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Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 15797

Special Issue Editor

“Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Revolutiei Av., 310414 Arad, Romania
Interests: nutraceuticals; (poly)phenols; natural products and drug-delivery; signal transduction pathway; molecular pharmacology; wound healing; fibrosis
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Special Issue Information

Dear Colleagues,

Liver fibrosis is the main response to chronic liver disease, characterized by an excess deposition of the extracellular matrix (ECM). During fibrogenesis, hepatic stellate cells (HSCs) are activated, followed by cytokine and chemokine release, which induces their trans-differentiation into myofibroblast-like cells. This step is marked by the increased expression of smooth muscle α-actin (α-SMA) and therefore leads to MMP/TIMP imbalance, finally resulting in enhanced production and accumulation of ECM components. Transforming growth factor-β1 (TGF-β1) produced by Kupffer cells, endothelial cells, and hepatocytes has been recognized as a key activator of HSCs in the pathogenesis of liver fibrosis and acts by activating the Smad signaling pathway.

However, liver fibrosis is not a unidirectional progressive process, ultimately leading to liver cirrhosis and organ failure, and could be reversible. The molecular and cellular mechanisms of liver fibrosis regression are modulated by stopping chronic damage, shifting the balance from inflammation to resolution, deactivating myofibroblasts, and finally by ECM degradation.

In recent years, significant progress has been made in the understanding of the contribution of fibrosis in the progression of liver chronic diseases, as well as the development of new antifibrotic therapeutic compounds. Therefore, the purpose of this Special Issue of the International Journal of Molecular Sciences is to collect original research articles and reviews on the cellular and molecular pathways of liver fibrosis resolution, as well as the current status and molecular pharmacology of the new therapeutic compounds (from natural to synthetic compounds) that target liver fibrosis.

Prof. Dr. Anca Hermenean
Guest Editor

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Keywords

  • liver
  • fibrosis
  • cellular signaling pathways
  • resolution
  • antifibrotic compounds
  • natural compounds
  • small molecule inhibitors
  • drug delivery systems

Published Papers (5 papers)

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Research

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13 pages, 2980 KiB  
Article
Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells
by Hye-Young Seo, So-Hee Lee, Eugene Han, Jae Seok Hwang, Sol Han, Mi Kyung Kim and Byoung Kuk Jang
Int. J. Mol. Sci. 2022, 23(19), 11636; https://doi.org/10.3390/ijms231911636 - 01 Oct 2022
Cited by 8 | Viewed by 1431
Abstract
Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate [...] Read more.
Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor β (TGF-β) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-β. In addition, evogliptin inhibited TGF-β-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy. Full article
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19 pages, 4751 KiB  
Article
Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model
by Eduardo E. Vargas-Pozada, Erika Ramos-Tovar, Juan D. Rodriguez-Callejas, Irina Cardoso-Lezama, Silvia Galindo-Gómez, Daniel Talamás-Lara, Verónica Rocío Vásquez-Garzón, Jaime Arellanes-Robledo, Víctor Tsutsumi, Saúl Villa-Treviño and Pablo Muriel
Int. J. Mol. Sci. 2022, 23(17), 9954; https://doi.org/10.3390/ijms23179954 - 01 Sep 2022
Cited by 11 | Viewed by 2668
Abstract
Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in [...] Read more.
Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway. Full article
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Review

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24 pages, 1082 KiB  
Review
Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities
by Qiying Pei, Qian Yi and Liling Tang
Int. J. Mol. Sci. 2023, 24(11), 9671; https://doi.org/10.3390/ijms24119671 - 02 Jun 2023
Cited by 7 | Viewed by 2546
Abstract
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response [...] Read more.
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach’s efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis. Full article
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21 pages, 1767 KiB  
Review
Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma
by Florian Weber, Oliver Treeck, Patricia Mester and Christa Buechler
Int. J. Mol. Sci. 2023, 24(4), 3473; https://doi.org/10.3390/ijms24043473 - 09 Feb 2023
Cited by 3 | Viewed by 2351
Abstract
BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are [...] Read more.
BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-β1R signaling. TGF-β is the best-studied ligand of TGF-βRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC. Full article
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20 pages, 4982 KiB  
Review
The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application
by Danyan Zhang, Yaguang Zhang and Bing Sun
Int. J. Mol. Sci. 2022, 23(20), 12572; https://doi.org/10.3390/ijms232012572 - 20 Oct 2022
Cited by 20 | Viewed by 5917
Abstract
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of [...] Read more.
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies. Full article
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