scholarly journals Liver fibrosis mechanisms – the role of stellate cells, oxidative and nitrosative stress

2019 ◽  
Vol 73 ◽  
pp. 1-19
Author(s):  
Grażyna Czechowska ◽  
Krzysztof Celiński ◽  
Grażyna Wójcicka
Keyword(s):  
Liver Fibrosis ◽  
Proinflammatory Cytokines ◽  
Nitrosative Stress ◽  
Epithelial Mesenchymal Transition ◽  
Cell Cancer ◽  
Stellate Cells ◽  
Biliary Duct ◽  
Oxidative And Nitrosative Stress ◽  
Mesenchymal Transition ◽  
Therapeutic Goals

Liver fibrosis is a chronic and complex pathological process, occuring in patients with chronic liver diseases. The most common cause of liver fibrosis is the alcoholic liver disease, viral hepatitis type B, C and D, as well as autoimmune diseases. Other causes include metabolic dysfunctions like hemachromatosis and Wilson’s disease, biliary duct disorders, damaging effects of medicine and parasite infections. Fibrosis’ dynamics and progres speed depend on the nature of underlying mechanisms and are characterized by accumulation of ECM elements. They vary from patient to patient and are directly correlated to aberrations of homeostasis degradation and production of liver connective tissue. In liver fibrosis the main source of ECM are hepatic stellate cells (HSCS), although other cells are also able to produce ECM such as: portal fibroblasts, narrow-derived cells, biliary duct epithelial cells and epithelial mesenchymal transition hepatocytes. The HSCS activity is stimulated by proinflammatory cytokines, oxidative and nitrosative stress which lead to different pathologies such as: inflammation, steatosis, fibrosis, cirrhosis, liver-cell cancer. Alcohol, the main fibrotic agents is metabolized almost entirely in the liver, so the organ is extremely sensitive to its negative intermediate and mediate influence. Factors influencing alcoholic liver failure are not only oxidative and nitrosative stress and proinflammatory cytokines activity, but also reductive stress, hepatocytes; hypoxia, mucous membranę dysfunction and intestine flora influence, as well as genetic and immunological factors. Though in last several yers there has been a great advancement in our knowledge of liver fibrosis mechanisms, it remains tough to diagnose the proces in its early stages and consequently apply an efficient therapy. The challenge for the futur is finding useful biomarkers and new therapeutic goals.

scholarly journals MicroRNA-30a Suppresses the Activation of Hepatic Stellate Cells by Inhibiting Epithelial-to-Mesenchymal Transition

2018 ◽  
Vol 46 (1) ◽  
pp. 82-92 ◽  
Author(s):  
Jianjian Zheng ◽  
Wei Wang ◽  
Fujun Yu ◽  
Peihong Dong ◽  
Bicheng Chen ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Stellate Cells ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cells ◽  
Fibrotic Liver ◽  
Mesenchymal Transition ◽  
Over Expression

Background/Aims: The activation of hepatic stellate cells (HSCs) is considered as a pivotal event in liver fibrosis and epithelial-mesenchymal transition (EMT) process has been reported to be involved in HSC activation. It is known that microRNAs (miRNAs) play a pro-fibrotic or anti-fibrotic role in HSC activation. Recently, emerging studies show that miR-30a is down-regulated in human cancers and over-expression of miR-30a inhibits tumor growth and invasion via suppressing EMT process. However, whether miR-30a could regulate EMT process in HSC activation is still unclear. Methods: miR-30a expression was quantified using real-time PCR in carbon tetrachloride (CCl4)-induced rat liver fibrosis, activated HSCs and patients with cirrhosis. Roles of miR-30a in liver fibrosis in vivo and in vitro were also analyzed. Luciferase activity assays were performed to examine the binding of miR-30a to the 3′-untranslated region of snail family transcriptional repressor 1 (Snai1). Results: miR-30a was down-regulated in human cirrhotic tissues. In CCl4 rats, reduced miR-30a was found in fibrotic liver tissues as well as isolated HSCs. There was a significant reduction in miR-30a in primary HSCs during culture days. miR-30a over-expression resulted in the suppression of CCl4-induced liver fibrosis. Restoration of miR-30a led to the inhibition of HSC activation including cell proliferation, α-SMA and collagen expression. Notably, miR-30a inhibited EMT process, with a reduction in TGF-β1 and Vimentin as well as an increase in GFAP and E-cadherin. miR-30a induced a significant reduction in Snai1 protein expression when compared with the control. Interestingly, Snail protein expression was increased during liver fibrosis, indicating that there may be a negative correlation between miR-30a level and Snai1 protein expression. Further studies demonstrated that Snai1 was a target of miR-30a. Conclusion: Our results suggest that miR-30a inhibits EMT process, at least in part, via reduction of Snai1, leading to the suppression of HSC activation in liver fibrosis.

Cryptotanshinone Suppresses Liver Fibrosis by Attenuating Epithelial-Mesenchymal Transition through Targeting Hedgehog Pathway

2020 ◽  
Vol 20 ◽  
Author(s):  
Shurong Ren ◽  
Qizhen Yue ◽  
Qiubo Wang ◽  
Yanli Zhang ◽  
Bei Zhang
Keyword(s):  
Animal Model ◽  
Liver Fibrosis ◽  
Liver Diseases ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Chronic Liver ◽  
Luciferase Assay ◽  
Induced Expression ◽  
Mesenchymal Transition ◽  
Realtime Pcr

Background: Chronic liver damages from viral infection or alcohol abuse result in liver fibrosis, which is a key pathological event in many types of liver diseases. Discovering new anti-fibrosis agents may provide alternative solutions to manage chronic liver diseases. Methods: We first used CCl4 induced liver fibrosis animal model to evaluate the beneficial effects of Cryptotanshinone (CRY). We next explored target miRNAs regulated by CRY in hepatocytes using microarray. The target miRNA candidate was confirmed with realtime-PCR. We also elucidated the downstream target and pathway directly regulated by the miRNA using luciferase assay, western blotting and Epithelial–Mesenchymal Transition (EMT) markers quantification. Lastly, we confirmed CRY induced expression changes of the target genes in vivo. Results: CRY oral administration markedly alleviated the liver injury caused by CCl4. miRNAs expression profiling and realtime-PCR validation revealed miR-539-3p was directly induced by CRY around 4 folds. The induction of miR-539-3p suppressed SMO expression and antagonized Hedgehog (Hh) pathway. Independently CRY treatment suppressed SMO and inhibited EMT process in hepatocytes. The CRY induced expression changes of both miR-539-3p (~ 2 folds increase) and SMO (~ 60% decrease) in livers were validated in animal model. Conclusion: Our study supported CRY could inhibit liver fibrosis by targeting Hh pathway during EMT. CRY could be used as anti-fibrosis agent candidate for managing chronic liver damages.

scholarly journals miR-1-3p suppresses the epithelial-mesenchymal transition property in renal cell cancer by downregulating Fibronectin 1

2019 ◽  
Vol Volume 11 ◽  
pp. 5573-5587 ◽  
Author(s):  
Jianghui Liu ◽  
Yingxiong Huang ◽  
Quanyong Cheng ◽  
Jifei Wang ◽  
Jidong Zuo ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cell Cancer ◽  
Mesenchymal Transition ◽  
Transition Property

scholarly journals TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1419 ◽  
Author(s):  
Dewidar ◽  
Meyer ◽  
Dooley ◽  
Meindl-Beinker
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cell ◽  
Reactive Oxygen Species Generation ◽  
Mesenchymal Transition ◽  
Therapeutic Benefits ◽  
Liver Fibrogenesis

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

scholarly journals Cholangiocyte proliferation and liver fibrosis

2009 ◽  
Vol 11 ◽  
Author(s):  
Shannon S. Glaser ◽  
Eugenio Gaudio ◽  
Tim Miller ◽  
Domenico Alvaro ◽  
Gianfranco Alpini
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Proliferative Response ◽  
Epithelial Mesenchymal Transition ◽  
Extrahepatic Bile Duct ◽  
In Vivo Model ◽  
Ductular Reaction ◽  
Mesenchymal Transition ◽  
Paracrine Signalling ◽  
Duct Ligation

Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion – a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.

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