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Zhang Q, Zhang Y, Guo S, Wang H. Emerging insights into the role of microRNAs regulation of ferroptosis in hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167642. [PMID: 39734007 DOI: 10.1016/j.bbadis.2024.167642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/03/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Hepatocellular carcinoma (HCC) is a major type of liver cancer and an important cause of cancer death. It has been reported that the hepatocyte death plays an important role in HCC. Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of free iron and lipid peroxidation. A series of studies have shown that ferroptosis contributes to the occurrence and development of HCC. MicroRNAs (miRNAs) are non-coding RNAs with a length of approximately 222 nt. In recent years, miRNAs have been shown to participate in regulating ferroptosis to play a vital role in HCC, but the related mechanisms are not fully understood. This review summarized the current understanding of ferroptosis, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ferroptosis in HCC, with the hope of providing new targets and ideas for the treatment of HCC.
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Affiliation(s)
- Qi Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Yingdan Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Shiyun Guo
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Honggang Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China.
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2
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Zhao J, Zhao Y, Qin H, Ye Y, Zhang L, Ding R, Cao W, Zhang Y, Duan C, Leng H, Li Y, Wang B, Hu L, Liu E, Qu P. Characterization of small RNAs in the spleen of MASH in a non-human primate model. Genomics 2024; 116:110953. [PMID: 39419194 DOI: 10.1016/j.ygeno.2024.110953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 10/08/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as a global health issue. This study examines the role of small RNAs in the spleen of MASH using a non-human primate model. We performed high-throughput small RNA sequencing on spleen tissues from MASH-primates, revealing significant alterations in the expression of small non-coding RNAs, especially miRNAs. Notably, miR-96, miR-182, miR-183, and miR-122 showed differential expression in MASH spleens. Predictive and validation studies have identified potential target genes, such as PTX3 and NFIX, that were significantly dysregulated in spleens of MASH. These findings characterized small RNAs in spleen of MASH and offer a novel insight for further research for MASH.
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Affiliation(s)
- Juan Zhao
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Yuelei Zhao
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Hongyu Qin
- Central Laboratory, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
| | - Yun Ye
- Central Laboratory, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
| | - Liwei Zhang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Ruike Ding
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Wenbin Cao
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Yanru Zhang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Chenjing Duan
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Haoze Leng
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China
| | - Yandong Li
- Xi'an International Medical Center Hospital, Xi'an, Shaanxi,China
| | - Bo Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China.
| | - Pengxiang Qu
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an, Shaanxi, China; Spring Biological Technology Development Co., Ltd, Fangchenggang, Guangxi 538000, China.
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3
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Zhou Y, Jian N, Jiang C, Wang J. m 6A modification in non-coding RNAs: Mechanisms and potential therapeutic implications in fibrosis. Biomed Pharmacother 2024; 179:117331. [PMID: 39191030 DOI: 10.1016/j.biopha.2024.117331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/07/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
N6-methyladenosine (m6A) is one of the most prevalent and reversible forms of RNA methylation, with increasing evidence indicating its critical role in numerous physiological and pathological processes. m6A catalyzes messenger RNA(mRNA) as well as regulatory non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs. This modification modulates ncRNA fate and cell functions in various bioprocesses, including ncRNA splicing, maturity, export, and stability. Key m6A regulators, including writers, erasers, and readers, have been reported to modify the ncRNAs involved in fibrogenesis. NcRNAs affect fibrosis progression by targeting m6A regulators. The interactions between m6A and ncRNAs can influence multiple cellular life activities. In this review, we discuss the impact of the interaction between m6A modifications and ncRNAs on the pathological mechanisms of fibrosis, revealing the possibility of these interactions as diagnostic markers and therapeutic targets in fibrosis.
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Affiliation(s)
- Yutong Zhou
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ni Jian
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Canhua Jiang
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha 410078, China
| | - Jie Wang
- Department of Immunology, Xiangya School of Medicine, Central South University, Changsha 410078, China.
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Guo Y, Wang H, Lyu R, Wang J, Wang T, Shi J, Lyu L. Nanocarrier-Mediated Delivery of MicroRNAs for Fibrotic Diseases. Mol Diagn Ther 2024; 28:53-67. [PMID: 37897655 DOI: 10.1007/s40291-023-00681-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/30/2023]
Abstract
MicroRNAs (miRNAs) are endogenous noncoding RNAs that mediate the fibrotic process by regulating multiple targets. MicroRNA-based therapy can restore or inhibit miRNA expression and is expected to become an effective approach to prevent and alleviate fibrotic diseases. However, the safe, targeted, and effective delivery of miRNAs is a major challenge in translating miRNA therapy from bench to bedside. In this review, we briefly describe the pathophysiological process of fibrosis and the mechanism by which miRNAs regulate the progression of fibrosis. Additionally, we summarize the miRNA nanodelivery tools for fibrotic diseases, including chemical modifications and polymer-based, lipid-based, and exosome-based delivery systems. Further clarification of the role of miRNAs in fibrosis and the development of a novel nanodelivery system may facilitate the prevention and alleviation of fibrotic diseases in the future.
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Affiliation(s)
- Yanfang Guo
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Hanying Wang
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Rumin Lyu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Juan Wang
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Ting Wang
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Jingpei Shi
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China.
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Kunming Medical University, Kunming, 650106, Yunnan, China.
| | - Lechun Lyu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China.
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5
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Jiang T, Leng W, Zhong S. Diagnostic Role of Circulating miRNAs in the Grading of Chronic Hepatitis B-Related Liver Fibrosis: A Systematic Review and Meta-Analysis. Lab Med 2023; 54:479-488. [PMID: 36637253 DOI: 10.1093/labmed/lmac151] [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] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE miRNAs are considered potential biomarkers that can be used for the grading of chronic hepatitis B (CHB)-related liver fibrosis. This meta-analysis aims to elucidate the diagnostic performance of miRNAs. METHODS Databases were used to search for meta-analyses. A bivariate model was used to calculate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). In addition, the area under the summary receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were calculated. RESULTS A total of 9 studies with 1159 patients with CHB-related liver fibrosis were assessed. For diagnosis of significant liver fibrosis, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.73 (95% CI, 0.68-0.78), 0.78 (95% CI, 0.70-0.84), 3.32 (95% CI, 2.52-4.37), 0.34 (95% CI, 0.30-0.39), 9.70 (95% CI, 7.10-13.24), and 0.81 (95% CI, 0.77-0.84), respectively. CONCLUSION miRNAs are potential biomarkers of CHB-related liver fibrosis.
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Affiliation(s)
- Ting Jiang
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Disease, Chengdu First People's Hospital, Chengdu, China
| | - Wenying Leng
- Emergency Department, Chengdu First People's Hospital, Chengdu, China
| | - Sen Zhong
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Paluschinski M, Kordes C, Vucur M, Buettner V, Roderburg C, Xu HC, Shinte PV, Lang PA, Luedde T, Castoldi M. Differential Modulation of miR-122 Transcription by TGFβ1/BMP6: Implications for Nonresolving Inflammation and Hepatocarcinogenesis. Cells 2023; 12:1955. [PMID: 37566034 PMCID: PMC10416984 DOI: 10.3390/cells12151955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
Chronic inflammation is widely recognized as a significant factor that promotes and worsens the development of malignancies, including hepatocellular carcinoma. This study aimed to explore the potential role of microRNAs in inflammation-associated nonresolving hepatocarcinogenesis. By conducting a comprehensive analysis of altered microRNAs in animal models with liver cancer of various etiologies, we identified miR-122 as the most significantly downregulated microRNA in the liver of animals with inflammation-associated liver cancer. Although previous research has indicated the importance of miR-122 in maintaining hepatocyte function, its specific role as either the trigger or the consequence of underlying diseases remains unclear. Through extensive analysis of animals and in vitro models, we have successfully demonstrated that miR-122 transcription is differentially regulated by the immunoregulatory cytokines, by the transforming growth factor-beta 1 (TGFβ1), and the bone morphogenetic protein-6 (BMP6). Furthermore, we presented convincing evidence directly linking reduced miR-122 transcription to inflammation and in chronic liver diseases. The results of this study strongly suggest that prolonged activation of pro-inflammatory signaling pathways, leading to disruption of cytokine-mediated regulation of miR-122, may significantly contribute to the onset and exacerbation of chronic liver disease.
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Affiliation(s)
- Martha Paluschinski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Claus Kordes
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Veronika Buettner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Haifeng C. Xu
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Prashant V. Shinte
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Philipp A. Lang
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
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7
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Song S, Li X, Geng C, Guo Y, Yang Y, Wang C. Uncovering key molecules and immune landscape in cholestatic liver injury: implications for pathogenesis and drug therapy. Front Pharmacol 2023; 14:1171512. [PMID: 37229242 PMCID: PMC10203247 DOI: 10.3389/fphar.2023.1171512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
Background: Cholestasis is a common pathological process in a variety of liver diseases that may lead to liver fibrosis, cirrhosis, and even liver failure. Cholestasis relief has been regarded as a principal target in the management of multiple chronic cholestasis liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) at present. However, complicated pathogenesis and limited acknowledgments fettered therapeutic development. Therefore, this study aimed to systematically analyze miRNA-mRNA regulatory networks in cholestatic liver injury in order to provide new treatment strategies. Methods: Gene Expression Omnibus (GEO) database (GSE159676) was used to screen differentially expressed hepatic miRNAs and mRNAs in the PSC vs. control comparison and the PBC vs. control comparison, respectively. MiRWalk 2.0 tool was used to predict miRNA-mRNA pairs. Subsequently, functional analysis and immune cell infiltration analysis were performed to explore the pivotal functions of the target genes. RT-PCR was used to verify the result. Results: In total, a miRNA-mRNA network including 6 miRNAs (miR-122, miR-30e, let-7c, miR-107, miR-503, and miR-192) and 8 hub genes (PTPRC, TYROBP, LCP2, RAC2, SYK, TLR2, CD53, and LAPTM5) was constructed in cholestasis. Functional analysis revealed that these genes were mainly involved in the regulation of the immune system. Further analysis revealed that resting memory CD4 T cells and monocytes could potentially participate in cholestatic liver injury. The expressions of DEMis and eight hub genes were verified in ANIT-induced and BDL-induced cholestatic mouse models. Furthermore, SYK was found to have an impact on the response to UDCA, and its mechanism was possibly associated with complement activation and monocyte reduction. Conclusion: In the present study, a miRNA-mRNA regulatory network was constructed in cholestatic liver injury, which mostly mediated immune-related pathways. Moreover, the targeted gene SYK and monocytes were found to be related to UDCA response in PBC.
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Affiliation(s)
- Shuailing Song
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Geng
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Yaoyu Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Yang
- Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunhui Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Nokkeaw A, Thamjamrassri P, Tangkijvanich P, Ariyachet C. Regulatory Functions and Mechanisms of Circular RNAs in Hepatic Stellate Cell Activation and Liver Fibrosis. Cells 2023; 12:cells12030378. [PMID: 36766720 PMCID: PMC9913196 DOI: 10.3390/cells12030378] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/22/2023] Open
Abstract
Chronic liver injury induces the activation of hepatic stellate cells (HSCs) into myofibroblasts, which produce excessive amounts of extracellular matrix (ECM), resulting in tissue fibrosis. If the injury persists, these fibrous scars could be permanent and disrupt liver architecture and function. Currently, effective anti-fibrotic therapies are lacking; hence, understanding molecular mechanisms that control HSC activation could hold a key to the development of new treatments. Recently, emerging studies have revealed roles of circular RNAs (circRNAs), a class of non-coding RNAs that was initially assumed to be the result of splicing errors, as new regulators in HSC activation. These circRNAs can modulate the activity of microRNAs (miRNAs) and their interacting protein partners involved in regulating fibrogenic signaling cascades. In this review, we will summarize the current knowledge of this class of non-coding RNAs for their molecular function in HSC activation and liver fibrosis progression.
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Affiliation(s)
- Archittapon Nokkeaw
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Medical Biochemistry Program, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pannathon Thamjamrassri
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Medical Biochemistry Program, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: (P.T.); (C.A.)
| | - Chaiyaboot Ariyachet
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: (P.T.); (C.A.)
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10
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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11
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Zhao X, Xue X, Cui Z, Kwame Amevor F, Wan Y, Fu K, Wang C, Peng C, Li Y. microRNAs-based diagnostic and therapeutic applications in liver fibrosis. WILEY INTERDISCIPLINARY REVIEWS. RNA 2022:e1773. [PMID: 36585388 DOI: 10.1002/wrna.1773] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 01/01/2023]
Abstract
Liver fibrosis is a process of over-extracellular matrix (ECM) aggregation and angiogenesis, which develops into cirrhosis and hepatocellular carcinoma (HCC). With the increasing pressure of liver fibrosis, new therapeutics to cure this disease requires much attention. Exosome-cargoed microRNAs (miRNAs) are emerging approaches in the precision of the liver fibrotic paradigm. In this review, we outlined the different types of hepatic cells derived miRNAs that drive intra-/extra-cellular interactive communication in liver fibrosis with different physiological and pathological processes. Specifically, we highlighted the possible mechanism of liver fibrosis pathogenesis associated with immune response and angiogenesis. In addition, potential clinical biomarkers and different stem cell transplant-derived miRNAs-based therapeutic strategies in liver fibrosis were summarized in this review. miRNAs-based approaches might help researchers devise new candidates for the cell-free treatment of liver fibrosis. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Xingtao Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhifu Cui
- College Science and Technology, Southwest University, Chongqing, China
| | - Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yan Wan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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12
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Kaneko S, Yanai K, Ishii H, Aomatsu A, Hirai K, Ookawara S, Ishibashi K, Morishita Y. miR-122-5p Regulates Renal Fibrosis In Vivo. Int J Mol Sci 2022; 23:ijms232315423. [PMID: 36499744 PMCID: PMC9736395 DOI: 10.3390/ijms232315423] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/01/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
The role of exogenous microRNAs (miRNAs) in renal fibrosis is poorly understood. Here, the effect of exogenous miRNAs on renal fibrosis was investigated using a renal fibrosis mouse model generated by unilateral ureteral obstruction (UUO). miRNA microarray analysis and quantitative reverse-transcription polymerase chain reaction showed that miR-122-5p was the most downregulated (0.28-fold) miRNA in the kidneys of UUO mice. The injection of an miR-122-5p mimic promoted renal fibrosis and upregulated COL1A2 and FN1, whereas an miR-122-5p inhibitor suppressed renal fibrosis and downregulated COL1A2 and FN1. The expression levels of fibrosis-related mRNAs, which were predicted targets of miR-122-5p, were evaluated. The expression level of TGFBR2, a pro-fibrotic mRNA, was upregulated by the miR-122-5p mimic, and the expression level of FOXO3, an anti-fibrotic mRNA, was upregulated by the miR-122-5p inhibitor. The protein expressions of TGFBR2 and FOXO3 were confirmed by immunohistochemistry. Additionally, the expression levels of LC3, downstream anti-fibrotic mRNAs of FOXO3, were upregulated by the miR-122-5p inhibitor. These results suggest that miR-122-5p has critical roles in renal fibrosis.
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Affiliation(s)
- Shohei Kaneko
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Katsunori Yanai
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroki Ishii
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Akinori Aomatsu
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
- Division of Intensive Care Unit, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Keiji Hirai
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
- Correspondence:
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13
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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14
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Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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15
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Babuta M, Szabo G. Extracellular vesicles in inflammation: Focus on the microRNA cargo of EVs in modulation of liver diseases. J Leukoc Biol 2022; 111:75-92. [PMID: 34755380 PMCID: PMC9235439 DOI: 10.1002/jlb.3mir0321-156r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous nanometer-ranged particles that are released by cells under both normal and pathological conditions. EV cargo comprises of DNA, protein, lipids cargo, metabolites, mRNA, and non-coding RNA that can modulate the immune system by altering inflammatory response. EV associated miRNAs contribute to the pathobiology of alcoholic liver disease, non-alcoholic liver disease, viral hepatitis, acetaminophen-induced liver injury, fibrosis, and hepatocellular carcinoma. In context of liver diseases, EVs, via their cargo, alter the inflammatory response by communicating with different cell types within the liver and between liver and other organs. Here, the role of EVs and its associated miRNA in inter-cellular communication in different liver disease and as a potential biomarker and therapeutic target is reviewed.
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Affiliation(s)
- Mrigya Babuta
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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16
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Wu Z, Wang J, Feng J, Ying L. MicroRNA-122-5p prevents proliferation and promotes apoptosis of hepatic stellate cells by suppressing the cellular-Abelsongene/histone deacetylases 2 pathway. Hum Exp Toxicol 2022; 41:9603271221084672. [PMID: 35303413 DOI: 10.1177/09603271221084672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Liver fibrosis is a wound-healing response and the activation of the hepatic stellate cell (HSC) is the core of hepatic fibrosis. MicroRNAs (miRNAs) participate in the development of fibrosis. It is reported that histone deacetylases (HDAC2) tyrosine phosphorylation by cellular-Abelsongene (c-Abl) induces malignant growth of cells. Here, we investigated the effect of miR-122-5p on the proliferation and apoptosis of HSCs. Normal human HSC line LX-2 and LX-2 cells stimulated by transforming growth factor (TGF)-β1 for 24 h were cultured and assigned into the blank group and the TGF-β1 group. The miR-122-5p inhibitor and its negative control were transfected into LX-2 cells and miR-122-5p mimic and its negative control were transfected into LX-2 cells stimulated by TGF-β1. The result showed that miR-122-5p expression was decreased in TGF-β1-stimulated LX-2 cells. miR-122-5p overexpression reduced the mRNA and protein levels of collagen I and α-smooth muscle actin, inhibited cell proliferation, and accelerated cell apoptosis. miR-122-5p targeted c-Abl. Meanwhile, miR-122-5p overexpression inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway. In summary, miR-122-5p overexpression exerted anti-fibrosis effect and inhibited HSC activation by suppressing the c-Abl/HDAC2 pathway.
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Affiliation(s)
- ZongYang Wu
- Department of Hepatobiliary and Pancreatic Surgery, 11797The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - JinBo Wang
- Department of Hepatobiliary and Pancreatic Surgery, 11797The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - JiYe Feng
- Department of Hepatobiliary and Pancreatic Surgery, 11797The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - LiPing Ying
- Department of Hepatobiliary and Pancreatic Surgery, 11797The Affiliated People's Hospital of Ningbo University, Ningbo, China
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17
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Chang Y, Han JA, Kang SM, Jeong SW, Ryu T, Park HS, Yoo JJ, Lee SH, Kim SG, Kim YS, Kim HS, Jin SY, Ryu S, Jang JY. Clinical impact of serum exosomal microRNA in liver fibrosis. PLoS One 2021; 16:e0255672. [PMID: 34506494 PMCID: PMC8432846 DOI: 10.1371/journal.pone.0255672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. METHODS This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. RESULTS NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. CONCLUSION Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae-A. Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Suk Min Kang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Han Seul Park
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
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18
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Tadokoro T, Morishita A, Masaki T. Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA. Int J Mol Sci 2021; 22:8139. [PMID: 34360904 PMCID: PMC8347497 DOI: 10.3390/ijms22158139] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called "exosomes" have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent.
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Affiliation(s)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (T.T.); (T.M.)
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19
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Zhou LY, Lin SN, Rieder F, Chen MH, Zhang SH, Mao R. Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn's Disease: The Path From Bench to Bedside. Inflamm Bowel Dis 2021; 27:971-982. [PMID: 33324986 PMCID: PMC8344842 DOI: 10.1093/ibd/izaa321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Indexed: 12/12/2022]
Abstract
Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs.
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Affiliation(s)
- Long-Yuan Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Si-Nan Lin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Min-Hu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Sheng-Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
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20
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Xing M, Wang X, Kiken RA, He L, Zhang JY. Immunodiagnostic Biomarkers for Hepatocellular Carcinoma (HCC): The First Step in Detection and Treatment. Int J Mol Sci 2021; 22:6139. [PMID: 34200243 PMCID: PMC8201127 DOI: 10.3390/ijms22116139] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) exerts huge effects on the health burden of the world because of its high mortality and poor prognosis. HCC is often clinically detected late in patients. If HCC could be detected and treated earlier, the survival rate of patients will be greatly improved. Therefore, identifying specific biomarkers is urgent and important for HCC. The liver is also recognized as an immune organ. The occurrence of HCC is related to exacerbation of immune tolerance and/or immunosurveillance escape. The host immune system plays an important role in the recognition and targeting of tumor cells in cancer immunotherapy, as can be seen from the clinical success of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Thus, there is a pressing medical need to discover immunodiagnostic biomarkers specific to HCC for understanding the pathological mechanisms of HCC, especially for immunotherapy targets. We have reviewed the existing literature to summarize the immunodiagnostic markers of HCC, including autoantibodies against tumor-associated antigens (TAAs) and exosomes, to provide new insights into HCC and early detection of this deadly cancer.
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Affiliation(s)
- Mengtao Xing
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
| | - Xinzhi Wang
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Robert A. Kiken
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
| | - Ling He
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
| | - Jian-Ying Zhang
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA; (X.W.); (R.A.K.)
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21
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Hegazy MA, Abd ALgwad I, Abuel Fadl S, Sayed Hassan M, Ahmed Rashed L, Hussein MA. Serum Micro-RNA-122 Level as a Simple Noninvasive Marker of MAFLD Severity. Diabetes Metab Syndr Obes 2021; 14:2247-2254. [PMID: 34040409 PMCID: PMC8142686 DOI: 10.2147/dmso.s291595] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/19/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a common disease worldwide. Micro-RNA-122 is known to be the most abundant micro-RNA expressed in the liver. OBJECTIVE To evaluate the association of micro-RNA-122 and the degree of steatosis and fibrosis in obese patients with MAFLD. METHODS The study included 120 obese Egyptian patients with MAFLD, which were diagnosed and classified according to ultra-sonographic liver findings. All patients enrolled in the study were subjected to thorough clinical examination and laboratory investigations (serum micro-RNA-122 levels by PCR, lipid profile, liver biochemistry, and functions). Fibro-scan was used to assess the level of fibrosis. RESULTS There was a significant increase in levels of micro-RNA-122 in obese patients with MAFLD compared to controls (p<0.001). Micro-RNA-122 level was lower in patients with mild liver steatosis than patients with moderate or severe steatosis (p<0.001). It was lower in patients with a mild degree of fibrosis than those with mild or moderate fibrosis (p<0.001). Micro-RNA-122 was significantly positively correlated with low-density cholesterol and triglycerides level, and liver enzymes, and negatively correlated to high-density cholesterol (p<0.001). CONCLUSION Serum micro-RNA-122 could be a useful predictor of assessing MAFLD severity regarding level of steatosis or fibrosis.
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Affiliation(s)
- Mona A Hegazy
- Internal Medicine Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
| | - Ibrahim Abd ALgwad
- Internal Medicine Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
| | - Soheir Abuel Fadl
- Internal Medicine Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
| | - Mohamed Sayed Hassan
- Internal Medicine Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
| | - Laila Ahmed Rashed
- Biochemistry Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
| | - Maha A Hussein
- Internal Medicine Department, Kasr Al-Aini Hospitals, Cairo University, Cairo, Egypt
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22
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Fawzy MS, Toraih EA. MicroRNA signatures as predictive biomarkers in transarterial chemoembolization‐treated hepatocellular carcinoma. PRECISION MEDICAL SCIENCES 2021. [DOI: 10.1002/prm2.12031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Manal S. Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
- Biochemistry Department, Faculty of Medicine Northern Border University Arar KSA
| | - Eman A. Toraih
- Department of Surgery Tulane University, School of Medicine New Orleans Louisiana USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
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23
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Moayedi J, Hashempour T, Musavi Z, Arefian E, Naderi M, Heidari MR, Dehghani B, Hasanshahi Z, Merat S. Evaluation of miR-122 Serum Level and IFN-λ3 Genotypes in Patients with Chronic HCV and HCV-Infected Liver Transplant Candidate. Microrna 2021; 10:58-65. [PMID: 33334303 DOI: 10.2174/2211536609666201217101414] [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: 03/17/2020] [Revised: 07/07/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most common markers of liver damage, but serum level interpretation can be complicated. In hepatocytes, microRNA-122 (miR-122) is the most abundant miRs and its high expression in the serum is a characteristic of liver disease. OBJECTIVE We aimed to compare the circulatory level of miR-122 in patients with Chronic Hepatitis C (CHC), Hepatitis C Virus (HCV) infected Liver Transplant Candidates (LTC) and healthy controls to determine if miR-122 can be considered as an indicator of chronic and advanced stage of liver disease. METHODS MiR-122 serum level was measured in 170 Interferon-naïve (IFN-naïve) CHC patients, 62 LTC patients, and 132 healthy individuals via TaqMan real-time PCR. Serum levels of miR-122 were normalized to the serum level of Let-7a and miR-221. Also, the ALT and AST levels were measured. RESULTS ALT and AST activities and the expression of circulatory miR-122 were similar in the CHC and LTC groups, but it had significantly increased compared to healthy individuals (P<0.001 and P<0.001, respectively). Up-regulation of miR-122 in the sample of patients with normal ALT and AST activities was also observed, indicating that miR-122 is a good marker with high sensitivity and specificity for diagnosing liver damage. CONCLUSION miR-122 seemed to be more specific for liver diseases in comparison with the routine ALT and AST liver enzymes. Since the lower levels of circulating miR-122 were observed in the LTC group compared to the CHC group, advanced liver damages might reduce the release of miR-122 from the hepatocytes, as a sign of liver function deficiency.
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Affiliation(s)
- Javad Moayedi
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayebeh Hashempour
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Musavi
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Mahmood Naderi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohamad Reza Heidari
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behzad Dehghani
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Hasanshahi
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahin Merat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Inhibition of miR-122 reduced atherosclerotic lesion formation by regulating NPAS3-mediated endothelial to mesenchymal transition. Life Sci 2020; 265:118816. [PMID: 33278397 DOI: 10.1016/j.lfs.2020.118816] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/14/2020] [Accepted: 11/20/2020] [Indexed: 12/30/2022]
Abstract
AIMS Endothelial to mesenchymal transition (EndMT) is closely related to atherosclerosis. Herein, we aim to determine whether miR-122 is involved in EndMT and the underlying mechanism in atherosclerosis. MAIN METHODS qRT-PCR was performed to detect miR-122 expression in ApoE-/- mice and cellular EndMT model induced by H2O2. MiR-122 expression in vivo was modulated by lenti-virus injection and by genetic manipulation. Hematoxylin and eosin (HE) and Oil-red O staining were used to observe the plaque size and lipid accumulation in the aortic roots. F4/80 staining, elastin staining, and masson staining were used to observe the components of atherosclerotic lesions. MiR-122 expression in endothelial cells was modulated by transfection of miR-122 mimic and inhibitor. Western blotting and co-localization of endothelial markers (VE-cadherin, CD31) and mesenchymal markers (Vimentin, α-SMA) were carried out to determine EndMT. KEY FINDINGS MiR-122 was upregulated in the aortic intima and serum of ApoE-/- mice induced by HFD and in cellular EndMT model. Inhibition of miR-122 repressed the atherosclerotic plaque progression and vulnerable plaque formation in ApoE-/- mice. In vitro, endothelial cells acquired a spindle-shaped morphology accompanying decrease of the endothelial markers (VE-cadherin, CD31) and increase of the mesenchymal markers (Vimentin, α-SMA) in the presence of H2O2, which was inhibited by miR-122 inhibitor. Furthermore, NPAS3 functions as a target of miR-122, and NPAS3 silencing abolished the anti-EndMT effect of miR-122 inhibitor. SIGNIFICANCE Inhibition of miR-122 prevents atherosclerosis and regulates NPAS3-mediated EndMT, suggesting that miR-122 may be a novel target in the treatment of EndMT-associated diseases including atherosclerosis.
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Wang S, Shuai C, Gao S, Jiang J, Luan J, Lv X. Chemokine CXCL14 acts as a potential genetic target for liver fibrosis. Int Immunopharmacol 2020; 89:107067. [PMID: 33039963 DOI: 10.1016/j.intimp.2020.107067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022]
Abstract
There are multiple causes of liver fibrosis, common ones include ethanol, toxins, and cholestasis. However, whether these different etiologies lead to the same pathological outcomes contain common genetic targets or signaling pathways, the current research has not attracted widespread attention. GSE40041 and GSE55747 were downloaded from the Gene Expression Omnibus (GEO) database. GSE40041 and GSE55747 represent the differential expression profiles in the liver of mice with bile duct ligation (BDL) and carbon tetrachloride (CCl4) induced liver fibrosis models, respectively. By using GEO2R, 701 differential expression genes (DEGs) in GSE40041 and 6540 DEGs in GSE55747 were identified. 260 co-DEGs were shared and extracted for gene ontology (GO) analysis. Through GO analysis, it was found that the regulation of cell migration in biological processes (BPs) was closely related to the pathogenesis of liver fibrosis, and the genes involved in this process include a key gene, chemokine (C-X-C motif) ligand 14 (CXCL14). Subsequently, further bioinformatic analysis showed that CXCL14 may be regulated by miR-122 to participate in the progression of liver fibrosis. Then real-time PCR and western blotting were performed to validate the expression of CXCL14 in liver tissue after liver fibrosis caused by different etiologies (ethanol, CCl4). The expression of CXCL4 in liver fibrosis induced by BDL was verified in another GEO dataset. Basically consistent with our bioinformatics results, our experimental results showed that the expression of CXCL14 was most significantly increased in alcoholic liver fibrosis model, followed by CCl4-induced liver fibrosis, which was also significantly increased in the BDL-induced model. Thus, CXCL14 can act as a common potential genetic target for different liver fibrosis diseases.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Chen Shuai
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Jia Jiang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China.
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China.
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26
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Zhu Z, Xu X, Wang F, Song Y, Zhu Y, Quan W, Zhang X, Bi C, He H, Li S, Li X. Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice. Mol Med Rep 2020; 22:3367-3377. [PMID: 32945497 PMCID: PMC7453650 DOI: 10.3892/mmr.2020.11444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 05/29/2020] [Indexed: 12/13/2022] Open
Abstract
In acute aristolochic acid nephropathy (AAN), aristolochic acid (AA) induces renal injury and tubulointerstitial fibrosis. However, the roles of microRNAs (miRNAs/miRs) and mRNAs involved in AAN are not clearly understood. The aim of the present study was to examine AA‑induced genome‑wide differentially expressed (DE) miRNAs and DE mRNAs using deep sequencing in mouse kidneys, and to analyze their regulatory networks. In the present self‑controlled study, mice were treated with 5 mg/kg/day AA for 5 days, following unilateral nephrectomy. AA‑induced renal injury and tubulointerstitial fibrosis were detected using hematoxylin and eosin staining and Masson's trichrome staining in the mouse kidneys. A total of 82 DE miRNAs and 4,605 DE mRNAs were identified between the AA‑treated group and the self‑control group. Of these DE miRNAs and mRNAs, some were validated using reverse transcription‑quantitative PCR. Expression levels of the profibrotic miR‑21, miR‑433 and miR‑132 families were significantly increased, whereas expression levels of the anti‑fibrotic miR‑122‑5p and let‑7a‑1‑3p were significantly decreased. Functions and signaling pathways associated with the DE miRNAs and mRNAs were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 767 DE pairs (in opposing directions) of miRNAs and their mRNA targets were identified. Among these, regulatory networks of miRNAs and mRNAs were analyzed using KEGG to identify enriched signaling pathways and extracellular matrix‑associated pathways. In conclusion, the present study identified genome‑wide DE miRNAs and mRNAs in the kidneys of AA‑treated mice, as well as their regulatory pairs and signaling networks. The present results may improve the understanding of the role of DE miRNAs and their mRNA targets in the pathophysiology of acute AAN.
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Affiliation(s)
- Ziqiang Zhu
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xinxing Xu
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Fengying Wang
- Department of Pediatrics, Sir Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China
| | - Yongrui Song
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yanping Zhu
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Wei Quan
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xueli Zhang
- Centre for Systems Biology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
- School of Medicine, Institute of Medical Sciences, Örebro University, SE-70182 Örebro, Sweden
| | - Cheng Bi
- Centre for Systems Biology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Hongxin He
- Centre for Systems Biology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Shuang Li
- Centre for Systems Biology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xiaozhong Li
- Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Green Tea Prevents NAFLD by Modulation of miR-34a and miR-194 Expression in a High-Fat Diet Mouse Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4168380. [PMID: 31885789 PMCID: PMC6914886 DOI: 10.1155/2019/4168380] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 10/11/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023]
Abstract
Background/Aims Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. It is currently the most common chronic liver disease with complex pathogenesis and challenging treatment. Here, we investigated the hepatoprotective role of green tea (GT) and determined the involvement of miRNAs and its mechanism of action. Methods Male C57Bl/6 mice were fed with a high-fat diet for 4 weeks. After this period, the animals received gavage with GT (500 mg/kg body weight) over 12 weeks (5 days/week). HepG2 cell lines were transfected with miR-34a or miR-194 mimetics and inhibitors to validate the in vivo results or were treated with TNF-α to evaluate miRNA regulation. Results GT supplementation protects against NAFLD development by altering lipid metabolism, increasing gene expression involved in triglycerides and fatty acid catabolism, and decreasing uptake and lipid accumulation. This phenotype was accompanied by miR-34a downregulation and an increase in their mRNA targets Sirt1, Pparα, and Insig2. GT upregulated hepatic miR-194 by inhibiting TNF-α action leading to a decrease in miR-194 target genes Hmgcs/Apoa5. Conclusion Our study identified for the first time that the beneficial effects of GT in the liver can be due to the modulation of miRNAs, opening new perspectives for the treatment of NAFLD focusing on epigenetic regulation of miR-34a and miR-194 as green tea targets.
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Pennisi G, Celsa C, Giammanco A, Spatola F, Petta S. The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives. Int J Mol Sci 2019; 20:ijms20225613. [PMID: 31717576 PMCID: PMC6887792 DOI: 10.3390/ijms20225613] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023] Open
Abstract
In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonography with or without alpha-fetoprotein (AFP) in patients with advanced fibrosis. Furthermore, the use of non-invasive tools could represent a strategy to implement surveillance performance. In this review, we analyzed the main risk factors of NAFLD-related HCC, the validated screening methods and the future perspectives.
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Affiliation(s)
- Grazia Pennisi
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
- Correspondence: (G.P.); (S.P.); Tel.: +39-0916552170 (G.P.); +39-0916552170 (S.P.)
| | - Ciro Celsa
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
| | - Antonina Giammanco
- Sezione di Astanteria e MCAU, PROMISE, University of Palermo, 90127 Palermo, Italy;
| | - Federica Spatola
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
| | - Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, 90127 Palermo, Italy; (C.C.); (F.S.)
- Correspondence: (G.P.); (S.P.); Tel.: +39-0916552170 (G.P.); +39-0916552170 (S.P.)
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Derakhshanfar A, Moayedi J, Vahedi M, Valizadeh A. Arum conophalloides Aqueous Extract Induced Hepatotoxicity in Rat; Histopathological, Biochemical, and mir-122 Assessments. Microrna 2019; 9:224-231. [PMID: 31622226 PMCID: PMC7366011 DOI: 10.2174/2211536608666191016142400] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 07/17/2019] [Accepted: 08/07/2019] [Indexed: 11/29/2022]
Abstract
Background Arum conophalloides (A. conophalloides) is a wild edible delicate plant, widely used in traditional medicine. Objective This study aimed to examine the effects of A. conophalloides extracts on biochemical, molecular, and histopathological changes in the rat. Methods Fifty adult male Sprague-Dawley rats were divided into 5 groups (10 each) as follows: G1 or control, received distilled water; G2 and G3, treated with the aqueous extract at doses of 200 and 400 mg/kg; G4 and G5, treated with the hydroalcoholic extract at doses of 200 and 400 mg/kg. Prior to and at the end of the experiments, the serum levels of biochemistry parameters and the relative expression of miR-122 were assessed. Moreover, the liver and kidney tissues were examined microscopically. Results Liver and kidney tissues showed normal structure in all groups. There were no significant changes in biochemical indices or the expression of miR-122 in the extract-treated groups at the dose of 200 mg/kg. However, the group that received the aqueous extract at the dose of 400 mg/kg exhibited a significantly lower level of HDL, LDL, ALT, and ALP in comparison to the control. Additionally, miR-122 expression in this group exhibited a 10-fold increase (P=0.009). Conclusion The serum level of hepatocyte-specific miR-122 will be more helpful in detecting hepatic changes in early stages than ALT and AST activity or histopathological evaluations of liver sections. Our findings highlight the potential hepatotoxicity of A. conophalloides aqueous extract in a rat model.
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Affiliation(s)
- Amin Derakhshanfar
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Moayedi
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahjoob Vahedi
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abouzar Valizadeh
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Khatun M, Ray RB. Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis. Cells 2019; 8:E1249. [PMID: 31615075 PMCID: PMC6829586 DOI: 10.3390/cells8101249] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/11/2019] [Accepted: 10/12/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.
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Affiliation(s)
- Mousumi Khatun
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
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El-Ahwany EGE, Mourad L, Zoheiry MMK, Abu-Taleb H, Hassan M, Atta R, Hassanien M, Zada S. MicroRNA-122a as a non-invasive biomarker for HCV genotype 4-related hepatocellular carcinoma in Egyptian patients. Arch Med Sci 2019; 15:1454-1461. [PMID: 31749873 PMCID: PMC6855160 DOI: 10.5114/aoms.2019.86621] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/22/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection persists in most infected individuals and can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have a crucial role in various liver diseases, especially HCC. The expression profiles of circulating microRNAs have been studied aiming at the identification of novel non-invasive biomarkers. This study aims to develop a non-invasive diagnostic tool based on measuring the serum levels of different miRNAs in order to detect HCV-induced HCC at the early stages of the disease. MATERIAL AND METHODS Five main miRNAs (miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a) were selected according to the literature that demonstrated their unique expression pattern during HCC development. Serum samples were collected from 42 cases of chronic hepatitis C (CHC) without cirrhosis, 45 cases of CHC with cirrhosis (LC), 38 cases of HCC with HCV, and 40 healthy individuals serving as a control. The five miRNAs were measured using real-time reverse transcription PCR. The conventional HCC markers α-fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) were measured with commercial kits. RESULTS Serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a were significantly lower (p < 0.01) in HCC than in CHC and LC groups. As a single marker, miRNA-122a had the highest sensitivity for HCC, followed by miRNA-199a, miRNA-145, miRNA-139, and miRNA-125a. CONCLUSIONS These findings indicate that measurement of serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a can differentiate HCC from CHC and LC. Our results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for HCV-induced HCC.
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Affiliation(s)
| | - Lobna Mourad
- Department of Biology, The American University, Cairo, Egypt
| | - Mona M. K. Zoheiry
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Hoda Abu-Taleb
- Department of Environmental Research, Theodor Bilharz Research Institute, Giza, Egypt
| | - Marwa Hassan
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Raafat Atta
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Moataz Hassanien
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Suher Zada
- Department of Biology, The American University, Cairo, Egypt
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Li J, Qiyu S, Wang T, Jin B, Li N. Improving the Detection of Hepatocellular Carcinoma Using Serum AFP Expression in Combination with GPC3 and Micro-RNA MiR-122 Expression. Open Life Sci 2019; 14:53-61. [PMID: 33817137 PMCID: PMC7874791 DOI: 10.1515/biol-2019-0007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 01/14/2019] [Indexed: 12/11/2022] Open
Abstract
Early diagnosis of hepatocellular carcinoma (HCC) greatly improves the survival and prognosisfor patients. In this study weevaluate the diagnostic promise of combining serum alpha-fetoprotein (AFP) expression with two potential biomarkers, serum glypican-3 (GPC3) and expression of the micro-RNA miR-122 for hepatitis C virus (HCV) related early-stage HCC. For this study serum samples from 47 patients with early-stage HCC, 54 chronic HCV (CH) carriers, 35 patients with liver cirrhosis (LC) and 54 health controls (HC) were collected. In addition to routine laboratory investigations, serum AFP, GPC3 and miR-122 were measured in all patients and healthy controls. Receiver operating characteristic (ROC) curves were used to present sensitivity and specificity for the biomarkers. The three markers were all significantly elevated in the serum samples from HCC patients. ROC curves showed the three markers had similar diagnostic capacities for distinguishing early-stage HCC from HCV-positive controls (LC + CH). In order to distinguish early-stage HCC from high-risk LC patients, the expression of miR-122 was superior to GPC3. Combination of the three markers as a panel showed a better diagnostic performance than any of the single markers (P <0.05). Overall, this study revealed that serum expression of GPC3 and miR-122 may be useful biomarkers to combine with serum AFP expression for the diagnosis of HCV related early-stage HCC.
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Affiliation(s)
- Jian Li
- Department of Hepatobiliary Surgery, Hospital Affiliated to Chengde Medical University, 36 Nanyingzi Road, Chengde, 067000, China
| | - Sun Qiyu
- Department of Hepatobiliary Surgery, Hospital Affiliated to Chengde Medical University, 36 Nanyingzi Road, Chengde, 067000, China
| | - Tiezheng Wang
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
| | - Boxun Jin
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
| | - Ning Li
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
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Nan Y, Niu X, Wang R, Zhao S, Fu N, Du J, Wang Y, Wang B, Zhang Y. microRNA-1273g-3p is a useful non-invasive test for the prediction of liver fibrosis in patients with chronic hepatitis C. Exp Ther Med 2019; 17:1817-1824. [PMID: 30783454 PMCID: PMC6364236 DOI: 10.3892/etm.2018.7114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 07/07/2017] [Indexed: 12/12/2022] Open
Abstract
Previous studies using microRNA (miRNA or miR) microarrays have demonstrated that miR-1273g-3p is upregulated in patients with hepatitis C virus (HCV)-associated fibrosis. As miRNAs have been suggested to be promising non-invasive biomarkers, the aim of the present study was to assess whether miR-1273g-3p may be useful as a potential indicator of fibrosis progression in patients with HCV. Liver biopsies were performed on 112 patients with chronic hepatitis C (CHC) and liver stiffness measurements (LSM) were performed using FibroTouch. Liver fibrosis was determined based on Meta-analysis of Histological Data in Viral Hepatitis classification, and the aspartate aminotransferase (AST)-to-platelet count (PLT) ratio index (APRI) and Fibrosis-4 score (FIB-4) were calculated. The diagnostic performance of miR-1273g-3p, LSM, APRI and FIB-4 in predicting fibrosis stage were evaluated and compared by receiver operating characteristic (ROC) analysis. It was demonstrated that miR-1273g-3p levels were significantly positively correlated with the liver fibrosis stage (r=0.657, P<0.001). The results of LSM, APRI and FIB-4, the three non-invasive diagnostic methods, had good consistency with liver biopsy results, and their correlation coefficients with fibrosis staging were 0.815, 0.417 and 0.522, respectively. The areas under the ROC curves of miR-1273g-3p for F≥2 and F=4 stage samples were 0.841 and 0.933, respectively, which were lower than LSM (0.890 and 0.937), and higher than FIB-4 (0.791 and 0.766) and APRI (0.719 and 0.760). Spearman analysis demonstrated that serum miR-1273g-3p levels were significantly positively correlated with age, body mass index, alanine aminotransferase, AST and total bilirubin (all P<0.05), and negatively correlated with PLT (P<0.05). However, no significant correlation was observed between miR-1273g-3p levels, baseline HCV RNA loads and genotype. Therefore, the results demonstrated that miR-1273g-3p levels, as a novel non-invasive test, may be a useful and easy method for predicting the stage of liver fibrosis in patients with CHC, and has a better diagnostic performance than FIB-4 and APRI. Further prospective studies are required to validate the efficacy of miR-1273g-3p as a predictor of liver fibrosis.
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Affiliation(s)
- Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
- Correspondence to: Professor Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050051, P.R. China, E-mail:
| | - Xuemin Niu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Rongqi Wang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Suxian Zhao
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Na Fu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Jinghua Du
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Yang Wang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Baoyu Wang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Yuguo Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
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Di Ciaula A, Wang DQH, Portincasa P. Cholesterol cholelithiasis: part of a systemic metabolic disease, prone to primary prevention. Expert Rev Gastroenterol Hepatol 2019; 13:157-171. [PMID: 30791781 DOI: 10.1080/17474124.2019.1549988] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease have relationships with various conditions linked with insulin resistance, but also with heart disease, atherosclerosis, and cancer. These associations derive from mechanisms active at a local (i.e. gallbladder, bile) and a systemic level and are involved in inflammation, hormones, nuclear receptors, signaling molecules, epigenetic modulation of gene expression, and gut microbiota. Despite advanced knowledge of these pathways, the available therapeutic options for symptomatic gallstone patients remain limited. Therapy includes oral litholysis by the bile acid ursodeoxycholic acid (UDCA) in a small subgroup of patients at high risk of postdissolution recurrence, or laparoscopic cholecystectomy, which is the therapeutic radical gold standard treatment. Cholecystectomy, however, may not be a neutral event, and potentially generates health problems, including the metabolic syndrome. Areas covered: Several studies on risk factors and pathogenesis of cholesterol gallstone disease, acting at a systemic level have been reviewed through a PubMed search. Authors have focused on primary prevention and novel potential therapeutic strategies. Expert commentary: The ultimate goal appears to target the manageable systemic mechanisms responsible for gallstone occurrence, pointing to primary prevention measures. Changes must target lifestyles, as well as experimenting innovative pharmacological tools in subgroups of patients at high risk of developing gallstones.
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Affiliation(s)
- Agostino Di Ciaula
- a Division of Internal Medicine , Hospital of Bisceglie , Bisceglie , Italy
| | - David Q-H Wang
- b Department of Medicine, Division of Gastroenterology and Liver Diseases , Marion Bessin Liver Research Center, Albert Einstein College of Medicine , Bronx , NY , USA
| | - Piero Portincasa
- c Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri" , University of Bari Medical School , Bari , Italy
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Sciveres M, Nastasio S, Maggiore G. Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis. Front Pediatr 2019; 7:382. [PMID: 31616649 PMCID: PMC6763601 DOI: 10.3389/fped.2019.00382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.
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Affiliation(s)
- Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy
| | - Silvia Nastasio
- Division of Gastroenterology, Hepatology, and Nutrition, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Giuseppe Maggiore
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy.,Section of Pediatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis. Int J Mol Sci 2018; 19:E3966. [PMID: 30544653 PMCID: PMC6320931 DOI: 10.3390/ijms19123966] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/03/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
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Taubert R, Hupa-Breier KL, Jaeckel E, Manns MP. Novel therapeutic targets in autoimmune hepatitis. J Autoimmun 2018; 95:34-46. [DOI: 10.1016/j.jaut.2018.10.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 02/07/2023]
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Chen QQ, Zhang C, Qin MQ, Li J, Wang H, Xu DX, Wang JQ. Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice. Front Pharmacol 2018; 9:1344. [PMID: 30538632 PMCID: PMC6277551 DOI: 10.3389/fphar.2018.01344] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/31/2018] [Indexed: 12/12/2022] Open
Abstract
Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.
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Affiliation(s)
- Qian-Qian Chen
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Cheng Zhang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Ming-Qiang Qin
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Jian Li
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - De-Xiang Xu
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Jian-Qing Wang
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
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MicroRNA Expression in Focal Nodular Hyperplasia in Comparison with Cirrhosis and Hepatocellular Carcinoma. Pathol Oncol Res 2018; 25:1103-1109. [PMID: 30411298 DOI: 10.1007/s12253-018-0528-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
Abstract
The liver disease focal nodular hyperplasia (FNH) has several histological features that resemble hepatic cirrhosis. Since cirrhosis may develop further into hepatocellular carcinoma (HCC) contrary to FNH, the aim of the present study was to identify microRNAs (miRNA), which, by their altered expression levels, may be associated with the benign, tumor-like nature of FNH. Altogether 106 surgically removed formalin-fixed paraffin-embedded liver samples were selected, including 22 FNH, 45 cirrhosis, 24 HCC and 15 normal liver tissues. Etiology of the cases of cirrhosis and HCC includes hepatitis C and alcoholism and the HCC cases developed in cirrhotic livers. Relative expression levels of 14 miRNAs were determined using TaqMan MicroRNA Assays. In comparison to normal liver, the levels of miR-34a and miR-224 were elevated not only in FNH but also in cirrhosis and HCC, while the expression of miR-17-5p, miR-18a and miR-210 was decreased in FNH. Further, the levels of miR-21 and miR-222 were increased in cirrhosis and HCC but were decreased in FNH and the expression of miR-17-5p, miR-18a, miR-195 and miR-210 was decreased in FNH as compared with cirrhosis and/or HCC. In conclusion, the elevation of miR-34a and miR-224 may be associated with both benign and malignant proliferative processes, nevertheless the increased expression of oncomiRs miR-21 and miR-222 in cirrhosis and HCC but not in FNH may be related to malignant processes of the liver. The decreased levels of miR-18a, miR-195 and miR-210 may further differentiate FNH from cirrhosis, reflecting the different pathogenesis of these two entities contrary to some histologically similar features.
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40
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Ma L, Zhao J, Xie X. Sevoflurane induces liver injury by modulating the expression of insulin-like growth factor 1 via miR-214. J Cell Physiol 2018; 233:6742-6749. [PMID: 29226348 DOI: 10.1002/jcp.26382] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 12/04/2017] [Indexed: 12/14/2022]
Abstract
This study aimed to detect the effect of sevoflurane anesthesia on liver injury through modulating IGF-1. The expression of IGF-1 and IGF-1R in liver tissues of sevoflurane-exposed rats was examined by qRT-PCR and Western blot. The expression levels of miR-214 in liver cells treated with different concentration of sevoflurane at different time points were detected by qRT-PCR. Enzyme-linked immunosorbent (ELISA) assay was used to analyze serum IGF-1 concentration in cell culture media. After pre-treatment with 100 nM miR-214 inhibitor followed by exposure to sevoflurane, the expression level of miR-214 and IGF-1 protein in liver cells was examined. Hematoxylin-Eosin (HE) staining and TUNEL assay was performed to analyze liver tissue necrosis and apoptosis. The expression levels of apoptosis-related proteins (caspase 3 and Bcl-xL) were examined using Western blot. The mRNA and protein expression level of IGF-1 and IGF-1R in rats was significantly down-regulated after 90 min exposure to sevoflurane. QRT-PCR results suggested that exposure to sevoflurane upregulated the expression level of miR-214 and decreased the concentration of IGF-1 in a dose and time dependent manner. Sevoflurane inhibited the expression of IGF-1 through up-regulating miR-214. IGF-1 inhibited the positive effect of sevoflurane on cell necrosis and apoptosis. Sevoflurane could induce liver injury by modulating IGF-1 expression via miR-214.
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Affiliation(s)
- Ligang Ma
- Department of Anesthesia, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China
| | - Jingjing Zhao
- Department of Outpatient, Luoyang DongFang Hospital, The Third Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
| | - Xiaojuan Xie
- Department of Anesthesia, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China
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Attallah AM, Omran D, Omran MM, Abdelrazek MA, Zayed R, Essawey RE, Saif S, Farid A, Hassany M, Yosry A, Omar A. Extracellular Matrix Proteins Substantiate IL-28B T allele Effect on Histological Outcome of Chronic Hepatitis C. Ann Hepatol 2018; 17:569-576. [PMID: 29893697 DOI: 10.5604/01.3001.0012.0918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM The correlation between interleukin-28B (IL-28B) polymorphisms and chronic hepatitis C (CHC) progression is debatable. Here, we aimed to evaluate the relation between IL-28B C/T genotypes and the development of cirrhotic liver. Extracellular matrix (ECM) proteins, FibroScan and model for end-stage liver disease (MELD) were used to substantiate the severity of liver disease. MATERIAL AND METHODS IL-28B rs12979860, liver stiffness and ECM proteins were assessed in 272 CHC patients. RESULTS Cirrhosis percentage increased to 10%, 52% and 96% with the increasing number of T alleles (CC, CT and TT, respectively). Also, elevated ECM proteins levels were correlated with the increasing number of T alleles. Interestingly, among cirrhotic patients, liver stiffness, MELD and ECM proteins were significantly (P < 0.0001) higher in patients with TT more than CT genotype. FibroScan, hyaluronic acid, Laminin, Collagen IV and the N-terminal pro-peptide of collagen type III have high accuracy to differentiate liver status in CC from TT genotype. Area under receiver-operating characteristic curve (95% CI) were 1.0 (1.0-1.0), 0.97 (0.96- 1.0), 0.93 (0.85-1.0), 0.98 (0.97-1.0) and 0.93 (0.91-0.97), respectively. CONCLUSION This study suggests that IL-28B T allele affects the natural course of CHC type 4 and also suggests that carriage of the IL-28B C allele protects from unfavorable clinical outcomes in CHC as coexistence of C allele with T allele reduced cirrhosis severity.
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Affiliation(s)
- Abdelfattah M Attallah
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | | | - Mohamed A Abdelrazek
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Rania Zayed
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Riham El Essawey
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Sameh Saif
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Azza Farid
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Omar
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
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Suehiro T, Miyaaki H, Kanda Y, Shibata H, Honda T, Ozawa E, Miuma S, Taura N, Nakao K. Serum exosomal microRNA-122 and microRNA-21 as predictive biomarkers in transarterial chemoembolization-treated hepatocellular carcinoma patients. Oncol Lett 2018; 16:3267-3273. [PMID: 30127924 DOI: 10.3892/ol.2018.8991] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 05/22/2018] [Indexed: 12/13/2022] Open
Abstract
Exosomal microRNAs (miRNAs) have been investigated as potential novel biomarkers, and miR-122 and miR-21 were shown to be important in hepatocellular carcinoma (HCC). We analyzed the importance of serum exosomal miRNA expression levels in HCC patients that underwent transarterial chemoembolization (TACE). Seventy-five HCC patients who underwent TACE as the initial treatment in Nagasaki University Hospital were enrolled. Exosomal miRNAs were isolated from serum samples collected before and after TACE. Exosomal miR-122 expression levels significantly decreased after TACE (P=0.012), while the exosomal miR-21 expression levels did not significantly change. The expression levels of exosomal miR-122 before TACE were shown to correlate significantly with aspartate aminotransferase (r=0.31, P=0.004) and alanine aminotransferase (r=0.33, P=0.003) levels, tumor diameter (r=0.29, P=0.010) and Child-Pugh score (r=-0.28, P=0.013). The median survival time for all patients was 47 months, and neither of the investigated exosomal miRNAs were shown to be independent factors associated with the disease-specific survival. According to the median relative expression of miR-122 after TACE/before TACE (miR-122 ratio) in liver cirrhosis patients (n=57), the patients with a higher miR-122 ratio had significantly longer disease-specific survival, compared with that of the patients with the lower miR-122 ratio (P=0.0461). Multivariate Cox proportional hazards regression analysis of clinical parameters revealed that a lower exosomal miR-122 ratio (HR 2.720; 95% confidence interval, 1.035-8.022; P=0.042) is associated with the disease-specific survival. Taken together, our results demonstrate that the exosomal miR-122 level alterations may represent a predictive biomarker in HCC patients with liver cirrhosis treated with TACE.
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Affiliation(s)
- Tomoyuki Suehiro
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yasuko Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takuya Honda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Eisuke Ozawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Czaja AJ. Emerging therapeutic biomarkers of autoimmune hepatitis and their impact on current and future management. Expert Rev Gastroenterol Hepatol 2018. [PMID: 29540068 DOI: 10.1080/17474124.2018.1453356] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis lacks a quantifiable biomarker that is close to its pathogenic mechanisms and that accurately reflects inflammatory activity, correlates with treatment response, and ensures inactive disease before treatment withdrawal. Areas covered: Micro-ribonucleic acids, programmed death-1 protein and its ligands, macrophage migration inhibitory factor, soluble CD163, B cell activating factor, and metabolite patterns in blood were considered the leading candidates as therapeutic biomarkers after search of PubMed from August 1981 to August 2017 using the search words 'biomarkers of autoimmune hepatitis'. Expert commentary: Each of the candidate biomarkers is close to the putative pathogenic mechanisms of autoimmune hepatitis, and each has attributes that support its potential role as a surrogate marker of inflammatory activity that can be monitored during treatment. Future studies must demonstrate the superiority of each biomarker to conventional indices of inflammatory activity and validate their correlation with treatment response and outcome. A reliable therapeutic biomarker would facilitate the individualization of current management algorithms, ensure that pathogenic mechanisms were disrupted or eliminated prior to treatment withdrawal, and reduce the frequency of relapse or unnecessary protracted therapy. The biomarker might also prove to be a target of next-generation therapies.
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Affiliation(s)
- Albert J Czaja
- a Division of Gastroenterology and Hepatology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA
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44
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Zhu D, Lyu L, Shen P, Wang J, Chen J, Sun X, Chen L, Zhang L, Zhou Q, Duan Y. rSjP40 protein promotes PPARγ expression in LX-2 cells through microRNA-27b. FASEB J 2018; 32:4798-4803. [PMID: 29608331 DOI: 10.1096/fj.201700520rr] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
miR-27b is reported to participate in the proliferation and differentiation of hepatic stellate cells (HSCs) and to regulate fat metabolism of rat HSCs by targeting retinoid X receptor α. Our previous study also indicated that the recombinant P40 protein from Schistosoma japonicum (rSjP40) inhibited the activation of HSCs. In this study, we observed the expression of miR-27b in rSjP40-treated LX-2 cells and explored its potential mechanisms. Quantitative real-time PCR showed that rSjP40 inhibits the expression of miR-27b in LX-2 cells. Further results obtained by Western blot and dual-luciferase reporter assay confirmed that miR-27b regulates peroxisome proliferator-activated receptor γ (PPARγ) expression in rSjP40-treated LX-2 cells by targeting the 3'-UTR of PPARγ. 5-AZA-2'-deoxycytidine (5-AZA-dC), which inhibits methylation of HSCs, partially reversed rSjP40-induced down-regulation expression of miR-27b in LX-2 cells. 5-AZA-dC also partially reversed rSjP40-induced up-regulation expression of PPARγ in LX-2 cells. The increased expression of PPARγ in rSjP40-treated LX-2 cells may be partially due to miR-27b methylation. Therefore, our study provides further insight into the mechanism by which rSjP40 inhibits HSC activation and provides a basis for future study of the blocking effect of rSjP40 in liver fibrosis.-Zhu, D., Lyu, L., Shen, P., Wang, J., Chen, J., Sun, X., Chen, L., Zhang, L., Zhou, Q., Duan, Y. rSjP40 protein promotes PPARγ expression in LX-2 cells through microRNA-27b.
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Affiliation(s)
- Dandan Zhu
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Lei Lyu
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China.,Nanjing Red Cross Blood Center, Nanjing, China; and
| | - Pei Shen
- Laboratory Medicine Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianxin Wang
- Laboratory Medicine Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Jinling Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Xiaolei Sun
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Liuting Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Li Zhang
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Qi Zhou
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
| | - Yinong Duan
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, China
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Zhai X, Cheng F, Ji L, Zhu X, Cao Q, Zhang Y, Jia X, Zhou Q, Guan W, Zhou Y. Leptin reduces microRNA-122 level in hepatic stellate cells in vitro and in vivo. Mol Immunol 2017; 92:68-75. [PMID: 29054053 DOI: 10.1016/j.molimm.2017.10.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 12/13/2022]
Abstract
Obese patients, often accompanied by hyperleptinemia, are more likely to develop liver fibrosis. Leptin, an adipocyte-derived hormone, augments inflammatory in liver and promotes hepatic stellate cell (HSC) activation (a key step for liver fibrogenesis) and liver fibrosis. microRNA-122 (miR-122) is the most abundant liver-specific miRNA and can attenuate liver fibrosis. This study examined the effect of leptin on miR-122 level in HSCs in vivo and in vitro. Results demonstrated that leptin reduced the levels of both miR-122 (mature miR-122) and primary miR-122 (pri-miR-122). The effects of leptin on the levels of miR-122 and pri-miR-122 were through at least hedgehog pathway. Leptin-induced decrease in sterol regulatory element-binding protein-1c (SREBP-1c) has been shown to contribute to leptin-induced HSC activation. We revealed a mutual promotional effect between SREBP-1c and miR-122. Further experiments indicated that miR-122 inhibited leptin-induced liver fibrosis in leptin-deficient mouse model. These data have potential implications for clarifying the mechanisms of hepatic fibrogenesis associated with elevated leptin level in human such as obese patients.
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Affiliation(s)
- Xuguang Zhai
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Fangyun Cheng
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Li Ji
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Xiaofei Zhu
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Qing Cao
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Yali Zhang
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Xin Jia
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Qian Zhou
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Wei Guan
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China
| | - Yajun Zhou
- Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
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Lou G, Yang Y, Liu F, Ye B, Chen Z, Zheng M, Liu Y. MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J Cell Mol Med 2017; 21:2963-2973. [PMID: 28544786 PMCID: PMC5661245 DOI: 10.1111/jcmm.13208] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/11/2017] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation alone may be insufficient for treatment of liver fibrosis because of complicated histopathological changes in the liver. Given that miR‐122 plays an essential role in liver fibrosis by negatively regulating the proliferation and transactivation of hepatic stellate cells (HSCs), this study investigated whether miR‐122 modification can improve the therapeutic efficacy of adipose tissue‐derived MSCs in treating liver fibrosis. MiR‐122‐modified AMSCs (AMSC‐122) were constructed through lentivirus‐mediated transfer of pre‐miR‐122. MiR‐122‐modified AMSCs expressed high level of miR‐122, while they retained their phenotype and differentiation potential as naïve AMSCs. AMSC‐122 more effectively suppressed the proliferation of and collagen maturation in HSCs than scramble miRNA‐modified AMSCs. In addition, AMSC‐derived exosomes mediated the miR‐122 communication between AMSCs and HSCs, further affecting the expression levels of miR‐122 target genes, such as insulin‐like growth factor receptor 1 (IGF1R), Cyclin G(1) (CCNG1) and prolyl‐4‐hydroxylase α1 (P4HA1), which are involved in proliferation of and collagen maturation in HSCs. Moreover, miR‐122 modification enhanced the therapeutic efficacy of AMSCs in the treatment of carbon tetrachloride (CCl4)‐induced liver fibrosis by suppressing the activation of HSCs and alleviating collagen deposition. Results demonstrate that miR‐122 modification improves the therapeutic efficacy of AMSCs through exosome‐mediated miR‐122 communication; thus, miR‐122 modification is a new potential strategy for treatment of liver fibrosis.
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Affiliation(s)
- Guohua Lou
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Yang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feifei Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bingjue Ye
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhi Chen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Yan Y, Deng X, Ning X, Li F, Cao J. Pathogenic mechanism of miR-21 in autoimmune lymphoid hyperplasia syndrome. Oncol Lett 2017; 13:4734-4740. [PMID: 28588726 PMCID: PMC5452897 DOI: 10.3892/ol.2017.6039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 01/19/2017] [Indexed: 11/30/2022] Open
Abstract
miR-21 plays an important role in immune responses and inflammatory diseases, but the mechanism of action of miR-21 in autoimmune lymphoid hyperplasia syndrome still remains unclear. The aim of the present study was to assess the mechanism of miR-21 in autoimmune disease, particularly, the autoimmune lymphoid hyperplasia syndrome. The pathology and immunity-related phenotypes of miR-21 transgenic mice, and the lymphocyte subsets were analyzed. The related T cell subsets and germinal center B (GCB) cells generated at the germinal center were detected with flow cytometry. The target genes of miR-21 were evaluated with the luciferase reporter gene method. The homeostatic proliferation of the lymphocytes was detected with the EdU incorporation assay. Inflammatory infiltration occurred to the lung and liver of the transgenic mice at 8 weeks. The frequency of the regulatory helper T cells decreased slightly. Significantly increased double negative T cells were observed in the spleen of the transgenic mice (P<0.05). The immunoglobulins IgG1, IgG2a, IgG2b, and IgG3 in the serum of the transgenic mice aged 8 weeks were significantly higher than those in the wild-type mice aged 8 weeks (P<0.05). The percentages of the GCB cells in the peripheral lymphoid organs such as lymph nodes, mesenteric lymph nodes, PP and spleen in the transgenic mice aged 8–52 weeks increased significantly (P<0.05). The percentage (26.32%) of the newly-formed GCB cells derived from transgenic mice was significantly higher than that (3.87%) of the GCB cells derived from the wild-type mice. miR-21 played a role of negative feedback regulation by inhibiting the NF-κB signal pathway. The highly-expressed miR-21 B cells promoted homeostatic proliferation of the T cells. miR-21 can promote homeostatic proliferation of lymphocytes by inhibiting the NF-κB signal pathway.
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Affiliation(s)
- Yonglong Yan
- Department of Rheumatology, Hebei Province General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xinna Deng
- Department of Medical Oncology, Hebei Province General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xiaoran Ning
- Department of Rheumatology, Hebei Province General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Fang Li
- Department of Rheumatology, Hebei Province General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Jingjing Cao
- Department of Rheumatology, Hebei Province General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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Ding W, Yang H, Gong S, Shi W, Xiao J, Gu J, Wang Y, He B. Candidate miRNAs and pathogenesis investigation for hepatocellular carcinoma based on bioinformatics analysis. Oncol Lett 2017; 13:3409-3414. [PMID: 28521446 PMCID: PMC5431310 DOI: 10.3892/ol.2017.5913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 01/26/2017] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to explore the mechanisms behind the development and progression of hepatocellular carcinoma (HCC) and identify information regarding HCC-related microRNAs (miRNAs) or marker genes for the gene therapy of HCC. Gene expression profile of GSE67882, generated from 4 hepatitis B virus infected HCC tissue samples (HCC group) and 8 chronic hepatitis B tissue samples with no fibrosis (control group) were downloaded from the Gene Expression Omnibus database. The differentially expressed miRNAs functional enrichment and pathway analyses of HCC were revealed, followed by transcription factor-miRNA interaction network construction and analyses. A total of 14 upregulated miRNAs and 16 downregulated miRNAs between HCC and control samples were obtained. Differentially expressed miRNAs were mainly involved in biological processes like the regulation of histone H3-K9 methylation, and the KEGG pathways in cancer map05200 demonstrates their involvement in cancer. A total of 3 outstanding regulatory networks of miRNAs: hsa-miR-15a, hsa-miR-125b and hsa-miR-122 were revealed. A total of 11 differentially expressed miRNAs including hsa-miR-146p-5b that regulated the marker genes of HCC were explored. miRNAs such as hsa-miR-15a, hsa-miR-125b, hsa-miR-122 and hsa-miR-146b-5p may be new biomarkers for the gene therapy of HCC. Furthermore, histone H3-K9 methylation and other pathways in cancer observed in the KEGG map05200 may be closely related with the development of HCC.
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Affiliation(s)
- Wenbin Ding
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Haixia Yang
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Shenchu Gong
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Weixiang Shi
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jing Xiao
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, Jiangsu 226019, P.R. China
| | - Jinhua Gu
- Department of Pathophysiology, Nantong University Medical School, Nantong, Jiangsu 226001, P.R. China
| | - Yilang Wang
- Department of Oncology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Bosheng He
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016; 22:10512-10522. [PMID: 28082803 PMCID: PMC5192262 DOI: 10.3748/wjg.v22.i48.10512] [Citation(s) in RCA: 442] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/12/2016] [Accepted: 11/15/2016] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.
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50
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Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016. [PMID: 28082803 DOI: 10.3748/wjg.v22.i48.10512.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.
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Affiliation(s)
- Chong-Yang Zhang
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei-Gang Yuan
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Pei He
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jia-Hui Lei
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Chun-Xu Wang
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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