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Chen C, Wang L. Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship. Front Med 2025:10.1007/s11684-025-1133-7. [PMID: 40316793 DOI: 10.1007/s11684-025-1133-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/09/2025] [Indexed: 05/04/2025]
Abstract
In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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Xue XP, Sheng Y, Ren QQ, Xu SM, Li M, Liu ZX, Lu CH. Inhibition of ATP1V6G3 prompts hepatic stellate cell senescence with reducing ECM by activating Notch1 pathway to alleviate hepatic fibrosis. Tissue Cell 2024; 91:102554. [PMID: 39316936 DOI: 10.1016/j.tice.2024.102554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/26/2024]
Abstract
Liver fibrosis is characterized by an excessive reparative response to various etiological factors, with the activated hepatic stellate cells (aHSCs) leading to extracellular matrix (ECM) accumulation. Senescence is a stable growth arrest, and the senescence of aHSCs is associated with the degradation of ECM and the regression of hepatic fibrosis, making it a promising approach for managing hepatic fibrosis. The role and specific mechanisms by which V-Type Proton ATPase Subunit G 3 (ATP6V1G3) influences senescence in activated HSCs during liver fibrosis remain unclear. Our preliminary results reveal upregulation of ATP6V1G3 in both human fibrotic livers and murine liver fibrosis models. Additionally, ATP6V1G3 inhibition induced senescence in aHSCs in vitro. Moreover, suppressing Notch1 reversed the senescence caused by ATP6V1G3 inhibition in HSCs. Thus, targeting ATP6V1G3, which appears to drive HSCs senescence through the Notch1 pathway, emerges as a potential therapeutic strategy for hepatic fibrosis.
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Affiliation(s)
- Xiao-Pei Xue
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department Gastroenterology, Rugao Hospital of traditional Chinese Medicine, Nantong 226500, China
| | - Yu Sheng
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Qi-Qi Ren
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Shi-Meng Xu
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Min Li
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhao-Xiu Liu
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
| | - Cui-Hua Lu
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
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Gao H, Nepovimova E, Adam V, Heger Z, Valko M, Wu Q, Kuca K. Age-associated changes in innate and adaptive immunity: role of the gut microbiota. Front Immunol 2024; 15:1421062. [PMID: 39351234 PMCID: PMC11439693 DOI: 10.3389/fimmu.2024.1421062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.
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Affiliation(s)
- Haoyu Gao
- College of Life Science, Yangtze University, Jingzhou, China
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czechia
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czechia
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Slovakia
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, China
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, Granada, Spain
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Yashaswini CN, Qin T, Bhattacharya D, Amor C, Lowe S, Lujambio A, Wang S, Friedman SL. Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis. J Hepatol 2024; 81:207-217. [PMID: 38508241 PMCID: PMC11269047 DOI: 10.1016/j.jhep.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND & AIMS Hepatic stellate cells (HSCs) are the key drivers of fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. HSCs are heterogenous, and a senescent subset of HSCs is implicated in hepatic fibrosis and HCC. Administration of anti-uPAR (urokinase-type plasminogen activator receptor) CAR T cells has been shown to deplete senescent HSCs and attenuate fibrosis in murine models. However, the comprehensive features of senescent HSCs in MASH, as well as their cellular ontogeny have not been characterized; hence, we aimed to comprehensively characterize and define the origin of HSCs in human and murine MASH. METHODS To comprehensively characterize the phenotype and ontogeny of senescent HSCs in human and murine MASH, we integrated senescence-associated beta galactosidase activity with immunostaining, flow cytometry and single-nucleus RNA sequencing (snRNAseq). We integrated the immunohistochemical profile with a senescence score applied to snRNAseq data to characterize senescent HSCs and mapped the evolution of uPAR expression in MASH. RESULTS Using pseudotime trajectory analysis, we establish that senescent HSCs arise from activated HSCs. While uPAR is expressed in MASH, the magnitude and cell-specificity of its expression evolve with disease stage. In early disease, uPAR is more specific to activated and senescent HSCs, while it is also expressed by myeloid-lineage cells, including Trem2+ macrophages and myeloid-derived suppressor cells, in late disease. Furthermore, we identify novel surface proteins expressed on senescent HSCs in human and murine MASH that could be exploited as therapeutic targets. CONCLUSIONS These data define features of HSC senescence in human and murine MASH, establishing an important blueprint to target these cells as part of future antifibrotic therapies. IMPACT AND IMPLICATIONS Hepatic stellate cells (HSCs) are the primary drivers of scarring in chronic liver diseases. As injury develops, a subset of HSCs become senescent; these cells are non-proliferative and pro-inflammatory, thereby contributing to worsening liver injury. Here we show that senescent HSCs are expanded in MASH (metabolic dysfunction-associated steatohepatitis) in humans and mice, and we trace their cellular origin from the activated HSC subset. We further characterize expression of uPAR (urokinase plasminogen activated receptor), a protein that marks senescent HSCs, and report that uPAR is also expressed by activated HSCs in early injury, and in immune cells as liver injury advances. We have integrated high-resolution single-nucleus RNA sequencing with immunostaining and flow cytometry to identify five other novel proteins expressed by senescent HSCs, including mannose receptor CD206, which will facilitate future therapeutic development.
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Affiliation(s)
- Chittampalli N Yashaswini
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Tianyue Qin
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Dipankar Bhattacharya
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Corina Amor
- Cold Spring Harbor Laboratory. Cold Spring Harbor, NY, United States
| | - Scott Lowe
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Howard Hughes Medical Institute, Chevy Chase, MD, United States
| | - Amaia Lujambio
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
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Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
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Du K, Jun JH, Dutta RK, Diehl AM. Plasticity, heterogeneity, and multifunctionality of hepatic stellate cells in liver pathophysiology. Hepatol Commun 2024; 8:e0411. [PMID: 38619452 PMCID: PMC11019831 DOI: 10.1097/hc9.0000000000000411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 01/26/2024] [Indexed: 04/16/2024] Open
Abstract
HSCs, the resident pericytes of the liver, have consistently been at the forefront of liver research due to their crucial roles in various hepatic pathological processes. Prior literature often depicted HSCs in a binary framework, categorizing them as either quiescent or activated. However, recent advances in HSC research, particularly the advent of single-cell RNA-sequencing, have revolutionized our understanding of these cells. This sophisticated technique offers an unparalleled, high-resolution insight into HSC populations, uncovering a spectrum of diversity and functional heterogeneity across various physiological states of the liver, ranging from liver development to the liver aging process. The single-cell RNA-sequencing revelations have also highlighted the intrinsic plasticity of HSCs and underscored their complex roles in a myriad of pathophysiological processes, including liver injury, repair, and carcinogenesis. This review aims to integrate and clarify these recent discoveries, focusing on how the inherent plasticity of HSCs is central to their dynamic roles both in maintaining liver homeostasis and orchestrating responses to liver injury. Future research will clarify whether findings from rodent models can be translated to human livers and guide how these insights are harnessed to develop targeted therapeutic interventions.
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Damba T, Zhang M, Serna Salas SA, Wu Z, van Goor H, Arenas AF, Muñoz-Ortega MH, Ventura-Juárez J, Buist-Homan M, Moshage H. Inhibition of endogenous hydrogen sulfide production reduces activation of hepatic stellate cells via the induction of cellular senescence. Cell Cycle 2024; 23:629-644. [PMID: 38836592 PMCID: PMC11229775 DOI: 10.1080/15384101.2024.2345477] [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: 09/28/2023] [Accepted: 04/04/2024] [Indexed: 06/06/2024] Open
Abstract
In chronic liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblast-like cells and produce large amounts of extracellular matrix components, e.g. collagen type 1. Cellular senescence is characterized by irreversible cell-cycle arrest, arrested cell proliferation and the acquisition of the senescence-associated secretory phenotype (SASP) and reversal of HSCs activation. Previous studies reported that H2S prevents induction of senescence via its antioxidant activity. We hypothesized that inhibition of endogenous H2S production induces cellular senescence and reduces activation of HSCs. Rat HSCs were isolated and culture-activated for 7 days. After activation, HSCs treated with H2S slow-releasing donor GYY4137 and/or DL-propargylglycine (DL-PAG), an inhibitor of the H2S-producing enzyme cystathionine γ-lyase (CTH), as well as the PI3K inhibitor LY294002. In our result, CTH expression was significantly increased in fully activated HSCs compared to quiescent HSCs and was also observed in activated stellate cells in a in vivo model of cirrhosis. Inhibition of CTH reduced proliferation and expression of fibrotic markers Col1a1 and Acta2 in HSCs. Concomitantly, DL-PAG increased the cell-cycle arrest markers Cdkn1a (p21), p53 and the SASP marker Il6. Additionally, the number of β-galactosidase positive senescent HSCs was increased. GYY4137 partially restored the proliferation of senescent HSCs and attenuated the DL-PAG-induced senescent phenotype. Inhibition of PI3K partially reversed the senescence phenotype of HSCs induced by DL-PAG. Inhibition of endogenous H2S production reduces HSCs activation via induction of cellular senescence in a PI3K-Akt dependent manner. Our results show that cell-specific inhibition of H2S could be a novel target for anti-fibrotic therapy via induced cell senescence.
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Affiliation(s)
- Turtushikh Damba
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Mengfan Zhang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Sandra A Serna Salas
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Zongmei Wu
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Aaron Fierro Arenas
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Javier Ventura-Juárez
- Chemistry Department, Basic Sciences Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Chen Y, Huang Y, Huang R, Chen Z, Wang X, Chen F, Huang Y. Interleukin-10 gene intervention ameliorates liver fibrosis by enhancing the immune function of natural killer cells in liver tissue. Int Immunopharmacol 2024; 127:111341. [PMID: 38081103 DOI: 10.1016/j.intimp.2023.111341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/01/2023] [Accepted: 12/02/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND AND AIMS Interleukin 10 (IL-10) and natural killer (NK) cells have the potential to combat liver fibrosis. However, whether NK cells play an important role in the anti-fibrotic effects of IL-10 is not sufficiently elucidated. In this study, we investigated the regulatory effects of IL-10 on NK cells during liver fibrosis. METHODS Fibrotic mice induced with carbon tetrachloride were treated with or without IL-10 in the presence or absence of NK cells. Liver damage and fibrosis were assessed using hematoxylin and eosin and Sirius Red staining and serum transaminase and liver hydroxyproline assays, respectively. NK cell distribution, quantity, activation, cytotoxicity, development, and origin were analyzed using immunohistochemistry, immunofluorescence, and flow cytometry. Enzyme-linked immunosorbent assay was used to determine chemokine levels. RESULTS In the presence of NK cells, IL-10 gene intervention improved liver fibrosis and enhanced NK cell accumulation and function in the liver, as evidenced by increased NKG2D, interferon-γ, and CD107a expression. Furthermore, IL-10 promoted the migration of circulating NK cells to the fibrotic liver and elevated C-C motif ligand 5 levels. However, depletion of NK cells exacerbated liver fibrosis and impaired the anti-fibrotic effect of IL-10. CONCLUSIONS The anti-fibrotic effect of IL-10 relies on the enhancement of NK cell immune function, including activation, cytotoxicity, development, and migration. These results provide valuable insights into the mechanisms through which IL-10 regulates NK cells to limit the progression of liver fibrosis.
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Affiliation(s)
- Yizhen Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Yixuan Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Rongfeng Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Zhixin Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Xiaozhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Fenglin Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
| | - Yuehong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, Fujian 350001, China.
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9
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Ma M, Wei N, Yang J, Ding T, Song A, Chen L, Zheng S, Jin H. Schisandrin B promotes senescence of activated hepatic stellate cell via NCOA4-mediated ferritinophagy. PHARMACEUTICAL BIOLOGY 2023; 61:621-629. [PMID: 37010139 PMCID: PMC10071970 DOI: 10.1080/13880209.2023.2189908] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 01/31/2023] [Accepted: 03/07/2023] [Indexed: 06/19/2023]
Abstract
CONTEXT Schisandrin B (Sch B), an active ingredient from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, possesses diverse pharmacological activities including antitumor, anti-inflammation, and hepatoprotection. OBJECTIVE To explore the effect of Sch B on activated HSCs senescence in hepatic fibrosis and the mechanisms implicated. MATERIALS AND METHODS ICR mice with CCl4-induced hepatic fibrosis were supplemented with Sch B (40 mg/kg) for 30 d and LX2 cells were treated with Sch B (5, 10 and 20 μM) for 24 h. Cellular senescence was assessed by senescence-related indicators senescence-associated β-galactosidase (SA-β-gal) activity and the expression of p16, p21, p53, γ-H2AX, H3K9me3, TERT, TRF1, and TRF2. Ferric ammonium citrate (FAC) and NCOA4 siRNA were used to evaluate the mechanisms underlying Sch B's regulation of cellular senescence. RESULTS Sch B (40 mg/kg) reduced serum levels of AST and ALT (53.2% and 63.6%), alleviated hepatic collagen deposition, and promoted activated HSCs senescence in mice. Treatment with Sch B (20 μM) decreased cell viability to 80.38 ± 4.87% and elevated SA-β-gal activity, with the levels of p16, p21 and p53 increased by 4.5-, 2.9-, and 3.5-fold and the levels of TERT, TRF1 and TRF2 decreased by 2.4-, 2.7-, and 2.6-fold in LX2 cells. FAC (400 μM) enhanced Sch B's effect mentioned above. NCOA4 siRNA weakened the effects of Sch B on iron deposition and HSCs senescence. CONCLUSIONS Sch B could ameliorate hepatic fibrosis through the promotion of activated HSCs senescence, which might be attributed to its induction of NCOA4-mediated ferritinophagy and subsequent iron overload.
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Affiliation(s)
- Mingyue Ma
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Na Wei
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Jieren Yang
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Tingting Ding
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Anping Song
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Lerong Chen
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Shuguo Zheng
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
- Laboratory of Pharmacology of Chinese Medicine, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
- Laboratory of Pharmacology of Chinese Medicine, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, P.R. China
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Song A, Ding T, Wei N, Yang J, Ma M, Zheng S, Jin H. Schisandrin B induces HepG2 cells pyroptosis by activating NK cells mediated anti-tumor immunity. Toxicol Appl Pharmacol 2023; 472:116574. [PMID: 37271225 DOI: 10.1016/j.taap.2023.116574] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/07/2023] [Accepted: 05/29/2023] [Indexed: 06/06/2023]
Abstract
Pyroptosis, an inflammatory programmed cell death, has been suggested as a novel molecular mechanism for the treatment of hepatocellular carcinoma (HCC) with chemotherapeutic agents. Recent studies showed that natural killer (NK) cells could inhibit apoptosis and regulate the progression of pyroptosis in tumor cells. Schisandrin B (Sch B), a lignan isolated from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, has various pharmacological activities including anti-cancer effects. The purpose of this study was to investigate the effect of NK cells on Sch B's regulation of pyroptosis in HCC cells and the molecular mechanisms implicated. The results showed that Sch B alone could decrease cell viability and induce apoptosis in HepG2 cells. However, Sch B induced apoptosis in HepG2 cells was transformed into pyroptosis in the presence of NK cells. The mechanisms underlying NK cell's effect on pyroptosis in Sch B-treated HepG2 cells was related to its activation of caspase 3-Gasdermin E (GSDME). Further studies revealed that NK cell induced caspase 3 activation was derived from its activation of perforin-granzyme B pathway. This study explored the effect of Sch B and NK cells on pyroptosis in HepG2 cells and revealed that perforin-granzyme B-caspase 3-GSDME pathway is involved in the process of pyroptosis. These results proposed an immunomodulatory mechanism of Sch B on HepG2 cells pyroptosis and suggested Sch B as a promising immunotherapy combination partner for the treatment of HCC.
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Affiliation(s)
- Anping Song
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Tingting Ding
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Na Wei
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Jieren Yang
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Mingyue Ma
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Shuguo Zheng
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China; Laboratory of Pharmacology of Chinese Medicine, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China.
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China; Laboratory of Pharmacology of Chinese Medicine, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China.
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11
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Ge T, Shao Y, Bao X, Xu W, Lu C. Cellular senescence in liver diseases: From mechanisms to therapies. Int Immunopharmacol 2023; 121:110522. [PMID: 37385123 DOI: 10.1016/j.intimp.2023.110522] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 06/05/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yunyun Shao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Wenxuan Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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12
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Yang M, Vanderwert E, Kimchi ET, Staveley-O’Carroll KF, Li G. The Important Roles of Natural Killer Cells in Liver Fibrosis. Biomedicines 2023; 11:1391. [PMID: 37239062 PMCID: PMC10216436 DOI: 10.3390/biomedicines11051391] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/05/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Ethan Vanderwert
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA
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Sun Y, Weng J, Chen X, Ma S, Zhang Y, Zhang F, Zhang Z, Wang F, Shao J, Zheng S. Oroxylin A activates ferritinophagy to induce hepatic stellate cell senescence against hepatic fibrosis by regulating cGAS-STING pathway. Biomed Pharmacother 2023; 162:114653. [PMID: 37086511 DOI: 10.1016/j.biopha.2023.114653] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/31/2023] [Accepted: 03/31/2023] [Indexed: 04/24/2023] Open
Abstract
In recent study, the pathological mechanism of liver fibrosis has been associated with hepatic stellate cell (HSC) senescence. Targeted induction of HSC senescence is considered as a new strategy to remove activated HSC. Nevertheless, little is known about the role of ferritinophagy in cell senescence. In this study, we reported that Oroxylin A from Scutellaria baicalensis Georgi can regulate HSC senescence induced by ferritinophagy through the cGAS-STING pathway to reduce liver fibrosis. We first found that Oroxylin A treatment alleviated the pathological changes of liver fibrosis, reduced collagen deposition, and significantly inhibited liver fibrosis. Interestingly, Oroxylin A treatment can activate HSC ferritinophagy and further induce HSC senescence. It is noteworthy that ferritinophagy is mediated by nuclear receptor coactivator 4 (NCOA4), an important selective mediator for ferritin degradation. NCOA4 siRNA causes Oroxylin A to reduce the degree of telomerase activity in HSCs and induce the expression of senescence markers, such as SA-β-Gal and related marker proteins. Importantly, the cGAS-STING pathway is crucial to the activation of HSC ferritinophagy by Oroxylin A. Specifically, Oroxylin A can promote the secretion of cytokines like IFN-β by the cGAS-STING pathway to regulate ferritinophagy. cGAS siRNA resulted in a dose-dependent decrease in the expression of NCOA4, a significant reduction in the expression level of autophagy-related phenotype, and a decrease in the content of ROS and iron ions in HSCs. In conclusion, we identified the new role of ferritinophagy and the GAS-STING pathway in Oroxylin A -mediated anti-hepatic fibrosis.
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Affiliation(s)
- Ying Sun
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingdan Weng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaolei Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuyao Ma
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuxin Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feixia Wang
- 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.
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
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14
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Bioactive coumarin-derivative esculetin decreases hepatic stellate cell activation via induction of cellular senescence via the PI3K-Akt-GSK3β pathway. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.102164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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15
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Wei Y, Bingyu W, Lei Y, Xingxing Y. The antifibrotic role of natural killer cells in liver fibrosis. Exp Biol Med (Maywood) 2022; 247:1235-1243. [PMID: 35475367 PMCID: PMC9379607 DOI: 10.1177/15353702221092672] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Liver fibrosis is the common pathological change of chronic liver diseases characterized by increased deposition of extracellular matrix and reduced matrix degradation. In response to liver injury caused by a variety of pathogenic agents, such as virus and alcohol, hepatic stellate cells (HSCs) are differentiated into myofibroblast-like cells and produce excessive collagens, thus resulting in fibrogenesis. Natural killer (NK) cells are the essential innate immune cells in the liver and generally control fibrosis by killing activated HSCs. This review briefly describes the fibrogenesis process and the phenotypic features of hepatic NK cells. Besides, it focuses on the antifibrotic mechanisms of NK cells and explores the potential of activating NK cells as a therapeutic strategy for the disease.
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Affiliation(s)
- Yuan Wei
- Department of Hepatology, The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha 410000, China
| | - Wang Bingyu
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, China
| | - Yang Lei
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, China
| | - Yuan Xingxing
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, China,Yuan Xingxing.
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16
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Zhang Y, Wu Y, Shen W, Wang B, Yuan X. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol Med Rep 2022; 25:208. [PMID: 35506449 PMCID: PMC9133963 DOI: 10.3892/mmr.2022.12724] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/19/2022] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is a common pathological process of chronic liver diseases, including viral hepatitis and alcoholic liver disease, and ultimately progresses to irreversible cirrhosis and cancer. Hepatic stellate cells (HSCs) are activated to produce amounts of collagens in response to liver injury, thus triggering the initiation and progression of fibrogenesis. Natural killer (NK) cells serve as the essential component of hepatic innate immunity and are considered to alleviate fibrosis by killing activated HSCs. Current antifibrotic interventions have improved fibrosis, but fail to halt its progression in the advanced stage. Clarifying the interaction between NK cells and HSCs will provide clues to the pathogenesis and potential therapies for advanced liver fibrosis.
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Affiliation(s)
- Yang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Yuan Wu
- The Graduate School, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Wenjuan Shen
- Department of Gynaecology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Bingyu Wang
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Xingxing Yuan
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
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17
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T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222212190. [PMID: 34830072 PMCID: PMC8623596 DOI: 10.3390/ijms222212190] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.
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18
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Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H. Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives. Mech Ageing Dev 2021; 199:111572. [PMID: 34536446 DOI: 10.1016/j.mad.2021.111572] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/15/2021] [Accepted: 09/10/2021] [Indexed: 02/08/2023]
Abstract
Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in which proliferating cells undergo irreversible cell cycle arrest. Senescent hepatic stellate cells were identified in liver fibrosis. Senescent hepatic stellate cells display decreased collagen production and proliferation. Therefore, induction of senescence could be a protective mechanism against progression of liver fibrosis and the concept of therapy-induced senescence has been proposed to treat liver fibrosis. In this review, characteristics of senescent hepatic stellate cells and the essential signaling pathways involved in senescence are reviewed. Furthermore, the potential impact of senescent hepatic stellate cells on other liver cell types are discussed. Senescent cells are cleared by the immune system. The persistence of senescent cells can remodel the microenvironment and interact with inflammatory cells to induce aging-related dysfunction. Therefore, senolytics, a class of compounds that selectively induce death of senescent cells, were introduced as treatment to remove senescent cells and consequently decrease the disadvantageous effects of persisting senescent cells. The effects of senescent hepatic stellate cells in liver fibrosis need further investigation.
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Affiliation(s)
- Mengfan Zhang
- Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Sandra Serna-Salas
- Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Turtushikh Damba
- Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Michaela Borghesan
- European Research Institute on the Biology of Aging (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Marco Demaria
- European Research Institute on the Biology of Aging (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Han Moshage
- Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis. Ann Hepatol 2021; 19:497-506. [PMID: 32673649 DOI: 10.1016/j.aohep.2020.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/06/2020] [Accepted: 05/28/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. MATERIALS AND METHODS CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. RESULTS AND CONCLUSIONS Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-β, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-β-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects.
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Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | | | | | | | - Rosa E Flores-Beltrán
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico.
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Wang W, Li F, Lai X, Liu H, Wu S, Han Y, Shen Y. Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107. Cell Death Discov 2021; 7:174. [PMID: 34234100 PMCID: PMC8263701 DOI: 10.1038/s41420-021-00536-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/29/2021] [Accepted: 05/29/2021] [Indexed: 12/13/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) is a key inducer of liver fibrogenesis in nonalcoholic fatty liver disease (NAFLD). Exosomes play an important role between hepatocytes and HSCs. This study aims to explore the role of exosomes derived from palmitic acid (PA)-treated hepatocytes in regulating HSCs (LX-2 cell) proliferation and activation and the underlying mechanisms. Exosomes were isolated from PA-treated human normal hepatocytes and incubated with LX-2 cells. Cell Counting Kit-8 (CCK-8) was performed to determine LX-2 cell proliferation, and the expression of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1) were examined to evaluateLX-2 cell activation. PA induced hepatocytes to release more exosomes enriched in miR-107. Mechanically, on the one hand, exosomes from PA-treated hepatocytes shuttled miR-107 to LX-2 cells, where miR-107 activated Wnt signaling by targeting DKK1 and thereby induced LX-2 cell activation; on the other hand, PA-treated hepatocytes derived exosomes also delivered miR-107 to CD4 + T lymphocytes, where miR-107 elevated IL-9 expression by targeting Foxp1, which bound to the IL-9 promoter in CD4 + T cells and suppressed Th9 cell differentiation and reduced IL-9 expression, and thus promoted LX-2 cell activation by activating Raf/MEK/ERK signaling pathway.
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Affiliation(s)
- Wei Wang
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Fangfang Li
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Xiaoyang Lai
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Han Liu
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Shuting Wu
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Yunqin Han
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, China.
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21
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Han QJ, Mu YL, Zhao HJ, Zhao RR, Guo QJ, Su YH, Zhang J. Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells. World J Gastroenterol 2021; 27:3581-3594. [PMID: 34239271 PMCID: PMC8240055 DOI: 10.3748/wjg.v27.i24.3581] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/09/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fasudil, as a Ras homology family member A (RhoA) kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis.
AIM To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide (TAA).
METHODS C57BL/6 mice were administered TAA once every 3 d for 12 times. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, followed by hematoxylin and eosin staining, sirius red staining, western blotting, and quantitative polymerase chain reaction (qPCR), and immune cell activation was assayed by fluorescence-activated cell sorting. Furthermore, the effects of Fasudil on hepatic stellate cells and natural killer (NK) cells were assayed in vitro.
RESULTS First, we found that TAA-induced liver injury was protected, and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment. Furthermore, western blot and qPCR assays showed that the levels of alpha smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor beta 1 (TGF-β1) were inhibited by Fasudil. Moreover, flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro. Furthermore, Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasing α-SMA and TGF-β1.
CONCLUSION Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation, thereby providing a feasible solution for the clinical treatment of liver fibrosis.
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Affiliation(s)
- Qiu-Ju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Yong-Liang Mu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Hua-Jun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Rong-Rong Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Quan-Juan Guo
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Yu-Hang Su
- Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
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22
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Zhou X, Yu L, Zhou M, Hou P, Yi L, Mi M. Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect. Nutr Metab (Lond) 2021; 18:64. [PMID: 34147124 PMCID: PMC8214786 DOI: 10.1186/s12986-021-00589-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background This study investigated the mechanisms underlying the preventive effect of dihydromyricetin (DHM) against liver fibrosis involving hepatic stellate cells (HSCs) and hepatic natural killer (NK) cells. Methods A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 mice to study the antifibrotic effect of DHM based on serum biochemical parameters, histological and immunofluorescence stainings, and the expression of several fibrosis-related markers. Based on the immunoregulatory role of DHM, the effect of DHM on NK cell activation ex vivo was evaluated by flow cytometry. Then, we investigated whether DHM-induced autophagy was involved in HSCs inactivation using enzyme-linked immunosorbent assays, transmission electron microscopy, and western blot analysis. Thereafter, the role of DHM in NK cell-mediated killing was studied by in vitro coculture of NK cells and HSCs, with subsequent analysis by flow cytometry. Finally, the mechanism by which DHM regulates NK cells was studied by western blot analysis. Results DHM ameliorated liver fibrosis in C57BL/6 mice, as characterized by decreased serum alanine transaminase and aspartate transaminase levels, decreased expressions of collagen I alpha 1 (CoL-1α1), collagen I alpha 2 (CoL-1α2), tissue inhibitor of metalloproteinases 1 (TIMP-1), α-smooth muscle actin (α-SMA) and desmin, as well as increased expression of matrix metalloproteinase 1 (MMP1). Interestingly, HSCs activation was significantly inhibited by DHM in vivo and in vitro. As expected, DHM also upregulated autophagy-related indicators in liver from CCl4-treated mice. DHM also prevented TGF-β1-induced activation of HSCs in vitro by initiating autophagic flux. In contrast, the autophagy inhibitor 3-methyladenine markedly abolished the antifibrotic effect of DHM. Surprisingly, the frequency of activated intrahepatic NK cells was significantly elevated by DHM ex vivo. Furthermore, DHM enhanced NK cell-mediated killing of HSCs by increasing IFN-γ expression, which was abolished by an anti-IFN-γ neutralizing antibody. Mechanistically, DHM-induced IFN-γ expression was through AhR-NF-κB/STAT3 pathway in NK cells. Conclusion These results demonstrated that DHM can ameliorate the progression of liver fibrosis and inhibition of HSCs activation by inducing autophagy and enhancing NK cell-mediated killing through the AhR-NF-κB/STAT3-IFN-γ signaling pathway, providing new insights into the preventive role of DHM in liver fibrosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00589-6.
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Affiliation(s)
- Xi Zhou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Li Yu
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Min Zhou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Pengfei Hou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Long Yi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
| | - Mantian Mi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
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23
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Guo Q, Chen M, Chen Q, Xiao G, Chen Z, Wang X, Huang Y. Silencing p53 inhibits interleukin 10-induced activated hepatic stellate cell senescence and fibrotic degradation in vivo. Exp Biol Med (Maywood) 2021; 246:447-458. [PMID: 33028080 PMCID: PMC7885051 DOI: 10.1177/1535370220960391] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Activated hepatic stellate cells are reported to play a significant role in liver fibrogenesis. Beside the phenotype reversion and apoptosis of activated hepatic stellate cells, the senescence of activated hepatic stellate cells limits liver fibrosis. Our previous researches have demonstrated that interleukin-10 could promote hepatic stellate cells senescence via p53 signaling pathway in vitro. However, the relationship between expression of p53 and senescence of activated hepatic stellate cells induced by interleukin-10 in fibrotic liver is unclear. The purpose of present study was to explore whether p53 plays a crucial role in the senescence of activated hepatic stellate cells and degradation of collagen mediated by interleukin-10. Hepatic fibrosis animal model was induced by carbon tetrachloride through intraperitoneal injection and transfection of interleukin-10 gene to liver was performed by hydrodynamic-based transfer system. Depletions of p53 in vivo and in vitro were carried out by adenovirus-based short hairpin RNA against p53. Regression of fibrosis was assessed by liver biopsy and collagen staining. Cellular senescence in the liver was observed by senescence-associated beta-galactosidase (SA-β-Gal) staining. Immunohistochemistry, immunofluorescence double staining, and Western blot analysis were used to evaluate the senescent cell and senescence-related protein expression. Our data showed that interleukin-10 gene treatment could lighten hepatic fibrosis induced by carbon tetrachloride and induce the aging of activated hepatic stellate cells accompanied by up-regulating the expression of aging-related proteins. We further demonstrated that depletion of p53 could abrogate up-regulation of interleukin-10 on the expression of senescence-related protein in vivo and vitro. Moreover, p53 knockout in fibrotic mice could block not only the senescence of activated hepatic stellate cells, but also the degradation of fibrosis induced by interleukin-10 gene intervention. Taken together, our results suggested that interleukin-10 gene treatment could attenuate carbon tetrachloride-induced hepatic fibrosis by inducing senescence of activated hepatic stellate cells in vivo, and this induction was closely related to p53 signaling pathway.
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Affiliation(s)
- Qilan Guo
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
- Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Minghua Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Qingduo Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Guitao Xiao
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Zhixin Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Xiaozhong Wang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yuehong Huang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China
- Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China
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24
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A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7171498. [PMID: 33082829 PMCID: PMC7556091 DOI: 10.1155/2020/7171498] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/18/2022]
Abstract
Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.
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25
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Wang W, Huang X, Fan X, Yan J, Luan J. Progress in evaluating the status of hepatitis C infection based on the functional changes of hepatic stellate cells (Review). Mol Med Rep 2020; 22:4116-4124. [PMID: 33000255 DOI: 10.3892/mmr.2020.11516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into myofibroblasts, which are important cells in the development of liver fibrosis. At present, HCV infection still lacks specific markers for the accurate detection of the disease condition and progression. Therefore, the present review focused on HSCs, which are closely related to HCV‑infected liver fibrosis, and analyzed the changes in the HSCs, including their surface‑specific markers, cytokine production, activation, cell function and morphological structure. The present review aimed to propose novel diagnostic markers, at both the cellular and molecular level, which would be of great significance for the timely diagnosis of the disease. According to this aim, the characteristic changes of HSCs during HCV infection were reviewed in the present article.
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Affiliation(s)
- Wei Wang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuelian Huang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuzhou Fan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingmei Yan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianfeng Luan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
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26
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Huang E, Peng N, Xiao F, Hu D, Wang X, Lu L. The Roles of Immune Cells in the Pathogenesis of Fibrosis. Int J Mol Sci 2020; 21:E5203. [PMID: 32708044 PMCID: PMC7432671 DOI: 10.3390/ijms21155203] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022] Open
Abstract
Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.
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Affiliation(s)
- Enyu Huang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Na Peng
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Fan Xiao
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Dajun Hu
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Xiaohui Wang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
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27
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Roife D, Sarcar B, Fleming JB. Stellate Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:67-84. [PMID: 32588324 DOI: 10.1007/978-3-030-44518-8_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma.
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Affiliation(s)
- David Roife
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Bhaswati Sarcar
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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28
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Rutz J, Janicova A, Woidacki K, Chun FKH, Blaheta RA, Relja B. Curcumin-A Viable Agent for Better Bladder Cancer Treatment. Int J Mol Sci 2020; 21:ijms21113761. [PMID: 32466578 PMCID: PMC7312715 DOI: 10.3390/ijms21113761] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/12/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Although the therapeutic armamentarium for bladder cancer has considerably widened in the last few years, severe side effects and the development of resistance hamper long-term treatment success. Thus, patients turn to natural plant products as alternative or complementary therapeutic options. One of these is curcumin, the principal component of Curcuma longa that has shown chemopreventive effects in experimental cancer models. Clinical and preclinical studies point to its role as a chemosensitizer, and it has been shown to protect organs from toxicity induced by chemotherapy. These properties indicate that curcumin could hold promise as a candidate for additive cancer treatment. This review evaluates the relevance of curcumin as an integral part of therapy for bladder cancer.
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Affiliation(s)
- Jochen Rutz
- Department of Urology, Goethe-University, 60438 Frankfurt am Main, Germany; (J.R.); (F.K.-H.C.)
| | - Andrea Janicova
- Department of Radiology and Nuclear Medicine, Experimental Radiology, Otto-von-Guericke University, 39106 Magdeburg, Germany; (A.J.); (K.W.); (B.R.)
| | - Katja Woidacki
- Department of Radiology and Nuclear Medicine, Experimental Radiology, Otto-von-Guericke University, 39106 Magdeburg, Germany; (A.J.); (K.W.); (B.R.)
| | - Felix K.-H. Chun
- Department of Urology, Goethe-University, 60438 Frankfurt am Main, Germany; (J.R.); (F.K.-H.C.)
| | - Roman A. Blaheta
- Department of Urology, Goethe-University, 60438 Frankfurt am Main, Germany; (J.R.); (F.K.-H.C.)
- Correspondence:
| | - Borna Relja
- Department of Radiology and Nuclear Medicine, Experimental Radiology, Otto-von-Guericke University, 39106 Magdeburg, Germany; (A.J.); (K.W.); (B.R.)
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29
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Wang Y, Lu J, Jiang B, Guo J. The roles of curcumin in regulating the tumor immunosuppressive microenvironment. Oncol Lett 2020; 19:3059-3070. [PMID: 32256807 PMCID: PMC7074405 DOI: 10.3892/ol.2020.11437] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer is a harmful threat to human health. In addition to surgery, a variety of anticancer drugs are increasingly used in cancer therapy; however, despite the developments in multimodality treatment, the morbidity and mortality of patients with cancer patients are on the increase. The tumor-specific immunosuppressive microenvironment serves an important function in tumor tolerance and escape from immune surveillance leading to tumor progression. Therefore, identifying new drugs or foods that can enhance the tumor immune response is critical to develop improved cancer prevention methods and treatment. Curcumin, a polyphenolic compound extracted from ginger, has been shown to effectively inhibit tumor growth, proliferation, invasion, metastasis and angiogenesis in a variety of tumors. Recent studies have also indicated that curcumin can modulate the tumor immune response and remodel the tumor immunosuppressive microenvironment, indicating its potential in the immunotherapy of cancer. In this review, a brief introduction to the effects of curcumin on the tumor immune response and tumor immune microenvironment is provided and recent clinical trials investigating the potential of curcumin in cancer therapy are discussed.
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Affiliation(s)
- Yizhi Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jun Lu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Bolun Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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30
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Lingzhi Z, Meirong L, Xiaobing F. Biological approaches for hypertrophic scars. Int Wound J 2019; 17:405-418. [PMID: 31860941 DOI: 10.1111/iwj.13286] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/01/2019] [Accepted: 12/05/2019] [Indexed: 12/11/2022] Open
Abstract
Scar formation is usually the pathological consequence of skin trauma. And hypertrophic scars (HSs) frequently occur in people after being injured deeply. HSs are unusually considered as the result of tissue contraction and excessive extracellular matrix component deposition. Myofibroblasts, as the effector cells, mainly differentiated from fibroblasts, play the crucial role in the pathophysiology of HSs. A number of growth factors, inflammatory cytokines involved in the process of HS occurrence. Currently, with in-depth exploration and clinical research of HSs, various creative and effective treatments budded. In here, we summarize the progress in the molecular mechanism of HSs, and review the available biotherapeutic methods for their pathophysiological characteristics. Additionally, we further prospected that the comprehensive therapy may be more suitable for HS treatment.
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Affiliation(s)
- Zhong Lingzhi
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
| | - Li Meirong
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China.,Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital Hainan Branch, Sanya, China
| | - Fu Xiaobing
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
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31
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Russo GL, Spagnuolo C, Russo M, Tedesco I, Moccia S, Cervellera C. Mechanisms of aging and potential role of selected polyphenols in extending healthspan. Biochem Pharmacol 2019; 173:113719. [PMID: 31759977 DOI: 10.1016/j.bcp.2019.113719] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/14/2019] [Indexed: 12/18/2022]
Abstract
Aging became a priority in medicine due to the rapid increase of elderly population and age-related diseases in the Western countries. Nine hallmarks have been identified based on their alteration during aging and their capacity to increase longevity. The pathways and the molecular mechanisms to improve lifespan and healthspan are controlled by behavioral, pharmacologic and dietary factors, which remain largely unknown. Among them, naturally occurring compounds, such as polyphenols, are considered potential antiaging agents, because of their ability to modulate some of the evolutionarily conserved hallmarks of aging, including oxidative damage, inflammation, cell senescence, and autophagy. Initially, these compounds gained researchers' attention due to their ability to extend the lifespan of simple model organisms. More recently, some of them have been proposed as senolytic agents to protect against age-related disorders, such as cancer, cardiovascular and neurodegenerative diseases. The intent of this review is to present the most validated molecular mechanisms regulating ageing and longevity and critically analyze how selected polyphenols, namely resveratrol, quercetin, curcumin and catechins, can interfere with these mechanisms.
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Affiliation(s)
- Gian Luigi Russo
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy.
| | - Carmela Spagnuolo
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy
| | - Maria Russo
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy
| | - Idolo Tedesco
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy
| | - Stefania Moccia
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy
| | - Carmen Cervellera
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy
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32
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Meng X, Wang H, Song X, Clifton AC, Xiao J. The potential role of senescence in limiting fibrosis caused by aging. J Cell Physiol 2019; 235:4046-4059. [PMID: 31637710 DOI: 10.1002/jcp.29313] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023]
Abstract
Fibrosis-related diseases carry with them a high mortality rate and their morbidity increases with age. Recent findings indicate that induced senescence in myofibroblasts can limit or reduce myocardial fibrosis, cirrhosis, and idiopathic pulmonary fibrosis, while also accelerating wound healing. However, more senescent cells are accumulated as organisms age, which exacerbates aging-related diseases. These two contradictory theories inspired us to summarize papers on the restrictive effect of senescence on fibrosis and to input the key findings into simple software that we developed to assist with data organization and presentation. In this review, we illustrate that senescent cells secrete more matrix metalloproteinases to solubilize excess collagen, while chemokines and cytokines activate immune cells to eliminate senescent cells. In the elderly, it is perhaps more effective to limit fibrosis by inducing myofibroblast senescence and then removing senescent cells that are not cleared via normal mechanisms by antisenescence therapies.
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Affiliation(s)
- Xinghua Meng
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agriculture University, Harbin, P. R. China
| | - Haoran Wang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agriculture University, Harbin, P. R. China
| | - Xiaopeng Song
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agriculture University, Harbin, P. R. China
| | - Alancia C Clifton
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agriculture University, Harbin, P. R. China
| | - Jianhua Xiao
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agriculture University, Harbin, P. R. China
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33
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Zang J, Ye J, Zhang C, Sha M, Gao J. Senescent hepatocytes enhance natural killer cell activity via the CXCL-10/CXCR3 axis. Exp Ther Med 2019; 18:3845-3852. [PMID: 31616512 PMCID: PMC6781833 DOI: 10.3892/etm.2019.8037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 08/15/2019] [Indexed: 12/14/2022] Open
Abstract
Cellular senescence and natural killer (NK) cells play an important role in liver diseases. Chemokines, a component of the senescence-associated secretory phenotype, can recruit NK cells and are involved in the development of various liver diseases. The effect of the C-X-C motif chemokine ligand (CXCL)-9, −10, −11/C-X-C motif chemokine receptor (CXCR)3 axis in senescent hepatocytes remains unknown. The chemokines secreted by senescent hepatocytes, the contribution of the CXCL-9, −10, −11/CXCR3 axis to the migration of NK cells, and the effect of senescent hepatocytes on the function of NK cells were investigated in the present study. The results demonstrated significantly increased levels of C-C motif chemokine ligand 2 and CXCL-1, −2 and −10 in the supernatant of senescent AML12 cells. Despite increased mRNA expression of CXCL-9, −10, and −11 in these cells, western blotting revealed significantly enhanced expression of only CXCL-10. The expression of CXCR3 on the surface of NK cells stimulated by senescent AML12 cells was upregulated (fold change, >3). Following incubation with the supernatant of senescent hepatocytes, both CD107a and interferon γ expression in NK cells increased by >2.5-fold. The cytotoxic effect of NK cells was notably higher stimulated by senescent AML12 cells. Chemotaxis and blocking assays demonstrated that the senescent hepatocytes enhanced the migration of NK cells via the CXCL-10/CXCR3 axis. The present study suggests that senescent hepatocytes secrete various chemokines, including CXCL-10, resulting in the upregulation and activation of CXCR3 in NK cells and the enhancement of NK cell migration via the CXCL-10/CXCR3 axis.
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Affiliation(s)
- Jinfeng Zang
- Department of Hepatobiliary Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University Medical School, Taizhou, Jiangsu 225300, P.R. China
| | - Jun Ye
- Central Laboratory, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University Medical School, Taizhou, Jiangsu 225300, P.R. China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University Medical School, Taizhou, Jiangsu 225300, P.R. China
| | - Min Sha
- Central Laboratory, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University Medical School, Taizhou, Jiangsu 225300, P.R. China
| | - Junye Gao
- Department of Hepatobiliary Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University Medical School, Taizhou, Jiangsu 225300, P.R. China
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Curcumin induces multiple signaling pathways leading to vascular smooth muscle cell senescence. Biogerontology 2019; 20:783-798. [PMID: 31372798 PMCID: PMC6790191 DOI: 10.1007/s10522-019-09825-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/24/2019] [Indexed: 01/01/2023]
Abstract
Curcumin, a phytochemical present in the spice named turmeric, and one of the promising anti-aging factors, is itself able to induce cellular senescence. We have recently shown that cells building the vasculature senesced as a result of curcumin treatment. Curcumin-induced senescence was DNA damage-independent; however, activation of ATM was observed. Moreover, neither increased ROS production, nor even ATM were indispensable for senescence progression. In this paper we tried to elucidate the mechanism of curcumin-induced senescence. We analyzed the time-dependence of the level and activity of numerous proteins involved in senescence progression in vascular smooth muscle cells and how inhibition p38 or p38 together with ATM, two proteins involved in canonical signaling pathways, influenced cell senescence. We showed that curcumin was able to influence many signaling pathways of which probably none was dominant and sufficient to induce senescence by itself. However, we cannot exclude that the switch between initiation and progression of senescence is the result of the impact of curcumin on signaling pathways engaging AMPK, ATM, sirtuin 1 and p300 and on their reciprocal interplay. Cytostatic concentration of curcumin induced cellular stress, which exceeded the adaptive response and, in consequence, led to cellular senescence, which is triggered by time dependent activation of several signaling pathways playing diverse roles in different phases of senescence progression. We also showed that activity of β-glucuronidase, the enzyme involved in deconjugation of the main metabolites of curcumin, glucuronides, increased in senescent cells. It suggests a possible local elevation of curcumin concentration in the organism.
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Bielak-Zmijewska A, Grabowska W, Ciolko A, Bojko A, Mosieniak G, Bijoch Ł, Sikora E. The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci 2019; 20:E1239. [PMID: 30871021 PMCID: PMC6429134 DOI: 10.3390/ijms20051239] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/27/2022] Open
Abstract
It is believed that postponing ageing is more effective and less expensive than the treatment of particular age-related diseases. Compounds which could delay symptoms of ageing, especially natural products present in a daily diet, are intensively studied. One of them is curcumin. It causes the elongation of the lifespan of model organisms, alleviates ageing symptoms and postpones the progression of age-related diseases in which cellular senescence is directly involved. It has been demonstrated that the elimination of senescent cells significantly improves the quality of life of mice. There is a continuous search for compounds, named senolytic drugs, that selectively eliminate senescent cells from organisms. In this paper, we endeavor to review the current knowledge about the anti-ageing role of curcumin and discuss its senolytic potential.
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Affiliation(s)
- Anna Bielak-Zmijewska
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Wioleta Grabowska
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Agata Ciolko
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Agnieszka Bojko
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Grażyna Mosieniak
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Łukasz Bijoch
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
| | - Ewa Sikora
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
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Antonangeli F, Zingoni A, Soriani A, Santoni A. Senescent cells: Living or dying is a matter of NK cells. J Leukoc Biol 2019; 105:1275-1283. [DOI: 10.1002/jlb.mr0718-299r] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 01/30/2019] [Accepted: 02/03/2019] [Indexed: 12/19/2022] Open
Affiliation(s)
- Fabrizio Antonangeli
- Department of Molecular MedicineSapienza University of RomeLaboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti Rome Italy
| | - Alessandra Zingoni
- Department of Molecular MedicineSapienza University of RomeLaboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti Rome Italy
| | - Alessandra Soriani
- Department of Molecular MedicineSapienza University of RomeLaboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti Rome Italy
| | - Angela Santoni
- Department of Molecular MedicineSapienza University of RomeLaboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti Rome Italy
- Neuromed I.R.C.C.S. Pozzilli (IS) Italy
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Affiliation(s)
| | - Eric Vivier
- Innate Pharma, Marseille, France. .,Aix Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France.,Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France
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Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis. Biomed Pharmacother 2018; 103:1262-1271. [PMID: 29864907 DOI: 10.1016/j.biopha.2018.04.156] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/08/2018] [Accepted: 04/23/2018] [Indexed: 12/21/2022] Open
Abstract
Autophagy has been regarded as an inflammation-associated defensive mechanism against chronic liver disease, which has been highlighted as a novel therapeutic target for the treatment of liver fibrosis. We herein aimed to study the effects of catalpol on liver fibrosis in vivo and in vitro, and to elucidate the role of autophagy in catalpol-induced anti-inflammation. Catalpol protected the liver against CCl4-induced injury, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. Catalpol decreased the serum levels of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and bilirubin as well as the liver/body weight ratio. Masson and sirius red staining along with hydroxyproline detection showed that catalpol decreased collagen deposition significantly compared to that of the model group. Catalpol inhibited CCl4-induced liver fibrosis, manifested as decreased expressions of α-SMA, fibronectin and α1(I)-procollagen at both transcriptional and translational levels. Inflammatory factors, such as IL-1β, TNF-α, IL-18, IL-6 and COX-2, were significantly elevated in rats receiving CCl4 and down-regulated by catalpol in a dose-dependent manner in vivo. Western blot and immunofluorescence assay revealed that catalpol activated the autophagy of rats with CCl4-caused liver fibrosis, as indicated by up-regulation of LC3-II and beclin1 and down-regulation of P62. The results of in vitro experiments were consistent. Interestingly, inhibition or depletion of autophagy by LY294002 or Atg5 siRNA significantly attenuated catalpol-induced anti-inflammatory effects on activated hepatic stellate cells in vitro. In conclusion, catalpol relieved liver fibrosis mainly by inhibiting inflammation, and autophagy inhibition attenuated the catalpol-induced anti-inflammatory effect on liver fibrosis.
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Bae M, Park YK, Lee JY. Food components with antifibrotic activity and implications in prevention of liver disease. J Nutr Biochem 2017; 55:1-11. [PMID: 29268106 DOI: 10.1016/j.jnutbio.2017.11.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/18/2017] [Accepted: 11/11/2017] [Indexed: 12/26/2022]
Abstract
Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.
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Affiliation(s)
- Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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Nrf2 activation is required for curcumin to induce lipocyte phenotype in hepatic stellate cells. Biomed Pharmacother 2017; 95:1-10. [PMID: 28826090 DOI: 10.1016/j.biopha.2017.08.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/20/2017] [Accepted: 08/07/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatic fibrosis is a reversible scarring response that commonly occurs with chronic liver injury. During hepatic fibrogenesis, the major effector hepatic stellate cells (HSCs) become activated, featured by disappeared intracellular lipid droplets, decreased retinoid storage, and dysregulated expression of genes associated with lipid and retinoid metabolism. Compelling evidence suggested that recovery of retinoid droplets could inhibit HSC activation, while the precise molecular basis underlying the phenotypical switch still remained unclear. In this study, curcumin increased the abundance of lipid droplets and content of triglyceride in activated HSCs. In addition, curcumin could concentration-dependently regulate genes associated with lipid and retinoid metabolism. Further, consistent results were obtained from in vivo experiments. Curcumin increased Nrf2 expression and nuclear translocation, and its binding activity to DNA, which might be associated with suppression of Kelch-like ECH-associated protein 1 in HSCs. Of interest was that Nrf2 overexpression plasmids, in contract to Nrf2 siRNA, strengthened the effect of curcumin on induction of lipocyte phenotype. In in vivo system, Nrf2 knockdown mediated by Nrf2 shRNA lentivirus not only accelerated the lipid degradation in HSCs but also promoted the progression of CCl4-induced hepatic fibrosis in mice. Noteworthily, Nrf2 knockdown abolished the protective effect of curcumin. In conclusion, curcumin could induce lipocyte phenotype of activated HSCs via activating Nrf2. Nrf2 could be a target molecule for antifibrotic strategy.
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