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1
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Wang M, Wang X, Wang Y, Gai Y, Ye J, Xu X, You X. Advances in the study of the mechanism of action of miR‑22 in liver lesions (Review). Oncol Lett 2024; 28:541. [PMID: 39310022 PMCID: PMC11413475 DOI: 10.3892/ol.2024.14674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/15/2024] [Indexed: 09/25/2024] Open
Abstract
Globally, nearly 2 million deaths annually are attributed to the development of liver diseases, with liver cancer and cirrhosis being particularly prominent, which makes liver disease a significant global health concern. Cirrhosis is closely linked to the evolution of hepatitis, hepatic fibrosis and fatty liver. However, most liver diseases have an insidious onset, are challenging to treat and the prognosis and efficacy of current therapies are unsatisfactory, which can result in irreversible functional damage to the liver. Therefore, there is an urgent need to explore the molecular mechanisms underlying liver disease and identify new biomarkers and therapeutic targets. In previous years, microRNAs (miRs), a class of short non-coding RNAs comprising 17-25 nucleotides, have attracted attention for their roles in various types of liver diseases. Among them, miR-22 serves a unique role in mediating multiple pathway mechanisms and epigenetic modifications and can act both as an inhibitor of liver cancer and a metabolic blocker. Given its close association with the liver, several studies have reported that the differential expression of miR-22 regulates the metabolic process of liver cancer and is involved in the evolution of hepatic fibrosis and steatohepatitis, making it a potential target for early diagnosis and treatment. The present manuscript aimed to comprehensively review the key role of miR-22 in the evolution of liver diseases and offer valuable references and guidance for subsequent studies by identifying its specific mechanism of action and future development prospects.
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Affiliation(s)
- Minghe Wang
- College of Second Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Xuejing Wang
- College of Second Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yanqi Wang
- College of Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yikuo Gai
- College of Second Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Jingran Ye
- College of Second Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Xinyan Xu
- College of Second Clinical Medical, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Xue You
- Lin He's Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining, Shandong 272067, P.R. China
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Wang Y, Liu K. Therapeutic potential of oleanolic acid in liver diseases. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4537-4554. [PMID: 38294504 DOI: 10.1007/s00210-024-02959-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 01/15/2024] [Indexed: 02/01/2024]
Abstract
Liver-associated diseases affect millions of individuals worldwide. In developed countries, the incidence of viral hepatitis is reducing due to advancements in disease prevention, diagnosis, and treatment. However, with improvements in living standards, the prevalence of metabolic liver diseases, such as non-alcoholic fatty liver disease and alcohol-related liver disease, is expected to increase; notably, this rise in the prevalence of metabolic liver disease can lead to the development of more severe liver diseases, including liver failure, cirrhosis, and liver cancer. The growing demand for natural alternative therapies for chronic diseases has highlighted the importance of studying the pharmacology of bioactive compounds in plants. One such compound is oleanolic acid (OA), a pentacyclic triterpenoid known for its antioxidant, anti-inflammatory, anti-ulcer, antibacterial, antiviral, antihypertensive, anti-obesity, anticancer, anti-diabetic, cardioprotective, hepatoprotective, and anti-neurodegenerative properties. Recent studies have demonstrated that OA treatment can reduce the risk of pathological liver damage, ultimately alleviating liver dysregulation and restoring overall liver function. This review aims to explore the latest research on the biological effects of OA and its derivatives. Notably, it explores the mechanisms of action of these compounds in both in vitro and in vivo research models and, ultimately, highlights OA as a promising candidate for alternative therapies in the treatment and management of chronic liver disease.
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Affiliation(s)
- Yongxin Wang
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China.
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Pu TY, Chuang KC, Tung MC, Yen CC, Chen YH, Cidem A, Ko CH, Chen W, Chen CM. Lactoferrin as a therapeutic agent for attenuating hepatic stellate cell activation in thioacetamide-induced liver fibrosis. Biomed Pharmacother 2024; 174:116490. [PMID: 38554526 DOI: 10.1016/j.biopha.2024.116490] [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: 01/18/2024] [Revised: 03/16/2024] [Accepted: 03/19/2024] [Indexed: 04/01/2024] Open
Abstract
Liver fibrosis is a chronic liver disease caused by prolonged liver injuries. Excessive accumulation of extracellular matrix replaces the damaged hepatocytes, leading to fibrous scar formation and fibrosis induction. Lactoferrin (LF) is a glycoprotein with a conserved, monomeric signal polypeptide chain, exhibiting diverse physiological functions, including antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, and antitumoral activities. Previous study has shown LF's protective role against chemically-induced liver fibrosis in rats. However, the mechanisms of LF in liver fibrosis are still unclear. In this study, we investigated LF's mechanisms in thioacetamide (TAA)-induced liver fibrosis in rats and TGF-β1-treated HSC-T6 cells. Using ultrasonic imaging, H&E, Masson's, and Sirius Red staining, we demonstrated LF's ability to improve liver tissue damage and fibrosis induced by TAA. LF reduced the levels of ALT, AST, and hydroxyproline in TAA-treated liver tissues, while increasing catalase levels. Additionally, LF treatment decreased mRNA expression of inflammatory factors such as Il-1β and Icam-1, as well as fibrogenic factors including α-Sma, Collagen I, and Ctgf in TAA-treated liver tissues. Furthermore, LF reduced TAA-induced ROS production and cell death in FL83B cells, and decreased α-SMA, Collagen I, and p-Smad2/3 productions in TGF-β1-treated HSC-T6 cells. Our study highlights LF's ability to ameliorate TAA-induced hepatocyte damage, oxidative stress, and liver fibrosis in rats, potentially through its inhibitory effect on HSC activation. These findings suggest LF's potential as a therapeutic agent for protecting against liver injuries and fibrosis.
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Affiliation(s)
- Tzu-Yu Pu
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Kai-Cheng Chuang
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Min-Che Tung
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung 435, Taiwan
| | - Chih-Ching Yen
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, China Medical University Hospital, and College of Health Care, China Medical University, Taichung 404, Taiwan
| | - Yu-Hsuan Chen
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Abdulkadir Cidem
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25250, Turkey
| | - Chu-Hsun Ko
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Wei Chen
- Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Chuan-Mu Chen
- Department of Life Sciences, and Doctorial Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; The iEGG and Animal Biotechnology Center, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan.
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Wei L, Li X, Yao Y, Wang S, Ai X, Liu S. Study on the molecular mechanism of dihydromyricetin in alleviating liver cirrhosis based on network pharmacology. Chem Biol Drug Des 2024; 103:e14421. [PMID: 38230771 DOI: 10.1111/cbdd.14421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 08/31/2023] [Accepted: 12/03/2023] [Indexed: 01/18/2024]
Abstract
Dihydromyricetin (DHM) is a bioactive flavonoid extracted from Hovenia dulcis, which has various activities. In the present study, the molecular mechanism of dihydromyricetin (DHM) in relieving liver cirrhosis was investigated through network pharmacology and experimental verification. The cell model was induced by TGF-β1 activating the human hepatic stellate cell line (HSC; LX-2). The protein levels of α-SMA, collagen I, and collagen III and pathway-related proteins within LX-2 cells were detected using Western blot. EdU staining was conducted to detect cell proliferation. Immunofluorescence staining was performed to detect the expression levels of α-SMA and collagen I. Next, the drug targets of DHM were screened from the PubChem database. The differentially expressed genes in the liver cirrhosis dataset GSE14323 were identified. The expression of the identified drug targets in LX-2 cells was verified using qRT-PCR. The results showed that TGF-β1 treatment notably increased LX-2 cell viability, promoted cell proliferation, and elevated α-SMA, collagen I, and collagen III protein contents. DHM treatment could partially eliminate TGF-β1 effects, as evidenced by the inhibited cell viability and proliferation and reduced α-SMA, collagen I, and collagen III contents. After network pharmacology analysis, nine differentially expressed target genes (MMP2, PDGFRB, PARP1, BCL2L2, ABCB1, TYR, CYP2E1, SQSTM1, and IL6) in liver cirrhosis were identified. According to qRT-PCR verification, DHM could inhibit the expression of MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, and IL6, and enhance ABCB1 expression levels within LX-2 cells. Moreover, DHM inhibited mTOR and MAPK signaling pathways in TGF-β1-induced HSCs. In conclusion, DHM could inhibit HSC activation, which may be achieved via acting on MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, IL6, and ABCB1 genes and their downstream signaling pathways, including mTOR and MAPK signaling pathway.
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Affiliation(s)
- Lin Wei
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Xiaoying Li
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
| | - Yuanzhi Yao
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
| | - Siqi Wang
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Xinghui Ai
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Shenggui Liu
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
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Lim JS, Lee SH, Yun H, Lee DY, Cho N, Yoo G, Choi JU, Lee KY, Bach TT, Park SJ, Cho YC. Inhibitory Effects of Ehretia tinifolia Extract on the Excessive Oxidative and Inflammatory Responses in Lipopolysaccharide-Stimulated Mouse Kupffer Cells. Antioxidants (Basel) 2023; 12:1792. [PMID: 37891872 PMCID: PMC10604099 DOI: 10.3390/antiox12101792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
Ehretia tinifolia (E. tinifolia) L., an evergreen tree with substantial biological activity, including antioxidant and anti-inflammatory effects, has been used in many herbal and traditional medicines. To elucidate its antioxidant and anti-inflammatory activity and the underlying mechanisms, we applied a methanol extract of E. tinifolia (ETME) to lipopolysaccharide (LPS)-stimulated mouse immortalized Kupffer cells. ETME suppressed the LPS-induced increase in nitric oxide, a mediator for oxidative stress and inflammation, and restored LPS-mediated depletion of total glutathione level by stabilizing antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) and the subsequent increase in heme oxygenase-1 levels. Furthermore, ETME inhibited the LPS-induced production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. The inhibitory effects of ETME on pro-inflammatory responses were regulated by ETME-mediated dephosphorylation of mitogen-activated protein kinases (MAPKs: p38, p44/p42, and stress-associated protein kinase/c-Jun N-terminal kinase) and inhibition of nuclear localization of nuclear factor kappa B (NF-κB). These results suggest that ETME is a possible candidate for protecting Kupffer cells from LPS-mediated oxidative stress and excessive inflammatory responses by activating antioxidant Nrf2/HO-1 and inhibiting pro-inflammatory NF-κB and MAPKs, respectively.
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Affiliation(s)
- Jae Sung Lim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Sung Ho Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Hyosuk Yun
- Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea;
| | - Da Young Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Namki Cho
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Guijae Yoo
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun 55365, Republic of Korea;
| | - Jeong Uk Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Kwang Youl Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
| | - Tran The Bach
- Institute of Ecology and Biological Resources, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Ha Noi 122000, Vietnam;
| | - Su-Jin Park
- Functional Biomaterial Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Republic of Korea
| | - Young-Chang Cho
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, 77 Yongbong-ro, Gwangju 61186, Republic of Korea; (J.S.L.); (S.H.L.); (D.Y.L.); (N.C.); (J.U.C.); (K.Y.L.)
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Lyu SY, Xiao W, Cui GZ, Yu C, Liu H, Lyu M, Kuang QY, Xiao EH, Luo YH. Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis. Front Genet 2023; 14:1124330. [PMID: 37056286 PMCID: PMC10086238 DOI: 10.3389/fgene.2023.1124330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Liver fibrosis is a repair response to injury caused by various chronic stimuli that continually act on the liver. Among them, the activation of hepatic stellate cells (HSCs) and their transformation into a myofibroblast phenotype is a key event leading to liver fibrosis, however the mechanism has not yet been elucidated. The molecular basis of HSC activation involves changes in the regulation of gene expression without changes in the genome sequence, namely, via epigenetic regulation. DNA methylation is a key focus of epigenetic research, as it affects the expression of fibrosis-related, metabolism-related, and tumor suppressor genes. Increasing studies have shown that DNA methylation is closely related to several physiological and pathological processes including HSC activation and liver fibrosis. This review aimed to discuss the mechanism of DNA methylation in the pathogenesis of liver fibrosis, explore DNA methylation inhibitors as potential therapies for liver fibrosis, and provide new insights on the prevention and clinical treatment of liver fibrosis.
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Affiliation(s)
- Shi-Yi Lyu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Wang Xiao
- Department of Gastrointestinal Surgery, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Guang-Zu Cui
- XiangYa School of Medicine, Central South University, Changsha, Hunan, China
| | - Cheng Yu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Huan Liu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Min Lyu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Qian-Ya Kuang
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - En-Hua Xiao
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Yong-Heng Luo
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
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Wang F, Zhan Y, Li M, Wang L, Zheng A, Liu C, Wang H, Wang T. Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway. ACS Pharmacol Transl Sci 2022; 6:76-87. [PMID: 36654751 PMCID: PMC9841780 DOI: 10.1021/acsptsci.2c00165] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Indexed: 12/12/2022]
Abstract
Accumulating evidence indicates that oxidative stress and inflammation are involved in the physiopathology of liver fibrogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor, which regulates the expression of redox regulators to establish cellular redox homeostasis. The Nrf2 modulator can serve as a primary cellular defense against the cytotoxic effects of oxidative stress. We designed a chimeric Keap1-Keap1 peptide (KKP1) based on the proteolysis-targeting chimera technology. The KKP1 peptide not only can efficiently penetrate into the rat hepatic stellate cell line (HSC-T6) cells but also can induce Keap1 protein degradation by the ubiquitination-proteasome degradation pathway, which releases Nrf2 and promotes the transcriptional activity of the Nrf2/antioxidant response element pathway. It then activates the protein expression of the downstream antioxidant factors, the glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 (HO-1). Finally, Keap1 protein degradation inhibits the nuclear factor-kappaB inflammatory signal pathway, the downstream inflammatory factor tumor necrosis factor alpha, and the interleukin-1beta protein expression and further inhibits the expression of the fibrosis biomarker gene. The current research suggests that our designed KKP1 may provide a new avenue for the future treatment of liver fibrosis.
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Affiliation(s)
- Fengqin Wang
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
| | - Ying Zhan
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
| | - Manman Li
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
| | - Lidan Wang
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China,Department
of Microbiology and Immunology, Medical School, China Three Gorges University, Yichang 443002, China
| | - Austin Zheng
- Institute
of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21215, United States
| | - Changbai Liu
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
| | - Hu Wang
- Hubei
Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China,Institute
of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21215, United States,
| | - Tao Wang
- The
First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei 443003, China,
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Garbuzenko DV. Current strategies for targeted therapy of liver fibrosis. BULLETIN OF SIBERIAN MEDICINE 2022. [DOI: 10.20538/1682-0363-2022-3-154-165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver fibrosis (LF) is an unfavorable event in the natural course of chronic liver diseases (CLD), therefore, early implementation and widespread use of antifibrotic therapy methods is a pressing issue in hepatology. The aim of the review was to describe current approaches to targeted therapy of LF.PubMed database, Google Scholar search engine, Cochrane Database of Systematic Reviews, eLIBRARY.RU scientific electronic library, as well as reference lists of articles were used to search for scientific articles. The publications that corresponded to the aim of the study were selected for the period from 1998 to 2021 by the terms “liver fibrosis”, “pathogenesis”, and “treatment”. Inclusion criteria were restricted to targeted therapy of LF.Despite the growing evidence for reversibility of LF, there are currently no effective or clinically approved regimens for its specific therapy. However, taking into account the relevance of the issue, scientific research in this area is necessary. Multiple drugs with a good safety profile have been studied, which, though intended for other purposes, can have a positive effect on LF. In addition, a number of innovative approaches that differ from pharmacotherapy inspire optimism about finding a solution to this problem. It is obvious that studies focused on well-characterized groups of patients with confirmed histologic, elastography, clinical, and radiological parameters are required. This is a challenging task, since the key point will be stratification of risk based on ethnicity, etiology, and clinical status, and very large samples will be required for a reliable assessment. Nevertheless, the solution will increase efficiency of treatment for patients with CLD, improve their prognosis and quality of life, and significantly reduce the need for liver transplantation, a demand for which remains extremely high worldwide.
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Yue L, Xue T, Su X, Liu Z, Liu H, Tan Z, Gan C, Xie Y, Ye T. Discovery and evaluation of phenacrylanilide derivatives as novel potential anti-liver fibrosis agents. Eur J Med Chem 2022; 242:114685. [PMID: 36037790 DOI: 10.1016/j.ejmech.2022.114685] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 08/11/2022] [Accepted: 08/11/2022] [Indexed: 11/04/2022]
Abstract
Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor β1 (TGF-β1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-β1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl4) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl4 mice and ameliorates CCl4-induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis.
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Affiliation(s)
- Lin Yue
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Taixiong Xue
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xingping Su
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhihao Liu
- Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hongyao Liu
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zui Tan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Cailing Gan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yuting Xie
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Tinghong Ye
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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Huang JY, Lin YC, Chen HM, Lin JT, Kao SH. RETRACTED: Adenine Combined with Cisplatin Promotes Anticancer Activity against Hepatocellular Cancer Cells through AMPK-Mediated p53/p21 and p38 MAPK Cascades. Pharmaceuticals (Basel) 2022; 15:795. [PMID: 35890094 PMCID: PMC9322617 DOI: 10.3390/ph15070795] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/24/2022] Open
Abstract
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells. Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells, which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin.
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Affiliation(s)
- Jhen-Yu Huang
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 402306, Taiwan;
| | - You-Cian Lin
- Cardiovascular Division, Surgical Department, China Medical University Hospital, Taichung City 404332, Taiwan;
- School of Medicine, College of Medicine, China Medical University, Taichung City 404332, Taiwan
| | - Han-Min Chen
- Institute of Applied Science and Engineering, Catholic Fu Jen University, New Taipei 242048, Taiwan;
| | - Jiun-Tsai Lin
- Energenesis Biomedical Co., Ltd., Taipei 114694, Taiwan;
| | - Shao-Hsuan Kao
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 402306, Taiwan;
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402306, Taiwan
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11
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Ghanim M, Amer J, Salhab A, Jaradat N. Ecballium elaterium improved stimulatory effects of tissue-resident NK cells and ameliorated liver fibrosis in a thioacetamide mice model. Biomed Pharmacother 2022; 150:112942. [PMID: 35429743 DOI: 10.1016/j.biopha.2022.112942] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/26/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022] Open
Abstract
Ecballium elaterium (EE), widely used plant in Mediterranean medicine, showed anticancer activity. This study aimed to investigate EE effects on liver fibrosis in an animal model of thioacetamide (TAA). Intraperitoneal administration of TAA was performed twice weekly for four weeks in C57BL6J mice. Livers were extracted and serum were evaluated for inflammatory markers (H&E staining, ALT, AST, ALP), pro-inflammatory cytokines, fibrosis (Sirius red staining, Masson's trichrome, α-smooth muscle actin and collagen III), and metabolic (cholesterol, triglyceride, C-peptide, and fasting-blood-sugar) profiles. Glutathione, glutathione peroxidase, and catalase liver antioxidant markers were assessed. Tissue-resident NK cells from mice livers were functionally assessed for activating receptors and cytotoxicity. Compared to vehicle-treated mice, the TAA-induced liver injury showed attenuation in the histopathology outcome following EE treatment. In addition, EE-treated mice resulted in decreased serum levels of ALT, AST, and ALP, associated with a decrease in IL-20, TGF-β, IL-17, IL-22 and MCP-1 concentrations. Moreover, EE-treated mice exhibited improved lipid profile of cholesterol, triglycerides, C-peptide, and FBS. EE treatment maintained GSH, GPX, and CAT liver antioxidant activity and led to elevated counts of tissue-resident NK (trNK) cells in the TAA-mice. Consequently, trNK demonstrated an increase in CD107a and IFN-γ with improved potentials to kill activated hepatic-stellate cells in an in vitro assay. EE exhibited antifibrotic and antioxidative effects, increased the number of trNK cells, and improved metabolic outcomes. This plant extract could be a targeted therapy for patients with advanced liver injury.
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Affiliation(s)
- Mustafa Ghanim
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Johnny Amer
- Department of Allied and Applied Medical Sciences, Division of Anatomy Biochemistry and Genetics, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Ahmad Salhab
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Nidal Jaradat
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
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12
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Lu ZN, Shan Q, Hu SJ, Zhao Y, Zhang GN, Zhu M, Yu DK, Wang JX, He HW. Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways. Bioorg Med Chem 2021; 49:116438. [PMID: 34610571 DOI: 10.1016/j.bmc.2021.116438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/09/2021] [Accepted: 09/18/2021] [Indexed: 11/19/2022]
Abstract
Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor β1 (TGFβ1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.
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Affiliation(s)
- Zhen-Ning Lu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Qi Shan
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shang-Jiu Hu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yue Zhao
- Beijing Changping Technology Innodevelop Group, Beijing 102200, China
| | - Guo-Ning Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Mei Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Dong-Ke Yu
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Ju-Xian Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
| | - Hong-Wei He
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
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Weng T, Yan D, Shi D, Zhu M, Liu Y, Wu Z, Tang T, Zhu L, Zhang H, Yao H, Li L. The MSP-RON pathway regulates liver fibrosis through transforming growth factor beta-dependent epithelial-mesenchymal transition. Liver Int 2021; 41:1956-1968. [PMID: 33786995 DOI: 10.1111/liv.14892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/28/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver fibrosis is pathologically important in the liver cirrhosis progression. The epithelial-mesenchymal transition (EMT) is crucial for organ fibrosis. Macrophage-stimulating protein (MSP) and its receptor tyrosine kinase, RON, promote cellular EMT. However, their role in liver fibrosis is unclear. Here, we clarify the biological profile, potential mechanisms and therapeutic targets of the MSP-RON pathway in liver fibrosis. MATERIALS AND METHODS Macrophage-stimulating protein expression and its correlation with clinicopathological characteristics of cirrhosis were evaluated in 57 clinical cases and a control group. The effect of MSP-RON pathway in liver fibrosis was determined in vitro and in vivo. The therapeutic effects of MSP or RON inhibition on liver fibrosis were evaluated in a mouse liver fibrosis model. RESULTS Macrophage-stimulating protein is upregulated in liver cirrhosis, which was associated with poor patient prognosis. The MSP-RON pathway promoted hepatocytes EMT. MSP-RON-induced EMT depends on the transforming growth factor beta (TGF-β) pathway and is regulated by TGF-β inhibitors. In animal models, an MSP blocking antibody and a small molecule inhibitor of RON, BMS-777607, both inhibited liver fibrosis progression. CONCLUSION Our study revealed that MSP is an important biomarker in liver cirrhosis progression and can be used to prognose patients. The MSP-RON pathway promotes the EMT of hepatocytes and the progress of fibrosis via a TGF-β related pathway. Consequently, we identified a new treatment strategy for liver cirrhosis through targeted inhibition of MSP/RON. This research increases the understanding of EMT-modulated liver fibrosis and provides new insights into biomarkers and therapeutic targets of liver fibrosis.
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Affiliation(s)
- Tianhao Weng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Danrong Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Miaojin Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yizhi Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhigang Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Taoming Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Linwei Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hangping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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14
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You H, Wang L, Bu F, Meng H, Pan X, Li J, Zhang Y, Wang A, Yin N, Huang C, Li J. The miR-455-3p/HDAC2 axis plays a pivotal role in the progression and reversal of liver fibrosis and is regulated by epigenetics. FASEB J 2021; 35:e21700. [PMID: 34105828 DOI: 10.1096/fj.202002319rrr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/29/2021] [Accepted: 05/11/2021] [Indexed: 12/29/2022]
Abstract
Histone deacetylases (HDACs), especially HDAC2, play a role in alleviating liver fibrosis; however, the specific upstream regulation mechanism is unknown. Herein, TargetScan was used to predict the potential upstream targets of HDAC2, and the role of miR-455-3p was explored. The dual luciferase reporter assay showed that miR-455-3p binds to the 3' UTR of HDAC2 mRNA. Additionally, miR-455-3p was downregulated in the liver tissues of patients with cirrhosis and mice with liver fibrosis, as well as in primary HSCs isolated from fibrotic mouse livers and TGF-β-treated LX-2 cells. In contrast, it is highly expressed in the reversal stage of hepatic fibrosis and MDI-cultured LX-2 cells. Our functional analyses showed that miR-455-3p overexpression facilitated apoptosis and reduced the expression of pro-fibrotic markers and the proliferation of activated LX-2 cells. On the contrary, miR-455-3p inhibition converted inactivated LX-2 cells into activated, proliferative, fibrogenic cells. Interestingly, restoration of HDAC2 expression partially blocked the function of miR-455-3p. Downregulated miR-455-3p expression can be restored by DNA methyltransferases in activated LX-2 cells. Methylation-specific PCR, bisulfite sequencing PCR, and chromatin immunoprecipitation assays indicated that the methylation level of miR-455-3p promoter CpG islands was elevated in TGF-β-treated LX-2 cells and that miR-455-3p was downregulated in activated LX-2 cells by DNA hypermethylation, which is mediated by DNMT3b and DNMT1. In conclusion, miR-455-3p acts as a liver fibrosis suppressor by targeting HDAC2, and its deficiency further aggravates the reversal phase of fibrosis. Thus, the epigenetics mediated miR-455-3p/HDAC2 axis may serve as a novel potential therapeutic target for clinical treatment of hepatic fibrosis.
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Affiliation(s)
- Hongmei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ling Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Fangtian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hongwu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xueyin Pan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juanjuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yafei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Nana Yin
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
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15
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He ZB, Niu WB, Peng C, Gao C, Gao HJ, Niu J. The relationship between integrin avß6 and HBV infection in patients with liver cirrhosis and hepatocellular carcinoma: a preliminary report. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:462-466. [PMID: 32450701 DOI: 10.17235/reed.2020.6607/2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE the aim of this study was to investigate the expression of integrin αvβ6 in normal, hepatitis B, HBV-associated cirrhosis and HBV-associated HCC liver tissues. METHODS immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to study the expression of integrin αvβ6 in HBV-associated cirrhosis (n = 88), chronic hepatitis B ( n= 11), HBV-associated HCC (n = 84) and normal (n = 10) human liver tissues. RESULTS the expression of integrin αvβ6 was significantly upregulated in HBV-associated liver cirrhosis and the expression increased with an increase in severity of cirrhosis. Furthermore, it was moderately or weakly expressed in chronic hepatitis B and HBV-associated HCC liver tissues when compared to normal liver tissue. CONCLUSION integrin αvβ6 could be a predictive marker for the progression of liver cirrhosis associated with HBV infection. Further studies are needed to determine the association between the expression of integrin αvβ6 in hepatitis B and HBV-associated HCC liver tissues.
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Affiliation(s)
- Zhao-Bin He
- Hepatobiliary Medicine, Qilu Hospital. Shandong University
| | - Wei-Bo Niu
- Hepatobiliary Medicine, Qilu Hospital. Shandong University
| | - Cheng Peng
- Hepatobiliary Medicine, Qilu Hospital. Shandong University
| | - Chao Gao
- Hepatobiliary Medicine, Qilu Hospital. Shandong University
| | - Hui-Jie Gao
- Hepatobiliary Medicine, Qilu Hospital. Shandong University
| | - Jun Niu
- Hepatobiliary Medicine, Qilu Hospital. Shandong University, China
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Association of α-fetoprotein levels with liver stiffness measurement in outpatients with chronic hepatitis B. Biosci Rep 2021; 41:227182. [PMID: 33289529 PMCID: PMC7789808 DOI: 10.1042/bsr20203048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/25/2020] [Accepted: 12/07/2020] [Indexed: 02/05/2023] Open
Abstract
The association between α-fetoprotein (AFP) levels with the assessment of liver stiffness (LS) in chronic hepatitis B (CHB) patients were explored. A total of 283 outpatients with CHB were enrolled. Patient age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AFP, platelet (PLT), total bilirubin (TB), direct bilirubin (DB), alkaline phosphatase (ALP), albumin (ALB), globulin, and albumin/globulin (A/G) levels were associated with LS values in the univariate model (P<0.05). Significant associations between AFP and PLT levels with LS values were observed when both variables were included in the multivariate analysis models. Receiver operation characteristic (ROC) analysis indicated that the combination of AFP and PLT levels could enhance the predictive performance of liver fibrosis (area under the curve (AUC) = 0.819, P<0.001) and that PLT levels (PLT < 100 × 109/l) combined with high AFP levels (AFP > 8 ng/ml) significantly increased the prediction of liver fibrosis (OR = 11.216). More importantly, LS values associated with higher AFP levels (AFP > 8 ng/ml), independently of higher ALT or AST values, were significantly higher than those of low AFP level groups. In conclusion, in Chinese outpatients with CHB, AFP outperformed ALT and/or AST levels in terms of their association with LS. AFP and PLT levels were independently associated with LS, and their combined assessment could enhance the diagnostic and predictive performance of liver fibrosis among CHB patients.
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17
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Wang Q, Zhang F, Lei Y, Liu P, Liu C, Tao Y. microRNA-322/424 promotes liver fibrosis by regulating angiogenesis through targeting CUL2/HIF-1α pathway. Life Sci 2020; 266:118819. [PMID: 33333053 DOI: 10.1016/j.lfs.2020.118819] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 12/14/2022]
Abstract
AIMS To investigate the effects and mechanism of miR-322/424 in liver fibrosis. MAIN METHODS miR-322/424 expression in liver cirrhosis patients, mouse and rat liver fibrosis was determined by qPCR. Mice liver fibrosis was established by CCl4, and intervened by miR-322/424 agomir or antagomir. Liver hydroxyproline content and Sirius red staining were used to evaluate collagen deposition. CD31 expression was used to evaluate liver microvessel density. In vitro, the effects of miR-322/424 mimic or inhibitor on human hepatic sinusoidal endothelial cells (HHSECs) migration and tube formation were investigated. A dual luciferase reporter assay was performed to confirm the direct interaction between miR-322/424 and Cullin2. mRNA expression of elongin B/C, Cullin2, and RBX1 was determined by qPCR. HIF-1α protein expression was determined by Western blotting. KEY FINDINGS miR-322/424 level in liver cirrhosis patients, mouse liver fibrosis induced by CCl4 and BDL, and rat liver fibrosis induced by CCl4 and dimethylnitrosamine was increased. miR-322/424 agomir exacerbated CCl4-induced mouse liver fibrosis, whereas the opposite effect was observed for miR-322/424 antagomir. miR-322/424 agomir significantly upregulated liver CD31 expression; opposite effects occurred with miR-322/424 antagomir. In vitro, miR-322/424 mimic significantly promoted tube formation and cell migration, and increased von Willebrand factor expression, whereas miR-322/424 inhibitor had the opposite effect. Dual-Luciferase Reporter Assay identified Cullin2 as miR-322/424 target. miR-322/424 decreased the mRNA expression of elongin B/C, Cullin2, and RBX1 and increased HIF-1α protein expression in HHSECs. SIGNIFICANCE miR-322/424 plays a central role in the pathogenesis of liver fibrosis by targeting Cullin2, and enhancing HIF-1α-mediated hepatic angiogenesis.
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Affiliation(s)
- Qinglan Wang
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; College of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feng Zhang
- College of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yang Lei
- College of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China; Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai, China.
| | - Yanyan Tao
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.
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Khan S, Rahman MM, Kabir F, Nahar K, Mamun F, Lasker S, Subhan N, Hossain MH, Nahar L, Sarker SD, Alam MA, Haque MA. Trichosanthes dioica Roxb. prevents hepatic inflammation and fibrosis in CCl4-induced ovariectomized rats. CLINICAL NUTRITION EXPERIMENTAL 2020. [DOI: 10.1016/j.yclnex.2020.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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19
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N-Acetylcysteine Reduced Ischemia and Reperfusion Damage Associated with Steatohepatitis in Mice. Int J Mol Sci 2020; 21:ijms21114106. [PMID: 32526845 PMCID: PMC7313069 DOI: 10.3390/ijms21114106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 01/22/2023] Open
Abstract
N-acetylcysteine (NAC) is a pharmacological alternative with great potential for reducing the deleterious effects of surgical procedures on patients with steatohepatitis. We evaluated the effect of NAC on hepatic ischemia/reperfusion (I/R) injury in C57BL/6J mice, 8 weeks-old, weighing 25-30 g, with steatohepatitis induced by a methionine- and choline-deficient (MCD) diet. Groups: MCD group (steatohepatitis), MCD-I/R group (steatohepatitis plus 30 min of 70% liver ischemia and 24 h of reperfusion), MCD-I/R+NAC group (same as MCD-I/R group plus 150 mg/kg NAC 15 min before ischemia), and control group (normal AIN-93M diet). Liver enzymes and histopathology; nitrite and TBARS (thiobarbituric acid reactive substances) levels; pro-inflammatory cytokines; antioxidants enzymes; Nrf2 (nuclear factor erythroid-2-related factor 2) expression; and apoptosis were evaluated. In the group treated with NAC, reductions in inflammatory infiltration; AST (aspartate aminotransferase), nitrite, and TBARS levels; GPx (gutathione peroxidase) activity; cytokines synthesis; and number of apoptotic cells were observed while the GR (glutathione reductase) activity was increased. No differences were observed in Nfr2 expression or in SOD (superoxide dismutase), CAT (catalase), and GST (glutathione S-transferase) activities. Thus, it may be concluded that NAC exerts beneficial effects on mice livers with steatohepatitis submitted to I/R by reducing oxidative stress, inflammatory response, and cell death.
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20
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Hussein KH, Park KM, Yu L, Kwak HH, Woo HM. Decellularized hepatic extracellular matrix hydrogel attenuates hepatic stellate cell activation and liver fibrosis. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 116:111160. [PMID: 32806289 DOI: 10.1016/j.msec.2020.111160] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/31/2020] [Accepted: 06/03/2020] [Indexed: 12/21/2022]
Abstract
Liver fibrosis results from excessive accumulation of extracellular matrix (ECM) proteins that distort the hepatic architecture. Progression of liver fibrosis results in cirrhosis and liver failure, and often, liver transplantation is required. The decellularized liver tissue contains different components that mimic the natural hepatic environment. We hypothesized that a decellularized liver hydrogel can be used to replace the necrotic hepatocytes and damaged ECM. Therefore, our aim in this study is to develop a therapy for treating liver fibrosis. Mice livers were decellularized and processed to form a hepatic hydrogel. We evaluated the biocompatibility and bioactivity of the hydrogel. The ability of the hydrogel to enhance the migration of hepatocytes and endothelial cells was investigated. Human hepatic stellate cell line (LX-2) activated by transforming growth factor-β1 (TGF-β1) was used as in vitro model for fibrogenesis. Then, the hydrogel was injected into the liver parenchyma of mice after the induction of liver fibrosis using thioacetamide. The resulting hydrogel maintained a complex composition, which included glycosaminoglycans, collagen, elastin, and growth factors. Hepatocytes and endothelial cells were shown to migrate toward the hydrogel in vitro. Liver hydrogel improved TGF-β1-induced LX-2 cells activation via blocking the TGF-β1/Smad pathway. The matrix was delivered successfully in vivo and enhanced the reduction of fibrosis and recovery to a nearly normal structure. In conclusion, we have demonstrated that the liver hydrogel can be utilized as an injectable biomaterial for liver tissue engineering in order to reduce the degree of fibrosis.
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Affiliation(s)
- Kamal H Hussein
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Department of Animal Surgery, College of Veterinary Medicine, Assiut University, Assiut 71515, Egypt
| | - Kyung-Mee Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Lina Yu
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Ho-Hyun Kwak
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
| | - Heung-Myong Woo
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
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Hasby Saad MA, El-Anwar N. Bevacizumab as a potential anti-angiogenic therapy in schistosomiasis: A double-edged, but adjustable weapon. Parasite Immunol 2020; 42:e12724. [PMID: 32338371 DOI: 10.1111/pim.12724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 11/30/2022]
Abstract
AIM Investigating the anti-angiogenic effect of bevacizumab on chronic schistosomiasis mansoni in a trial to hinder the Schistosome-induced angiogenesis and porto-systemic shunting complications. METHODS The immunohistochemical expression of CD34, VEGF-R1, PCNA and α-SMA (angiogenesis markers) was analysed in the lung, liver and gastrointestinal junctions of chronic S mansoni infected mice after intraperitoneal injection of bevacizumab. The effect of prolonged administration of bevacizumab with praziquantel was also assessed through parasitic load, protective index, granuloma and fibrous tissue evaluation. RESULTS A regression in the vascular activity and microvascular density was observed in the infected mice after receiving bevacizumab. They had a significantly less VEGF-R1, PCNA, CD-34 and α-SMA expression in comparison to the infected untreated mice. The least tissue egg count was reported in mice received bevacizumab for 6 weeks (Mean = 27 120). However, they had persistent liver granulomas, and massively amalgamated fibrosis. Interestingly, the least faecal egg and tissue worms counts (Mean = 112, 13.4), and the highest protection index (39.26) were reported in mice received bevacizumab for 3 weeks, with marked granuloma, and fibrous tissue resolution. CONCLUSIONS Bevacizumab has a promising protective effect against the Schistosoma-induced angiogenesis. As an adjuvant to praziquantel, it is important to adjust the appropriate duration of administration that achieves the best schistosomicidal effect without impeding granuloma and fibrous tissue resolution.
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Affiliation(s)
- Marwa A Hasby Saad
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Gharbia Governorate, Egypt
| | - Noha El-Anwar
- Department of Pathology, Tanta University, Faculty of Medicine, Tanta, Egypt
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22
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Hao M, Sun J, Zhang Y, Zhang D, Han J, Zhang J, Qiao H. Exploring the Role of SRC in Extraocular Muscle Fibrosis of the Graves' Ophthalmopathy. Front Bioeng Biotechnol 2020; 8:392. [PMID: 32457885 PMCID: PMC7225279 DOI: 10.3389/fbioe.2020.00392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/07/2020] [Indexed: 11/13/2022] Open
Abstract
The Graves’ disease is an autoimmune disease highly associated with thyroid cancer. The Graves’ ophthalmopathy (GO) is a special Graves’ disease with inflammatory ophthalmopathy being a typical extrathymic complication. GO is caused by the formation of orbital fat and extraocular muscle fibrosis due to the inflammation of orbital connective tissues. Thus, controlling extraocular muscle fibrosis is critical for the prognosis of GO. The objective of this study is to identify and experimentally validate key genes associated with GO and explore their potential function mechanisms especially on extraocular muscle fibrosis. Specifically, we first created a GO mouse model, and performed RNA sequencing on the extraocular muscles of fibrotic GO mice and controls. SRC was identified as the most significant unstudied differentially expressed gene between GO mice and controls. Thus, we conducted a few in vitro analyses to explore the roles and functions of SRC in GO, for which we selected primary cultured orbital fibroblast (OF) as the in vitro cell line model. It is known that myofibroblast (MFB), which expresses α-SMA, is an important target cell in the process of fibrosis. Our experiment suggests that TGF-β can induce the transformation from OF to MFB, however, the transformation was inhibited by silencing the SRC gene in OF. In addition, we also inhibited TGF-β/Smad, NF-κB, and PI3K/Akt signaling pathways to analyze the interaction between these pathways and SRC. In conclusion, the silence of SRC in OF can inhibit the transformation from OF to MFB, which might be associated with the interaction between SRC and a few pathways such as TGF-β/Smad, NF-κB, and PI3K/Akt.
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Affiliation(s)
- Mingyu Hao
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingxue Sun
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yaguang Zhang
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dexin Zhang
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Han
- The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jirong Zhang
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong Qiao
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Shi MJ, Yan XL, Dong BS, Yang WN, Su SB, Zhang H. A network pharmacology approach to investigating the mechanism of Tanshinone IIA for the treatment of liver fibrosis. JOURNAL OF ETHNOPHARMACOLOGY 2020; 253:112689. [PMID: 32101775 DOI: 10.1016/j.jep.2020.112689] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/30/2020] [Accepted: 02/19/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL REVELVANCE Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine salvia miltiorrhiza (Danshen), which activates blood circulation and treats chronic hepatitis and liver fibrosis. However, the underlying molecular mechanism of TIIA against hepatic fibrosis is still largely unknown. AIM OF THE STUDY The present study aimed to evaluate the antifibrotic effects of TIIA in liver fibrosis and investigate its underlying mechanism through network pharmacology-based prediction and experimental verification. MATERIALS AND METHODS In this study, a "TIIA-targets-liver fibrosis" network was constructed by combining the TIIA-specific and hepatic fibrosis-specific targets with protein-protein interactions (PPIS), and network pharmacology was applied to identify the potential targets and mechanisms of TIIA in the treatment of hepatic fibrosis. The antifibrotic effect of TIIA was investigated in CCl4-induced liver fibrosis in rats in vivo and in the human HSC line LX2 in vitro. RESULTS We identified 75 potential targets of TIIA and 1382 targets of liver fibrosis. Subsequently, the 29 target proteins that overlapped between the potential TIIA targets and the liver fibrosis targets indicated that TIIA has potential antifibrotic effects through regulating multiple targets, including c-Jun, c-Myc, CCND1, MMP9 and P65. Pathway and functional enrichment analysis of these putative targets showed that TIIA could regulate the MAPK, PI3K/Akt and Wnt signaling pathways. Consistently, in vivo and in vitro experiments indicated that TIIA attenuated CCl4-induced liver injury and fibrosis and inhibited hepatic stellate cell (HSC) proliferation and activation; these findings were concomitant with the decreased expression of α-smooth muscle actin (α-SMA) and human α2 (I) collagen (COL1A2). Moreover, TIIA remarkably downregulated the expression of c-Jun, c-Myc, MMP9, PI3K and P38 proteins, which were upregulated in CCl4-induced hepatic fibrosis in vivo. TIIA significantly downregulated the expression of c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38 proteins, which were upregulated during HSC activation in vitro. CONCLUSION Our study demonstrated that TIIA could significantly improve liver function, decrease liver injury, alleviate ECM accumulation, and attenuate HSC proliferation and activation, thus exerting an antifibrotic effect. The possible molecular mechanism involved MAPK, Wnt and PI3K/Akt signaling pathways via inhibiting c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38. Overall, our results suggest that TIIA could alleviate liver fibrosis through multiple targets and multiple signaling pathways and provide deep insight into the pharmacological mechanisms of TIIA in the treatment of hepatic fibrosis.
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Affiliation(s)
- Miao-Juan Shi
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiu-Li Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ben-Sheng Dong
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wen-Na Yang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Zhu K, Huang W, Wang W, Liao L, Li S, Yang S, Xu J, Li L, Meng M, Xie Y, He S, Tang W, Zhou H, Liang L, Gao H, Zhao Y, Hou Z, Tan J, Li R. Up-regulation of S100A4 expression by HBx protein promotes proliferation of hepatocellular carcinoma cells and its correlation with clinical survival. Gene 2020; 749:144679. [PMID: 32330536 DOI: 10.1016/j.gene.2020.144679] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/02/2020] [Accepted: 04/14/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most common cancers worldwide. HBV-related HCC has characteristics of faster progression and worse prognosis. Previous studies have confirmed that HBx protein plays numbers of important roles in development of HBV-HCC. However, the molecular mechanism of carcinogenicity of HBx is still not well documented. METHODS Firstly, a HCC cell line over-expressing HBx was established and its function was verified. Subsequently, the differentially expressed genes were detected by transcriptome sequencing technology and use the Western Blot technology to detect the up-regulated genes in HBx overexpressed cells, and the functional correlation of the genes was analyzed. Finally, tissue microarray was used to correlate up-regulated gene with clinical follow-up data to verify correlation with clinical prognosis. RESULTS Over-expression of HBx could promote cell proliferation, and over-expression of HBx could up-regulate the expression of S100A4 protein. ShRNA experiments showed that HBx promoted cell proliferation by upregulating the expression of S100A4. IFN-α2b can down-regulate the expression of S100A4 and inhibit the proliferation of HCC cells. The expression of S100A4 in cancer was significantly up-regulated compared with adjacent tissues, and was also significantly associated with tumors volume, the expression of PD-L1 and the survival time of patients with HCC. CONCLUSION In general, S100A4 may be an effective therapeutic target for HBV-HCC. And the connection between S100A4 and HBV are not clear yet. This study may play a guiding role in the future clinical treatment of HCC.
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Affiliation(s)
- Kai Zhu
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Wenwen Huang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Wenju Wang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Liwei Liao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Shuo Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Songlin Yang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Jingyi Xu
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Lin Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Mingyao Meng
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Yanhua Xie
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Shan He
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Weiwei Tang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Haodong Zhou
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Luxin Liang
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Hui Gao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Yiyi Zhao
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Zongliu Hou
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China
| | - Jing Tan
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China.
| | - Ruhong Li
- Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China; The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, China.
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Shi Z, Ren M, Rockey DC. Myocardin and myocardin-related transcription factor-A synergistically mediate actin cytoskeletal-dependent inhibition of liver fibrogenesis. Am J Physiol Gastrointest Liver Physiol 2020; 318:G504-G517. [PMID: 31928221 PMCID: PMC7099496 DOI: 10.1152/ajpgi.00302.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis.NEW & NOTEWORTHY Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.
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Affiliation(s)
- Zengdun Shi
- Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Mudan Ren
- Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Don C. Rockey
- Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina
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Chen L, Yao X, Yao H, Ji Q, Ding G, Liu X. Exosomal miR-103-3p from LPS-activated THP-1 macrophage contributes to the activation of hepatic stellate cells. FASEB J 2020; 34:5178-5192. [PMID: 32061112 DOI: 10.1096/fj.201902307rrr] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 12/16/2022]
Abstract
Hepatic fibrosis occurs during chronic hepatic injury and is involved in hepatic stellate cells (HSCs) activated by several types of immune cells. Among the immune cells, hepatic macrophages and their crosstalk with HSCs play a vital role in all stages of hepatic fibrosis. Exosomes, which are 30-150 nm lipid bilayer vehicles, can transfer specific lipid, nucleic acids, proteins, and other bioactive molecules. Exosomes can act as good communication between macrophages and HSCs. Herein, we investigated the role of exosomes between THP-1 macrophage and HSCs in the progression of liver fibrosis. Exosomes originating from lipopolysaccharide (LPS)-treated THP-1 macrophages promoted HSCs proliferation and induced the increased expression of fibrotic genes. LPS could alter the miRNA profile in exosomes secreted from THP-1 macrophages. The changed miR-103-3p in exosomes could promote HSCs proliferation and activation by targeting Krüppel-like factor 4 (KLF4) and it plays important roles in the crosstalk between THP-1 macrophages and HSCs during the progression of liver fibrosis. Moreover, miR-103-3p in serum exosomes from liver fibrosis patients could be a biomarker for liver fibrosis. Therefore, exosomes may have important roles in the crosstalk between macrophage and HSCs in the progression of chronic liver diseases.
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Affiliation(s)
- Lisha Chen
- Central Laboratory of Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xingwang Yao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hongbing Yao
- The Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Qin Ji
- Department of Hepatobiliary and Pancreatic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guo Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiangfeng Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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Li X, Chen R, Kemper S, Brigstock DR. Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation. Cells 2020; 9:cells9020290. [PMID: 31991791 PMCID: PMC7072607 DOI: 10.3390/cells9020290] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/20/2020] [Accepted: 01/23/2020] [Indexed: 12/12/2022] Open
Abstract
During chronic liver injury, hepatic stellate cells (HSC) undergo activation and are the principal cellular source of collagenous scar. In this study, we found that activation of mouse HSC (mHSC) was associated with a 4.5-fold increase in extracellular vesicle (EV) production and that fibrogenic gene expression (CCN2, Col1a1) was suppressed in Passage 1 (P1; activated) mHSC exposed to EVs from Day 4 (D4; relatively quiescent) mHSC but not to EVs from P1 mHSC. Conversely, gene expression (CCN2, Col1a1, αSMA) in D4 mHSC was stimulated by EVs from P1 mHSC but not by EVs from D4 mHSC. EVs from Day 4 mHSC contained only 46 proteins in which histones and keratins predominated, while EVs from P1 mHSC contained 337 proteins and these were principally associated with extracellular spaces or matrix, proteasome, collagens, vesicular transport, metabolic enzymes, ribosomes and chaperones. EVs from the activated LX-2 human HSC (hHSC) line also promoted fibrogenic gene expression in D4 mHSC in vitro and contained 524 proteins, many of which shared identity or had functional overlap with those in P1 mHSC EVs. The activation-associated changes in production, function and protein content of EVs from HSC likely contribute to the regulation of HSC function in vivo and to the fine-tuning of fibrogenic pathways in the liver.
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Affiliation(s)
- Xinlei Li
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - Ruju Chen
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - David R Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +1-614-355-2824; Fax: +1-614-722-5892
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Li X, Chen R, Kemper S, Brigstock DR. Extracellular Vesicles From Hepatocytes Are Therapeutic for Toxin-Mediated Fibrosis and Gene Expression in the Liver. Front Cell Dev Biol 2020; 7:368. [PMID: 31998720 PMCID: PMC6966099 DOI: 10.3389/fcell.2019.00368] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs) are nano-sized membrane-limited organelles that are liberated from their producer cells, traverse the intercellular space, and may interact with other cells resulting in the uptake of the EV molecular payload by the recipient cells which may become functionally reprogramed as a result. Previous in vitro studies showed that EVs purified from normal mouse AML12 hepatocytes ("EVNorm") attenuate the pro-fibrogenic activities of activated hepatic stellate cells (HSCs), a principal fibrosis-producing cell type in the liver. In a 10-day CCl4 injury model, liver fibrogenesis, expression of hepatic cellular communication network factor 2 [CCN2, also known as connective tissue growth factor (CTGF)] or alpha smooth muscle actin (αSMA) was dose-dependently blocked during concurrent administration of EVNorm. Hepatic inflammation and expression of inflammatory cytokines were also reduced by EVNorm. In a 5-week CCl4 fibrosis model in mice, interstitial collagen deposition and mRNA and/or protein for collagen 1a1, αSMA or CCN2 were suppressed following administration of EVNorm over the last 2 weeks. RNA sequencing (RNA-seq) revealed that EVNorm therapy of mice receiving CCl4 for 5 weeks resulted in significant differences [false discovery rate (FDR) <0.05] in expression of 233 CCl4-regulated hepatic genes and these were principally associated with fibrosis, cell cycle, cell division, signal transduction, extracellular matrix (ECM), heat shock, cytochromes, drug detoxification, adaptive immunity, and membrane trafficking. Selected gene candidates from these groups were verified by qRT-PCR as targets of EVNorm in CCl4-injured livers. Additionally, EVNorm administration resulted in reduced activation of p53, a predicted upstream regulator of 40% of the genes for which expression was altered by EVNorm following CCl4 liver injury. In vitro, EVs from human HepG2 hepatocytes suppressed fibrogenic gene expression in activated mouse HSC and reversed the reduced viability or proliferation of HepG2 cells or AML12 cells exposed to CCl4. Similarly, EVs produced by primary human hepatocytes (PHH) protected PHH or human LX2 HSC from CCl4-mediated changes in cell number or gene expression in vitro. These findings show that EVs from human or mouse hepatocytes regulate toxin-associated gene expression leading to therapeutic outcomes including suppression of fibrogenesis, hepatocyte damage, and/or inflammation.
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Affiliation(s)
- Xinlei Li
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Ruju Chen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - David R. Brigstock
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
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Bordeleau F, Wang W, Simmons A, Antonyak MA, Cerione RA, Reinhart-King CA. Tissue transglutaminase 2 regulates tumor cell tensional homeostasis by increasing contractility. J Cell Sci 2020; 133:jcs.231134. [PMID: 31822629 DOI: 10.1242/jcs.231134] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 12/01/2019] [Indexed: 12/21/2022] Open
Abstract
Abnormal tensional cellular homeostasis is now considered a hallmark of cancer. Despite this, the origin of this abnormality remains unclear. In this work, we investigated the role of tissue transglutaminase 2 (TG2, also known as TGM2), a protein associated with poor prognosis and increased metastatic potential, and its relationship to the EGF receptor in the regulation of the mechanical state of tumor cells. Remarkably, we observed a TG2-mediated modulation of focal adhesion composition as well as stiffness-induced FAK activation, which was linked with a distinctive increase in cell contractility, in experiments using both pharmacological and shRNA-based approaches. Additionally, the increased contractility could be reproduced in non-malignant cells upon TG2 expression. Moreover, the increased cell contractility mediated by TG2 was largely due to the loss of EGFR-mediated inhibition of cell contractility. These findings establish intracellular TG2 as a regulator of cellular tensional homeostasis and suggest the existence of signaling switches that control the contribution of growth factor receptors in determining the mechanical state of a cell.
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Affiliation(s)
- Francois Bordeleau
- CHU de Québec-Université Laval Research Center (Oncology division), Université Laval Cancer Research Center and Faculty of Medecine, Université Laval, Québec G1R 3S3, Canada .,Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA
| | - Wenjun Wang
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA
| | - Alysha Simmons
- Pathobiology Graduate Program, Brown University, Providence, RI 02912, USA
| | - Marc A Antonyak
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Richard A Cerione
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
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Antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate gum resin in CCl 4-induced hepatotoxicity. Exp Ther Med 2019; 19:1313-1321. [PMID: 32010304 PMCID: PMC6966228 DOI: 10.3892/etm.2019.8353] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 10/11/2019] [Indexed: 12/14/2022] Open
Abstract
The present study aims to investigate the potential antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate (BS) gum resin against carbon tetrachloride (CCl4)-induced liver damage. Four groups consisting of eight rats each were designated: Group I, normal healthy control; group II, CCl4-induced liver fibrosis; group III, CCl4-induced liver fibrosis followed by BS treatment daily for two weeks; and group IV, CCl4-induced liver fibrosis followed by silymarin treatment daily for two weeks. Expression of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NF-κB), interleukin-6 (IL-6), transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) were assessed, in addition to histopathological and fibrotic changes in liver tissues isolated from the rats. BS significantly ameliorated CCl4-induced increases in serum aspartate (AST) and alanine transaminase (ALT) levels, reduced lactate dehydrogenase (LDH) activities in addition to restoring total bilirubin, triglyceride and albumin levels. BS treatment also alleviated oxidative stress and improved total antioxidant capacity in the liver, and reduced the expression of TNF-α, NF-κB, TGF-β, IL-6 and COX-2. On a histopathological level, BS treatment also exhibited antifibrotic activity. In conclusion, these findings suggest that BS contains potentially hepatoprotective effects against CCl4-induced liver injury via its antioxidant, anti-inflammatory and antifibrotic characteristics.
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Umbelliferone Ameliorates CCl 4-Induced Liver Fibrosis in Rats by Upregulating PPARγ and Attenuating Oxidative Stress, Inflammation, and TGF-β1/Smad3 Signaling. Inflammation 2019; 42:1103-1116. [PMID: 30741365 DOI: 10.1007/s10753-019-00973-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Umbelliferone (UMB) is a natural coumarin that has diverse biological activities. However, its potential to protect against liver fibrosis has not been reported yet. This study aimed to investigate the protective effect of UMB against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats received CCl4 and UMB for 8 weeks and samples were collected for analyses. CCl4 induced a significant increase in serum levels of liver function markers and pro-inflammatory cytokines. Treatment with UMB significantly ameliorated liver function markers and pro-inflammatory cytokines and prevented CCl4-induced histological alterations. CCl4 promoted significant upregulation of α-smooth muscle actin (SMA), collagen I, collagen III, NF-κB p65, TGF-β1, and p-Smad3. Masson's trichrome staining revealed a significant fibrogenesis in CCl4-induced rats. Treatment with UMB suppressed TGF-β1/Smad3 signaling and downregulated α-SMA, collagen I, collagen III, and NF-κB p65. In addition, UMB diminished malondialdehyde and nitric oxide levels, boosted reduced glutathione and antioxidant enzymes, and upregulated the expression of PPARγ. In conclusion, our results demonstrated that UMB prevented CCl4-induced liver fibrosis by attenuating oxidative stress, inflammation, and TGF-β1/Smad3 signaling, and upregulating PPARγ. Therefore, UMB may be a promising candidate for preventing hepatic fibrogenesis, given that further research is needed to delineate the exact molecular mechanisms underlying its antifibrotic efficacy.
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Chen CH, Chang CL, Chen KH, Cheng BC, Chen HH, Chiang JY, Sung PH, Yip HK. Level and Value of T Cell-derived Circulating Microparticles in Liver Cirrhosis Patients. In Vivo 2019; 33:2265-2272. [PMID: 31662566 DOI: 10.21873/invivo.11732] [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: 07/09/2019] [Revised: 07/18/2019] [Accepted: 07/25/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM We examined the hypothesis that T cell-derived-circulating microparticles (MPs) are increased in liver-cirrhosis (LC) patients compared to normal subjects and are also increased in chronic hepatitis compared to acute-decompensated-liver cirrhosis (ADLC). PATIENTS AND METHODS A total of 66 LC patients, including 35 with ADLC and 31 with non-decompensated-LC (NDLC), were enrolled in the study. Ten volunteers served as controls. RESULTS Flow-cytometric analysis showed that circulating levels of T-cell derived MPs (i.e., total MPs and CD4+/CD8+/CD54+MPs) were higher in LC patients than in the controls (all p<0.003). Total MPs and CD8+MPs were higher in NDLC than in ADLC patients. There were good correlations between CD8+MPs and ADLC as well as between total MPs and chronic hepatitis. Multivariate-linear-regression analysis showed that NDLC was independently predictive of increased circulating CD8+MPs levels (p<0.05) and chronic hepatitis independently predictive of increased circulating total MPs levels (p<0.001)/CD4+MPs (p<0.05). CONCLUSION Circulating levels of T-cell-derived MPs were increased in ADLC patients and were even more elevated in NDLC patients compared to healthy-control subjects.
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Affiliation(s)
- Chih-Hung Chen
- Division of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C
| | - Chia-Lo Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C
| | - Ben-Chung Cheng
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C
| | - Hong-Hwa Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan, R.O.C.,Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C. .,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, R.O.C
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C. .,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, R.O.C.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, R.O.C.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, R.O.C.,Department of Nursing, Asia University, Taichung, Taiwan, R.O.C
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Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease. Cells 2019; 8:cells8111337. [PMID: 31671832 PMCID: PMC6912497 DOI: 10.3390/cells8111337] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/11/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022] Open
Abstract
Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention.
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Cao G, Zhu R, Jiang T, Tang D, Kwan HY, Su T. Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 63:153055. [PMID: 31377585 DOI: 10.1016/j.phymed.2019.153055] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/03/2019] [Accepted: 07/26/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS Carbon tetrachloride (CCl4)-induced rat HF model and TGF-β1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.
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Affiliation(s)
- Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ting Jiang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongxin Tang
- First Affiliated Hospital of Guiyang College of Traditional Chinese Medicine, Guiyang, China
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Therapeutic Effect of Dunaliella salina Microalgae on Thioacetamide- (TAA-) Induced Hepatic Liver Fibrosis in Rats: Role of TGF-β and MMP9. BIOMED RESEARCH INTERNATIONAL 2019. [DOI: 10.1155/2019/7028314] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver fibrosis represents a serious global health-care problem and is the outcome of many chronic liver diseases, cirrhosis, hepatitis, and toxin accumulation. The present study aimed to evaluate the antifibrotic curative effect of Dunaliella salina (D. salina) on thioacetamide- (TAA-) induced liver fibrosis in rats. Liver fibrosis was induced by TAA (200mg/kg; i.p.) twice per week for 6 weeks. D. salina was given orally (100 and 200 mg/kg) and silymarin was given orally (100 mg/kg) daily, for 4 weeks after TAA. Serum transaminase activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA significantly (p<0.05) elevated serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum levels of total bilirubin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β) with a reduction in albumin. In addition, TAA increased hepatic contents of collagen I, a-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase (TIMP-1), reduced matrix metalloproteinase 9 (MMP9), and finally produced marked degeneration and fibrosis of hepatocytes. Treatment with D. salina or silymarin improved the histological feature of hepatocytes and ameliorated the deleterious effects of TAA in a dose-dependent manner. Based on these results, it could be concluded that the use of D. salina could be assigned for liver fibrosis treatment via its anti-inflammatory and antifibrotic properties.
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Wei Y, Zhang X, Wen S, Huang S, Huang Q, Lu S, Bai F, Nie J, Wei J, Lu Z, Lin X. Methyl helicterate inhibits hepatic stellate cell activation through downregulating the ERK1/2 signaling pathway. J Cell Biochem 2019; 120:14936-14945. [PMID: 31009108 DOI: 10.1002/jcb.28756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 12/22/2018] [Accepted: 01/07/2019] [Indexed: 11/11/2022]
Abstract
The present study was to investigate the inhibitory effect of methyl helicterate (MH) on hepatic stellate cells (HSC-T6), primarily elucidating the underlying mechanism of MH against liver fibrosis. HSC-T6 cells were activated by platelet-derived growth factor (PDGF) stimulation, and then the effects of MH on cell viability, cytomembrane integrity, colony, migration, apoptosis, and cell cycle were detected. Moreover, the regulative mechanism of MH on HSCs was investigated by detecting the activation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway. The results showed that MH significantly inhibited HSC-T6 cell viability and proliferation in a concentration-dependent manner. It notably promoted the release of lactate dehydrogenase, destroying cell membrane integrity. MH also markedly inhibited HSC-T6 cell clonogenicity and migration. Moreover, MH treatment significantly induced cell apoptosis and arrested cell cycle at the G2 phase. The further study showed that MH inhibited the expression of ERK1, ERK2, c-fos, c-myc, and Ets-1, blocking the ERK1/2 pathway. In conclusion, this study demonstrates that MH significantly inhibits HSC activation and promotes cell apoptosis via downregulation of the ERK1/2 signaling pathway.
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Affiliation(s)
- Yuanyuan Wei
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Xiaolin Zhang
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Shujuan Wen
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Shaode Huang
- Pharmaceutical College, Guangxi Agricultural Vocational College, Nanning, China
| | - Quanfang Huang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Shengjuan Lu
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Facheng Bai
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Jinlan Nie
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Jinbin Wei
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Zhongpeng Lu
- Department of Pharmacy, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
- Pharmaceutical College, University of Arkansas Medical School, Little Rock, Arkansas
| | - Xing Lin
- Life Sciences Institute and Pharmaceutical College, Guangxi Medical University, Nanning, China
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Pedroza M, To S, Smith J, Agarwal SK. Cadherin-11 contributes to liver fibrosis induced by carbon tetrachloride. PLoS One 2019; 14:e0218971. [PMID: 31269038 PMCID: PMC6608953 DOI: 10.1371/journal.pone.0218971] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 06/12/2019] [Indexed: 11/18/2022] Open
Abstract
Background and aims Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) leading to impaired function and cirrhosis. Previous reports support a role for cadherin-11 (CDH11) in regulating the development of dermal and pulmonary fibrosis. In the current report, the extent to which CDH11 modulates the development of liver fibrosis induced by carbon tetrachloride (CCL4) was assessed. Methods Wild type (WT) and CDH11 deficient (CDH11-/-) mice were treated with CCl4 or vehicle control for 8 weeks to induce liver fibrosis. Liver fibrosis was assessed by histology, collagen content, and RTPCR of fibrotic mediators. Results Livers from WT mice treated with CCl4 had increased levels of CDH11 which localized to injured hepatocytes, hepatic stellate cells, and macrophages. Interestingly, CDH11-/- mice had decreased histological evidence of liver fibrosis, collagen deposition, α-smooth muscle actin (α-SMA) accumulation, and mRNA levels of fibrotic mediators such as Col1-α1, Snail, TGF-β and IL-6. Conclusions These data demonstrate that CDH11 is increased during liver fibrosis, is an important regulator of liver fibrosis induced by CCL4 and suggest that CDH11 may be a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Mesias Pedroza
- Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, United States of America
| | - Sarah To
- Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, United States of America
| | - Jennifer Smith
- Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, United States of America
| | - Sandeep K. Agarwal
- Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, United States of America
- * E-mail:
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Mukherji A, Bailey SM, Staels B, Baumert TF. The circadian clock and liver function in health and disease. J Hepatol 2019; 71:200-211. [PMID: 30930223 PMCID: PMC7613420 DOI: 10.1016/j.jhep.2019.03.020] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/15/2019] [Accepted: 03/21/2019] [Indexed: 02/06/2023]
Abstract
Each day, all organisms are subjected to changes in light intensity because of the Earth's rotation around its own axis. To anticipate this geo-physical variability, and to appropriately respond biochemically, most species, including mammals, have evolved an approximate 24-hour endogenous timing mechanism known as the circadian clock (CC). The 'clock' is self-sustained, cell autonomous and present in every cell type. At the core of the clock resides the CC-oscillator, an exquisitely crafted transcriptional-translational feedback system. Remarkably, components of the CC-oscillator not only maintain daily rhythmicity of their own synthesis, but also generate temporal variability in the expression levels of numerous target genes through transcriptional, post-transcriptional and post-translational mechanisms, thus, ensuring proper chronological coordination in the functioning of cells, tissues and organs, including the liver. Indeed, a variety of physiologically critical hepatic functions and cellular processes are CC-controlled. Thus, it is not surprising that modern lifestyle factors (e.g. travel and jet lag, night and rotating shift work), which force 'circadian misalignment', have emerged as major contributors to global health problems including obesity, non-alcoholic fatty liver disease and steatohepatitis. Herein, we provide an overview of the CC-dependent pathways which play critical roles in mediating several hepatic functions under physiological conditions, and whose deregulation is implicated in chronic liver diseases including non-alcoholic steatohepatitis and alcohol-related liver disease.
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Affiliation(s)
- Atish Mukherji
- Institut de Recherche sur les Maladies Virales et Hépatiques INSERM, UMR 1110, Université de Strasbourg, Strasbourg, France.
| | - Shannon M. Bailey
- Department of Pathology, School of Medicine, University of Alabama at Birmingham, USA
| | - Bart Staels
- Université de Lille-European Genomic Institute for Diabetes, Institut Pasteur de Lille, CHU de Lille, INSERM UMR 1011, Lille, France
| | - Thomas F. Baumert
- Institut de Recherche sur les Maladies Virales et Hépatiques INSERM, UMR 1110, Université de Strasbourg Strasbourg, France,Pôle Hépato-Digestif, Institut Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Jain A, Barve A, Zhao Z, Fetse JP, Liu H, Li Y, Cheng K. Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis. ADVANCED THERAPEUTICS 2019; 2. [PMID: 33072857 DOI: 10.1002/adtp.201900046] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Liver fibrosis is a wound healing process with excessive accumulation of extracellular matrix in the liver. We recently discovered a PCBP2 siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs), which are the key players in liver fibrogenesis. However, targeted delivery of siRNAs to HSCs still remains a challenge. Herein, we developed a new strategy to fabricate a multicomponent nanocomplex using siRNA/PNA hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. We modified the nanocomplex with an insulin growth factor 2 receptor (IGF2R)-specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex shows a controllable size and high serum stability. The nanocomplex also demonstrates high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex was evaluated in rats with carbon tetrachloride-induced liver fibrosis. Treatment with the PCBP2 siRNA nanocomplex significantly inhibits the mRNA expressions of PCBP2 and type I collagen in fibrotic liver. Histology study revealed that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. Our data suggest that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.
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Affiliation(s)
- Akshay Jain
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Ashutosh Barve
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - John Peter Fetse
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Hao Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Yuanke Li
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
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D'Souza JC, Sultan LR, Hunt SJ, Schultz SM, Brice AK, Wood AKW, Sehgal CM. B-mode ultrasound for the assessment of hepatic fibrosis: a quantitative multiparametric analysis for a radiomics approach. Sci Rep 2019; 9:8708. [PMID: 31213661 PMCID: PMC6581954 DOI: 10.1038/s41598-019-45043-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 05/29/2019] [Indexed: 01/03/2023] Open
Abstract
Hepatic fibrosis and cirrhosis are a growing global health problem with increasing mortality rates. Early diagnosis and staging of hepatic fibrosis represent a major challenge. Currently liver biopsy is the gold standard for fibrosis assessment; however, biopsy requires an invasive procedure and is prone to sampling error and reader variability. In the current study we investigate using quantitative analysis of computer-extracted features of B-mode ultrasound as a non-invasive tool to characterize hepatic fibrosis. Twenty-two rats were administered diethylnitrosamine (DEN) orally for 12 weeks to induce hepatic fibrosis. Four control rats did not receive DEN. B-mode ultrasound scans sampling throughout the liver were acquired at baseline, 10, and 13 weeks. Computer extracted quantitative parameters representing brightness (echointensity, hepatorenal index) and variance (heterogeneity, anisotropy) of the liver were studied. DEN rats showed an increase in echointensity from 37.1 ± SD 7.8 to 53.5 ± 5.7 (10 w) to 57.5 ± 6.1 (13 w), while the control group remained unchanged at an average of 34.5 ± 4.5. The three other features studied increased similarly over time in the DEN group. Histologic analysis showed METAVIR fibrosis grades of F2-F4 in DEN rats and F0-F1 in controls. Increasing imaging parameters correlated with increasing METAVIR grades, and anisotropy showed the strongest correlation (ρ = 0.58). Sonographic parameters combined using multiparametric logistic regression were able to differentiate between clinically significant and insignificant fibrosis. Quantitative B-mode ultrasound imaging can be implemented in clinical settings as an accurate non-invasive tool for fibrosis assessment.
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Affiliation(s)
- Julia C D'Souza
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.,Penn Image-Guided Interventions Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Laith R Sultan
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
| | - Stephen J Hunt
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.,Penn Image-Guided Interventions Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Susan M Schultz
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Angela K Brice
- University Laboratory Animal Resources, University of Pennsylvania, Philadelphia, PA, USA.,Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew K W Wood
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.,Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Chandra M Sehgal
- Ultrasound Research Lab, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
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Substance P Promotes Liver Sinusoidal Endothelium-Mediated Hepatic Regeneration by NO/HGF Regulation. J Interferon Cytokine Res 2019; 39:147-154. [DOI: 10.1089/jir.2018.0111] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Nishimura T, Takami T, Sasaki R, Aibe Y, Matsuda T, Fujisawa K, Matsumoto T, Yamamoto N, Tani K, Taura Y, Sakaida I. Liver regeneration therapy through the hepatic artery-infusion of cultured bone marrow cells in a canine liver fibrosis model. PLoS One 2019; 14:e0210588. [PMID: 30673721 PMCID: PMC6343920 DOI: 10.1371/journal.pone.0210588] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/25/2018] [Indexed: 01/02/2023] Open
Abstract
Background We previously reported regenerative therapies for decompensated cirrhosis based on peripheral venous drip infusion using non-cultured whole bone marrow (BM) cells, or the less invasive cultured BM-derived mesenchymal stem cells (BMSCs). Here, we assessed the efficacy and safety of hepatic arterial infusion using cultured autologous BMSCs, comparing it with peripheral infusion, using our established canine liver fibrosis model. Methods Canine BM cells were harvested and cultured, and the resultant BMSCs were returned to carbon tetrachloride (CCl4)-induced liver cirrhosis model canines via either a peripheral vein (Vein group) or hepatic artery (Artery group). A variety of assays were performed before and 4, 8, and 12 weeks after BMSC infusion, and liver fibrosis and indocyanine green (ICG) half-life (t1/2) were compared to those in a control group that received CCl4 but not BMSCs. The safety of this approach was evaluated by contrast-enhanced computed tomography (CT) and serial blood examinations after infusion. Results Four weeks after infusing BMSCs, a significant improvement was observed in the Vein group (n = 8) compared to outcome in the Control group (n = 10), along with a decrease in ICG t1/2. In the Artery group (n = 4), ICG t1/2 was significantly shorter than that in the Vein group at 8 weeks (Δt1/2: −3.8 ± 1.7 min vs. +0.4 ± 2.4 min; p < 0.01) and 12 weeks (Δt1/2: −4.2 ± 1.7 min vs. +0.4 ± 2.7 min; p < 0.01) after BMSC administration. Post-infusion contrast-enhanced CT showed no liver infarction, and blood tests showed no elevations in either serum lactate dehydrogenase concentrations or hypercoagulability. Conclusions We confirmed the efficacy and safety of the hepatic arterial infusion of cultured autologous BMSCs using a canine model, thereby providing non-clinical proof-of-concept.
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Affiliation(s)
- Tatsuro Nishimura
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Taro Takami
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Center for Regenerative and Cell Therapy, Yamaguchi University Organization for Research Initiatives, Ube, Yamaguchi, Japan
- * E-mail:
| | - Ryo Sasaki
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yuki Aibe
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Takashi Matsuda
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Koichi Fujisawa
- Center for Reparative Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Toshihiko Matsumoto
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Naoki Yamamoto
- Yamaguchi University Health Administration Center, Yamaguchi, Yamaguchi, Japan
| | - Kenji Tani
- Department of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi, Yamaguchi, Japan
| | - Yasuho Taura
- Department of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi, Yamaguchi, Japan
| | - Isao Sakaida
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Center for Regenerative and Cell Therapy, Yamaguchi University Organization for Research Initiatives, Ube, Yamaguchi, Japan
- Center for Reparative Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
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Thuy LTT, Hai H, Hieu VN, Dat NQ, Hoang DV, Kawada N. Antifibrotic Therapy for Liver Cirrhosis. THE EVOLVING LANDSCAPE OF LIVER CIRRHOSIS MANAGEMENT 2019:167-189. [DOI: 10.1007/978-981-13-7979-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Zhang Q, Chen K, Wu T, Song H. Swertiamarin ameliorates carbon tetrachloride-induced hepatic apoptosis via blocking the PI3K/Akt pathway in rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 23:21-28. [PMID: 30627006 PMCID: PMC6315090 DOI: 10.4196/kjpp.2019.23.1.21] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 04/04/2018] [Accepted: 06/01/2018] [Indexed: 01/07/2023]
Abstract
Swertiamarin (STM) is an iridoid compound that is present in the Gentianaceae swertia genus. Here we investigated antiapoptotic effects of STM on carbon tetrachloride (CCl4)-induced liver injury and its possible mechanisms. Adult male Sprague Dawley rats were randomly divided into a control group, an STM 200 mg/kg group, a CCl4 group, a CCl4+STM 100 mg/kg group, and a CCl4+STM 200 mg/kg group. Rats in experimental groups were subcutaneously injected with 40% CCl4 twice weekly for 8 weeks. STM (100 and 200 mg/kg per day) was orally given to experimental rats by gavage for 8 consecutive weeks. Hepatocyte apoptosis was determined by TUNEL assay and the expression levels of Bcl-2, Bax, and cleaved caspase-3 proteins were evaluated by western blot analysis. The expression of TGF-β1, collagen I, collagen III, CTGF and fibronectin mRNA were estimated by qRT-PCR. The results showed that STM significantly reduced the number of TUNEL-positive cells compared with the CCl4 group. The levels of Bax and cleaved caspase-3 proteins, and TGF-β1, collagen I, collagen III, CTGF, and fibronectin mRNA were significantly reduced by STM compared with the CCl4 group. In addition, STM markedly abrogated the repression of Bcl-2 by CCl4. STM also attenuated the activation of the PI3K/Akt pathway in the liver. These results suggested that STM ameliorated CCl4-induced hepatocyte apoptosis in rats.
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Affiliation(s)
- Qianrui Zhang
- Department of Pharmacy, General Hospital of the Yangtze River Shipping, Wuhan 430022, China
| | - Kang Chen
- Department of Pharmacy, Huanggang Central Hospital, Huanggang 438000, China
| | - Tao Wu
- Department of Pharmacy, Wuhan NO.4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongping Song
- Department of Pharmacy, Wuhan NO.4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Use of anti-platelet agents in the prevention of hepatic fibrosis in patients at risk for chronic liver disease: a systematic review and meta-analysis. Hepatol Int 2018; 13:84-90. [PMID: 30539518 DOI: 10.1007/s12072-018-9918-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 11/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS While the association between platelet activation and hepatic fibrosis has been previously demonstrated in animal studies; the utility of anti-platelet agents in reversing the progression of hepatic fibrosis requires further review. Utilizing systematic review methods, we provide to our knowledge the first meta-analysis combining evidence from all studies aimed to establish the effect of anti-platelet agents in the prevention of hepatic fibrosis. METHODS We searched Medline, EMBASE and PubMed databases from inception to October 2018 to identify all studies aimed at evaluating the role of anti-platelet agents in the prevention of hepatic fibrosis. The primary outcome was hepatic fibrosis. The initial title, abstract, and full-text screening were performed in duplicate. Risk of bias was evaluated using the Newcastle-Ottawa Scale. A fixed-effect generic inverse variance method was used to create a pooled estimate of the odds of hepatic fibrosis in patients with anti-platelet agents versus without anti-platelet agents. RESULTS Among the 2310 unique articles identified during the title screening, 4 studies with a combined population of 3141 patients were deemed eligible for inclusion into the meta-analysis establishing the effect of anti-platelet agents on hepatic fibrosis. One study failed to report their findings in the entire cohort, electing to instead summarize the effects of anti-platelets within subgroups categorized by fibrotic risk factors. Use of anti-platelets was associated with 32% decreased odds of hepatic fibrosis, (adjusted pooled OR 0.68; CI 0.56-0.82, p ≤ 0.0001). The statistical heterogeneity among the studies was insignificant. CONCLUSION Use of anti-platelet agents is associated with the decreased odds of hepatic fibrosis. Due to limited evidence, future high-quality randomized controlled trials with larger comparative samples are required to further delineate the potential beneficial effects of these drugs in preventing hepatic fibrosis.
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Morsy MA, Nair AB. Prevention of rat liver fibrosis by selective targeting of hepatic stellate cells using hesperidin carriers. Int J Pharm 2018; 552:241-250. [PMID: 30291958 DOI: 10.1016/j.ijpharm.2018.10.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 09/29/2018] [Accepted: 10/02/2018] [Indexed: 12/15/2022]
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Stahl EC, Haschak MJ, Popovic B, Brown BN. Macrophages in the Aging Liver and Age-Related Liver Disease. Front Immunol 2018; 9:2795. [PMID: 30555477 PMCID: PMC6284020 DOI: 10.3389/fimmu.2018.02795] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022] Open
Abstract
The number of individuals aged 65 or older is projected to increase globally from 524 million in 2010 to nearly 1. 5 billion in 2050. Aged individuals are particularly at risk for developing chronic illness, while being less able to regenerate healthy tissue and tolerate whole organ transplantation procedures. In the liver, these age-related diseases include non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis. Hepatic macrophages, a population comprised of both Kupffer cells and infiltrating monocyte derived macrophages, are implicated in several chronic liver diseases and also play important roles in the homeostatic functions of the liver. The effects of aging on hepatic macrophage population dynamics, polarization, and function are not well understood. Studies performed on macrophages derived from other aged sources, such as the bone marrow, peritoneal cavity, lungs, and brain, demonstrate general reductions in autophagy and phagocytosis, dysfunction in cytokine signaling, and altered morphology and distribution, likely mediated by epigenetic changes and mitochondrial defects, that may be applicable to hepatic macrophages. This review highlights recent findings in macrophage developmental biology and function, particularly in the liver, and discusses the role of macrophages in various age-related liver diseases. A better understanding of the biology of aging that influences hepatic macrophages and thus the progression of chronic liver disease will be crucial in order to develop new interventions and treatments for liver disease in aging populations.
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Affiliation(s)
- Elizabeth C Stahl
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Martin J Haschak
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Branimir Popovic
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Bryan N Brown
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Modulation of inducible nitric oxide synthase pathway by eugenol and telmisartan in carbon tetrachloride-induced liver injury in rats. Life Sci 2018; 216:207-214. [PMID: 30452970 DOI: 10.1016/j.lfs.2018.11.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/08/2018] [Accepted: 11/15/2018] [Indexed: 01/18/2023]
Abstract
AIMS Inducible nitric oxide synthase (iNOS) pathway has been in the limelight since its discovery as a key mediator in the process of liver fibrogenesis. Therefore, the objective of the current study was to elucidate the in vivo molecular mechanism underlying the hepatic preventive relevance of eugenol (EUG) and telmisartan (TEL) through iNOS pathway modulation against carbon tetrachloride (CCl4)-induced hepatic injury. METHODS Sixty healthy male albino rats were used in this study. Serum aminotransferases activities and NO levels were assessed. Hepatic malondialdehyde (MDA), total nitrite/nitrate content and reduced glutathione (GSH) concentration were estimated. Liver NF-kB, TNF-α, IL-6 and iNOS proteins expressions were investigated by western blot assay. Histopathological examination was done. KEY FINDINGS CCl4 resulted in damage to centrilobular regions of the liver, elevation of serum aminotransferases, rise in oxidative parameters level, and up-regulation of NF-kB, TNF-α, IL-6 as well as iNOS proteins expressions. Treatment of fibrotic rats with either EUG or TEL significantly alleviated CCl4-induced biochemical, inflammatory and histopathological changes. Moreover, the combined administration of EUG with TEL has an ameliorative effect which is greater than either of them alone. SIGNIFICANCE In conclusion, the combination therapy between EUG and TEL is more effective than either drug alone which is attributed to suppression of NO production and iNOS protein expression. The results support that use of EUG and TEL exerts beneficial effects in the attenuation of CCl4-induced liver fibrosis in rats.
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Abd El-Aal NF, Abdelbary EH. Paeoniflorin in experimental BALB/c mansoniasis: A novel anti-angiogenic therapy. Exp Parasitol 2018; 197:85-92. [PMID: 30414842 DOI: 10.1016/j.exppara.2018.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/15/2018] [Accepted: 11/04/2018] [Indexed: 12/14/2022]
Abstract
Chronic hepatic schistosomiasis causes portal hypertension, fibrosis and lethal hepatosplenic complications. Previous studies focused mainly on schistosomicidal drugs and neglected the therapeutic approaches against the vascular complications after portal hypertension. Investigating a novel anti-angiogenic therapy is an urgent. The current study is to evaluate the performance of Paeoniflorin (PAE) as an anti-angiogenic therapy, being a powerful anti-fibrotic, compared to artemether (ART) and praziqantel (PZQ) in schistosomiasis mansoni BALB/c mice. Thirty two laboratory bred male BALB/c Swiss albino mice. The mice were classified into four groups (8 mice each), control infected (CI), PZQ (300 mg/kg/12 h), ART (0.1 ml/mg/d) and PAE (50 mg/kg/d) treated groups for one month. All mice groups were sacrificed 15 weeks post infection for assessment of the drugs' efficacy by parasitological, histopathological and immunohistochemical studies. Our results in PAE group showed marked reduction in the mean egg count/gram stool, worm burden, egg count/gram liver tissue, granuloma diameter and pro-angiogenic factors as vascular endothelial growth factor (VEGF), Proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (α-SMA) and CD34; conversely, there was an augmentation of the tissue inhibitor metalloproteinases-2 (TIMP-2) as an anti-angiogenic expression that was exceeded ART and PZQ treated groups compared to CI group (p˂0.001). Conclusively, PAE has an anti-angiogenic impact with no vascular proliferative activity or recanalization, no micro-vessel density (MVD) changes, granuloma resolution and fibrosis regression. PAE is predicted to be a potential therapy for chronic hepatic diseases associated with fibrosis and angiogenesis, hopeful in protecting from advanced serious complications; cancer and metastasis.
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Mansour HM, Salama AAA, Abdel-Salam RM, Ahmed NA, Yassen NN, Zaki HF. The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats. Can J Physiol Pharmacol 2018; 96:1308-1317. [PMID: 30398909 DOI: 10.1139/cjpp-2018-0338] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.
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Affiliation(s)
- Heba M Mansour
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Abeer A A Salama
- b Pharmacology Department, National Research Centre, Giza, Egypt
| | - Rania M Abdel-Salam
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Naglaa A Ahmed
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Noha N Yassen
- d Pathology Department, National Research Centre, Giza, Egypt
| | - Hala F Zaki
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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