doses-dependent (P < 0.05, respectively); LC 3B protein expression was significantly increased
with doses-dependent (P < 0.05, respectively). Conclusion: Allicin improved hepatic fibrosis by authophagy up regulation via regulation Notrch1/AKT/mTOR pathway by vivo study.
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Affiliation(s)
- Wenxiang Li
- Department of Gastroenterology, Guangrao County People’s Hospital, Dongying, Shandong, 257300, China
| | - Yajing Sun
- Department of Obstetrics, Guangrao County People’s Hospital, Dongying, Shandong, 257300, China
| | - Zaixing Wang
- Department of Gastroenterology, Guangrao County People’s Hospital, Dongying, Shandong, 257300, China
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Circular RNA Expression Profile in Patients with Lumbar Spinal Stenosis Associated with Hypertrophied Ligamentum Flavum. Spine (Phila Pa 1976) 2021; 46:E916-E925. [PMID: 33534519 DOI: 10.1097/brs.0000000000003975] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Sequencing and experimental analysis of the expression profile of circular RNAs (circRNAs) in hypertrophic ligamentum flavum (LFH). OBJECTIVES The aim of this study was to identify differentially expressed circRNAs between LFH and nonhypertrophic ligamentum flavum tissues from lumbar spinal stenosis (LSS) patients. SUMMARY OF BACKGROUND DATA Hypertrophy of the ligamentum flavum (LF) can cause LSS. circRNAs are important in various diseases. However, no circRNA expression patterns related to LF hypertrophy have been reported. METHODS A total of 33 patients with LSS participated in this study. LF tissue samples were obtained when patients underwent decompressive laminectomy during surgery. The expression profile of circRNAs was analyzed by transcriptome high-throughput sequencing and validated with quantitative real-time polymerase chain reaction (PCR). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed for the differentially expressed circRNA-associated genes and related pathways. The connections between circRNAs and microRNAs were explored using Cytoscape. The role of hsa_circ_0052318 on LF cell fibrosis was assessed by analyzing the expression of collagen I and collagen III. RESULTS The results showed that 2439 circRNAs of 4025 were differentially expressed between the LFH and nonhypertrophic ligamentum flavum tissues, including 1276 upregulated and 1163 downregulated circRNAs. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these differentially expressed circRNAs functioned in biological processes, cellular components, and molecular functions. Autophagy and mammalian target of rapamycin were the top two signaling pathways affected by these circRNAs. Five circRNAs (hsa_circ_0021604, hsa_circ_0025489, hsa_circ_0002599, hsa_circ_0052318, and hsa_circ_0003609) were confirmed by quantitative real-time PCR. The network indicated a strong relationship between circRNAs and miRNAs. Furthermore, hsa_circ_0052318 overexpression decreased mRNA and protein expression of collagen I and III in LF cells from LFH tissues. CONCLUSION This study identified circRNA expression profiles characteristic of hypertrophied LF in LSS patients, and demonstrated that hsa_circ_0052318 may play an important role in the pathogenesis of LF hypertrophy.Level of Evidence: N/A.
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Huang X, Glessner JT, Huang J, Zhou D, March ME, Wang H, Xia Q, Hakonarson H, Li J. Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection. Front Cell Dev Biol 2021; 9:690882. [PMID: 34458256 PMCID: PMC8397444 DOI: 10.3389/fcell.2021.690882] [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: 04/04/2021] [Accepted: 07/06/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as HMGB1 and ATF3, which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1–/– mice and RNA-seq data from mouse liver tissue overexpressing ATF3, we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.
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Affiliation(s)
- Xubo Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Joseph T Glessner
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jinxia Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Desheng Zhou
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Michael E March
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hongna Wang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Qianghua Xia
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Division of Human Genetics and Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jin Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
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Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, Chen X, Ma S, Xiao Z. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021; 99:108051. [PMID: 34426110 DOI: 10.1016/j.intimp.2021.108051] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis represents as a dynamic pathological process characterized by the net accumulation of extracellular matrix in the progression of various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and metabolic associated fatty liver disease (MAFLD). Activation of hepatic stellate cells (HSCs) is well-defined to play a central role in the initiation and progression of hepatic fibrosis. However, the activation of HSCs is affected by the complicated microenvironments in liver, which largely attributes to the communication between hepatocytes and multiple tissue-resident cells, including sinusoidal endothelial cells, bile duct epithelial cells, platelets, T cells, B cells, macrophages, natural killer cells, neutrophils, dendritic cells, in the direct or indirect mechanisms. Cellular crosstalk between HSCs and surrounding cells contributes to the activation of HSCs and the progression of hepatic fibrosis. Currently, accumulating evidence have proven the complexity and plasticity of HSCs activation, and further clarification of cellular communication between HSCs and surrounding cells will provide sufficient clue to the development of novel diagnostic methods and therapeutic strategies for hepatic fibrosis.
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Affiliation(s)
- Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanmin Li
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yaokun Hao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Chenxiao Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Pan Jia
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
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Liu M, Shan M, Zhang Y, Guo Z. Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma. J Inflamm Res 2021; 14:3891-3904. [PMID: 34408470 PMCID: PMC8367219 DOI: 10.2147/jir.s322724] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/23/2021] [Indexed: 12/17/2022] Open
Abstract
Purpose Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms. Methods In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms. Results We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis. Conclusion Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.
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Affiliation(s)
- Meixuan Liu
- Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People's Republic of China.,Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, People's Republic of China
| | - Mengtian Shan
- Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People's Republic of China
| | - Yunxuan Zhang
- Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Zhongliang Guo
- Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People's Republic of China.,Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, People's Republic of China
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Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, Ding WX. Autophagy in liver diseases: A review. Mol Aspects Med 2021; 82:100973. [PMID: 34120768 DOI: 10.1016/j.mam.2021.100973] [Citation(s) in RCA: 202] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/29/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023]
Abstract
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Jessica Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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Feng W, Wang J, Yan X, Zhang Q, Chai L, Wang Q, Shi W, Chen Y, Liu J, Qu Z, Li S, Xie X, Li M. ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension. Cell Prolif 2021; 54:e13048. [PMID: 33948998 PMCID: PMC8168414 DOI: 10.1111/cpr.13048] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/05/2021] [Accepted: 04/12/2021] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVES High-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues. METHODS Primary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization. RESULTS HMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model. CONCLUSIONS HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH.
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Affiliation(s)
- Wei Feng
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Jian Wang
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Xin Yan
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Qianqian Zhang
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Limin Chai
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Qingting Wang
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Wenhua Shi
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Yuqian Chen
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Jin Liu
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Zhan Qu
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Shaojun Li
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Xinming Xie
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
| | - Manxiang Li
- Department of Respiratory and Critical Care Medicinethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an, ShaanxiChina
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Lucantoni F, Martínez-Cerezuela A, Gruevska A, Moragrega ÁB, Víctor VM, Esplugues JV, Blas-García A, Apostolova N. Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol 2021; 254:216-228. [PMID: 33834482 DOI: 10.1002/path.5678] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis (LF) occurs as a result of persistent liver injury and can be defined as a pathologic, chronic, wound-healing process in which functional parenchyma is progressively replaced by fibrotic tissue. As a phenomenon involved in the majority of chronic liver diseases, and therefore prevalent, it exerts a significant impact on public health. This impact becomes even more patent given the lack of a specific pharmacological therapy, with LF only being ameliorated or prevented through the use of agents that alleviate the underlying causes. Hepatic stellate cells (HSCs) are fundamental mediators of LF, which, activated in response to pro-fibrotic stimuli, transdifferentiate from a quiescent phenotype into myofibroblasts that deposit large amounts of fibrotic tissue and mediate pro-inflammatory effects. In recent years, much effort has been devoted to understanding the mechanisms through which HSCs are activated or inactivated. Using cell culture and/or different animal models, numerous studies have shown that autophagy is enhanced during the fibrogenic process and have provided specific evidence to pinpoint the fundamental role of autophagy in HSC activation. This effect involves - though may not be limited to - the autophagic degradation of lipid droplets. Several hepatoprotective agents have been shown to reverse the autophagic alteration present in LF, but clinical confirmation of these effects is pending. On the other hand, there is evidence that implicates autophagy in several anti-fibrotic mechanisms in HSCs that stimulate HSC cell cycle arrest and cell death or prevent the generation of pro-fibrotic mediators, including excess collagen accumulation. The objective of this review is to offer a comprehensive analysis of published evidence of the role of autophagy in HSC activation and to provide hints for possible therapeutic targets for the treatment and/or prevention of LF related to autophagy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Federico Lucantoni
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | | | - Aleksandra Gruevska
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Ángela B Moragrega
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Víctor M Víctor
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
| | - Ana Blas-García
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
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Ni YA, Chen H, Nie H, Zheng B, Gong Q. HMGB1: An overview of its roles in the pathogenesis of liver disease. J Leukoc Biol 2021; 110:987-998. [PMID: 33784425 DOI: 10.1002/jlb.3mr0121-277r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 01/06/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is an abundant architectural chromosomal protein that has multiple biologic functions: gene transcription, DNA replication, DNA-damage repair, and cell signaling for inflammation. HMGB1 can be released passively by necrotic cells or secreted actively by activated immune cells into the extracellular milieu after injury. Extracellular HMGB1 acts as a damage-associated molecular pattern to initiate the innate inflammatory response to infection and injury by communicating with neighboring cells through binding to specific cell-surface receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). Numerous studies have suggested HMGB1 to act as a key protein mediating the pathogenesis of chronic and acute liver diseases, including nonalcoholic fatty liver disease, hepatocellular carcinoma, and hepatic ischemia/reperfusion injury. Here, we provide a detailed review that focuses on the role of HMGB1 and HMGB1-mediated inflammatory signaling pathways in the pathogenesis of liver diseases.
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Affiliation(s)
- Yuan-Ao Ni
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
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Astragali Radix Contributes to the Inhibition of Liver Fibrosis via High-Mobility Group Box 1-Mediated Inflammatory Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5574010. [PMID: 33790974 PMCID: PMC7984916 DOI: 10.1155/2021/5574010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/20/2022]
Abstract
Astragali Radix (AR), the dried root of Astragali Radix membranaceus (Fisch.) Bge. or Astragali Radix membranaceus (Fisch.) Bge. var. mongholicus (Bge) Hsiao, is a commonly used traditional Chinese medicine for the treatment of liver diseases. This study aimed to comprehensively evaluate the pharmacological action and explore the potential mechanism of AR on liver fibrosis. Rats were administered with carbon tetrachloride for eight weeks, followed by oral treatment with AR for six weeks. The efficacy was confirmed by measuring liver function and liver fibrosis levels. The underlying mechanisms were explored by detecting the expression of related proteins. AR significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (COL-IV), hyaluronic acid (HA), laminin (LN), and precollagen type III (PCIII). In addition, AR inhibited the deposition of collagen and the activation of hepatic stellate cells. Those data strongly demonstrated that AR alleviated liver fibrosis by CCl4. In order to illustrate the potential inflammatory, the mRNA levels of IL-6, TNF-α, and IL-1β were detected. Subsequently, immunohistochemistry analysis was performed to further verify the expression of type I collagen. Finally, the expression of key proteins in the inflammatory signaling pathway was detected. AR significantly reduced the expression of high-mobility group box 1 (HMGB1), TLR4, Myd88, RAGE, and NF-κ B p65 genes and proteins. In addition, western blotting showed AR decreased the protein expression of RAGE, p-MEK1/2, p-ERK1/2, and p-c-Jun. Taken together, our data reveal that AR significantly inhibits liver fibrosis by intervening in the HMGB1-mediated inflammatory signaling pathway and secretion signaling pathway. This study will provide valuable references for the in-depth research and development of Astragali Radix against liver fibrosis.
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Zhao C, Li Y, Hu X, Wang R, He W, Wang L, Qi L, Tong S. LncRNA HCP5 Promotes Cell Invasion and Migration by Sponging miR-29b-3p in Human Bladder Cancer. Onco Targets Ther 2020; 13:11827-11838. [PMID: 33235469 PMCID: PMC7680190 DOI: 10.2147/ott.s249770] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bladder cancer (BC) is one of the most common malignant tumors in the urinary system. In this study, the roles of lncRNA HCP5 (human major histocompatibility complex p5) and miR-29b-3p in human BC were investigated. Their regulations involved in cell invasion and migration were also evaluated. METHODS Luciferase reporter assay was performed to detect the binding between miR-29b-3p and HCP5 or high-mobility group box 1 (HMGB1). Cell viability, migration, invasion and apoptosis were assessed by CCK-8, colony formation, transwell assay and flow cytometry, respectively. Expression levels of HMGB1/toll-like receptor 4 (TLR4) proteins were measured by Western blot. Xenograft model was built, and tumor volumes and weights were calculated. RESULTS The results revealed dysregulation of HCP5 and miR-29b-3p in BC samples and cells. HCP5 negatively regulated the expression of miR-29b-3p and enhanced cell viability, migration and invasion. MiR-29b-3p mediated the effect of HCP5 on cell viability, proliferation, migration and invasion in RT4 cells. In addition, miR-29b-3p could regulate the expression of HMGB1 through interaction with HMGB1. CONCLUSION The findings in this study supported that lncRNA HCP5 could promote cell invasion and migration by sponging miR-29b-3p in human BC.
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Affiliation(s)
- Cheng Zhao
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Yangle Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Xiheng Hu
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Ruizhe Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Wei He
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Long Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Lin Qi
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
| | - Shiyu Tong
- Department of Urology, Xiangya Hospital, Central South University, Changsha City, Hunan Province410008, People’s Republic of China
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Tang M, Jia H, Chen S, Yang B, Patpur BK, Song W, Chang Y, Li J, Yang C. Significance of MR/OPN/HMGB1 axis in NAFLD-associated hepatic fibrogenesis. Life Sci 2020; 264:118619. [PMID: 33091447 DOI: 10.1016/j.lfs.2020.118619] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
AIMS The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis, however non-alcoholic fatty liver disease (NAFLD) associated liver fibrogenesis have been poorly understood. We aimed to determine the significance of mineralocorticoid receptor (MR)/osteopontin (OPN)/high-mobility group box-1 (HMGB1) axis in this setting. MAIN METHODS Liver specimens were collected from NAFLD patients and murine NAFLD models established with 12-week high fat diet (HFD) for analysis of both upstream signals of MR and intrahepatic MR/OPN/HMGB1 axis. The in vitro cell model of NAFLD-associated liver fibrogenesis was established by treating LX-2 (a cell line of human HSCs) with free fatty acids (FFA). The effects of MR signaling were evaluated using with ALD (MR activator) or eplerenone (Ep, MR antagonist). Moreover, the in vitro loss- and gain- of function approaches were applied to confirm the upstream and downstream relationships of mediators contained in the intracellular MR/OPN/HMGB1 axis of LX-2. KEY FINDINGS In NAFLD condition, both human and mouse liver tissue samples demonstrated a significant up-regulation of MR/OPN/HMGB1 axis simultaneously with enhanced expression of pro-fibrogenic markers, including ACTA2, TIMP1, TGFB1 and COL1A1. Besides, enhanced production of serum aldosterone (ALD) was also observed in mouse NAFLD models. Moreover, the in vitro data demonstrated MR play an essential role in FFA-induced HSCs fibrogenesis. Meanwhile, MR acts as the upstream effector mediator of OPN and shares downstream HMGB1 with OPN. SIGNIFICANCE The MR/OPN/HMGB1 axis could be therapeutically targeted to treat NAFLD associated hepatic fibrogenesis.
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Affiliation(s)
- Min Tang
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Haoyu Jia
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Shuai Chen
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Bo Yang
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Bhuvanesh Kinish Patpur
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Weiping Song
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Yizhong Chang
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Jing Li
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
| | - Changqing Yang
- Department of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
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Ge S, Wu X, Xiong Y, Xie J, Liu F, Zhang W, Yang L, Zhang S, Lai L, Huang J, Li M, Yu YQ. HMGB1 Inhibits HNF1A to Modulate Liver Fibrogenesis via p65/miR-146b Signaling. DNA Cell Biol 2020; 39:1711-1722. [PMID: 32833553 DOI: 10.1089/dna.2019.5330] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
High mobility group box 1 (HMGB1) is essential for the pathogenesis of liver injury and liver fibrosis. We previously revealed that miR-146b promotes hepatic stellate cells (HSCs) activation and proliferation. Nevertheless, the potential mechanisms are still unknown. Herein, HMGB1 increased HSCs proliferation and COL1A1 and α-SMA protein levels. However, the knockdown of miR-146b inhibited HSCs proliferation and COL1A1 and α-SMA protein levels induced via HMGB1 treatment. miR-146b was upregulated by HMGB1 and miR-146b targeted hepatocyte nuclear factor 1A (HNF1A) 3'-untranslated region (3'UTR) to modulate its expression negatively. Further, we confirmed that HMGB1 might elicit miR-146b expression via p65 within HSCs. Knockdown or block of HMGB1 relieved the CCl4-induced liver fibrosis. In fibrotic liver tissues, miR-146b expression was positively correlated with p65 mRNA, but HNF1A mRNA was inversely correlated with p65, and miR-146b expression. In summary, our findings suggest that HMGB1/p65/miR-146b/HNF1A signaling exerts a crucial effect on liver fibrogenesis via the regulation of HSC function.
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Affiliation(s)
- Shanfei Ge
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoping Wu
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ying Xiong
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Xie
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fei Liu
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenfeng Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lixia Yang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Song Zhang
- Department of Infectious Disease, ShangRao People's Hospital, ShangRao, Jiangxi, China
| | - Lingling Lai
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jiansheng Huang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ming Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yan-Qing Yu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Zhang Z, Guo M, Li Y, Shen M, Kong D, Shao J, Ding H, Tan S, Chen A, Zhang F, Zheng S. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy 2020; 16:1482-1505. [PMID: 31679460 PMCID: PMC7469536 DOI: 10.1080/15548627.2019.1687985] [Citation(s) in RCA: 316] [Impact Index Per Article: 63.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/23/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis-inducing compounds, the ubiquitin ligase FBXW7/CDC4 (F-box and WD repeat domain containing 7) decreased ZFP36 protein expression by recognizing SFSGLPS motif. FBXW7 plasmid contributed to classical ferroptotic events, whereas ZFP36 plasmid impaired FBXW7 plasmid-induced HSC ferroptosis. Interestingly, ZFP36 plasmid inhibited macroautophagy/autophagy activation by destabilizing ATG16L1 (autophagy related 16 like 1) mRNA. ATG16L1 plasmid eliminated the inhibitory action of ZFP36 plasmid on ferroptosis, and FBXW7 plasmid enhanced the effect of ATG16L1 plasmid on autophagy. Importantly, ZFP36 plasmid promoted ATG16L1 mRNA decay via binding to the AU-rich elements (AREs) within the 3'-untranslated region. The internal mutation of the ARE region abrogated the ZFP36-mediated ATG16L1 mRNA instability, and prevented ZFP36 plasmid-mediated ferroptosis resistance. In mice, treatment with erastin and sorafenib alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific overexpression of Zfp36 impaired erastin- or sorafenib-induced HSC ferroptosis. Noteworthy, we analyzed the effect of sorafenib on HSC ferroptosis in fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. Overall, these results revealed novel molecular mechanisms and signaling pathways of ferroptosis, and also identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis. ABBREVIATIONS ARE: AU-rich elements; ATG: autophagy related; BECN1: beclin 1; CHX: cycloheximide; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FBXW7/CDC4: F-box and WD repeat domain containing 7; FN1: fibronectin 1; FTH1: ferritin heavy chain 1; GPX4/PHGPx: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LSEC: liver sinusoidal endothelial cell; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RBP: RNA-binding protein; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; TP53/p53: tumor protein p53; UTR: untranslated region; ZFP36/TTP: ZFP36 ring finger protein.
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Affiliation(s)
- Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mei Guo
- Department of Pathogenic biology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Shen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Desong Kong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hai Ding
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Shanzhong Tan
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, USA
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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The Role of Autophagy and NLRP3 Inflammasome in Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7269150. [PMID: 32733951 PMCID: PMC7369671 DOI: 10.1155/2020/7269150] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is an intrinsic repair process of chronic injury with excessive deposition of extracellular matrix. As an early stage of various liver diseases, liver fibrosis is a reversible pathological process. Therefore, if not being controlled in time, liver fibrosis will evolve into cirrhosis, liver failure, and liver cancer. It has been demonstrated that hepatic stellate cells (HSCs) play a crucial role in the formation of liver fibrosis. In particular, the activation of HSCs is a key step for liver fibrosis. Recent researches have suggested that autophagy and inflammasome have biological effect on HSC activation. Herein, we review current studies about the impact of autophagy and NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome on liver fibrosis and the underlying mechanisms.
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Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Am J Cancer Res 2020; 10:7993-8017. [PMID: 32724454 PMCID: PMC7381749 DOI: 10.7150/thno.47826] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/16/2020] [Indexed: 01/18/2023] Open
Abstract
Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.
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Abstract
Viruses manipulate cellular lipids and membranes at each stage of their life cycle. This includes lipid-receptor interactions, the fusion of viral envelopes with cellular membranes during endocytosis, the reorganization of cellular membranes to form replication compartments, and the envelopment and egress of virions. In addition to the physical interactions with cellular membranes, viruses have evolved to manipulate lipid signaling and metabolism to benefit their replication. This review summarizes the strategies that viruses use to manipulate lipids and membranes at each stage in the viral life cycle.
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Affiliation(s)
- Ellen Ketter
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, USA;
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, USA;
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Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020; 9:cells9040875. [PMID: 32260126 PMCID: PMC7226751 DOI: 10.3390/cells9040875] [Citation(s) in RCA: 681] [Impact Index Per Article: 136.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/28/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
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Affiliation(s)
- Natascha Roehlen
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Emilie Crouchet
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
- Pôle Hepato-digestif, Institut Hopitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Correspondence: ; Tel.: +33-366853703
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Li B, Huang Z, Meng J, Yu W, Yang H. MiR-202-5p attenuates neurological deficits and neuronal injury in MCAO model rats and OGD-induced injury in Neuro-2a cells by targeting eIF4E-mediated induction of autophagy and inhibition of Akt/GSK-3β pathway. Mol Cell Probes 2019; 51:101497. [PMID: 31877332 DOI: 10.1016/j.mcp.2019.101497] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/13/2019] [Accepted: 12/22/2019] [Indexed: 12/28/2022]
Abstract
Ischemic stroke is a common cerebrovascular disease caused by insufficient blood supply to the brain. In recent years, studies have demonstrated that microRNAs (miRNAs) are involved in a variety of biological processes in the nervous system. However, the effects of miR-202-5p on cerebral ischemic stroke injury have not been completely elucidated. In our study, N2a cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment, and middle cerebral artery occlusion (MCAO) rat models were constructed. Our results indicated that decreased miR-202-5p expression was connected to N2a cells after OGD/R-induced injury and rats after MCAO. In addition, high miR-202-5p expression increased proliferation and prevented apoptosis and autophagy of OGD/R-treated N2a cells, while also effectively decreasing the infarct volume in MCAO model rats. We validated the interplay between miR-202-5p and eukaryotic translation initiation factor 4E (eIF4E), and found that miR-202-5p downregulated eIF4E by targeted combination. Moreover, we demonstrated that miR-202-5p accelerated proliferation and suppressed autophagy of OGD/R-induced N2a cells by targeting eIF4E. Meanwhile, our other results suggest that upregulation of miR-202-5p may activate the Akt/GSK-3β pathway in ischemic brain injury. Our findings suggest that miR-202-5p may serve as a protective agent for ischemia-reperfusion injury in stroke via eIF4E.
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Affiliation(s)
- Bing Li
- Department of Neurosurgery, The Affiliated Hospital of Gui Zhou Medical University, Guiyang, 550004, China; Department of Ophthalmology, The Affiliated Hospital of Gui Zhou Medical University, Guiyang, 550004, China; Key Laboratory of Endemic and Ethnic Diseases, Key Laboratory of Medical Molecular Biology in Guizhou Medical University, Guiyang, 550002, China
| | - Zhi Huang
- School of Basic Medical Sciences, Gui Zhou Medical University, Guiyang, 550025, China; Department of Interventional Radiology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550005, China; Department of Interventional Radiology, The Second Affiliated Hospital, Guizhou Medical University, Kaili, 556000, China
| | - Ju Meng
- Department of Vascular Surgery, The Affiliated Hospital of Gui Zhou Medical University, Guiyang, 550004, China
| | - Wenfeng Yu
- Key Laboratory of Endemic and Ethnic Diseases, Key Laboratory of Medical Molecular Biology in Guizhou Medical University, Guiyang, 550002, China.
| | - Hua Yang
- Department of Neurosurgery, The Affiliated Hospital of Gui Zhou Medical University, Guiyang, 550004, China.
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