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World Journal of Gastroenterology Mar 2023Liver fibrosis is a wound-healing response following chronic liver injury caused by hepatitis virus infection, obesity, or excessive alcohol. It is a dynamic and... (Review)
Review
Liver fibrosis is a wound-healing response following chronic liver injury caused by hepatitis virus infection, obesity, or excessive alcohol. It is a dynamic and reversible process characterized by the activation of hepatic stellate cells and excess accumulation of extracellular matrix. Advanced fibrosis could lead to cirrhosis and even liver cancer, which has become a significant health burden worldwide. Many studies have revealed that noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, are involved in the pathogenesis and development of liver fibrosis by regulating signaling pathways including transforming growth factor-β pathway, phosphatidylinositol 3-kinase/protein kinase B pathway, and Wnt/β-catenin pathway. NcRNAs in serum or exosomes have been reported to tentatively applied in the diagnosis and staging of liver fibrosis and combined with elastography to improve the accuracy of diagnosis. NcRNAs mimics, ncRNAs in mesenchymal stem cell-derived exosomes, and lipid nanoparticles-encapsulated ncRNAs have become promising therapeutic approaches for the treatment of liver fibrosis. In this review, we update the latest knowledge on ncRNAs in the pathogenesis and progression of liver fibrosis, and discuss the potentials and challenges to use these ncRNAs for diagnosis, staging and treatment of liver fibrosis. All these will help us to develop a comprehensive understanding of the role of ncRNAs in liver fibrosis.
Topics: Humans; RNA, Untranslated; MicroRNAs; Liver Cirrhosis; Fibrosis; RNA, Long Noncoding; Wnt Signaling Pathway
PubMed: 36998425
DOI: 10.3748/wjg.v29.i9.1446 -
Seminars in Liver Disease Feb 2017Liver fibrosis is the final common pathway of chronic or iterative liver damage. Advanced chronic fibrosis is described as cirrhosis with a loss of architecture and... (Review)
Review
Liver fibrosis is the final common pathway of chronic or iterative liver damage. Advanced chronic fibrosis is described as cirrhosis with a loss of architecture and attendant functional failure and the development of life-threatening complications. However, compelling evidence from rodent models and human studies indicates that if the injury is removed liver fibrosis is reversible. Hepatocytes, activated hepatic stellate cells, endothelial and immune cells, particularly macrophages, cooperate in the establishment and resolution of liver fibrosis. Here the authors provide a short overview of the mechanisms regulating the profibrotic and proresolution response, with the aim of highlighting potential new therapeutic targets. Liver disease is a major unmet medical need; currently, the sole approaches are the withdrawal of the injurious stimulus and liver transplantation. The authors conclude with a brief review of the feasibility of macrophage-based cell therapy for liver fibrosis.
Topics: Animals; Disease Models, Animal; Extracellular Matrix; Hepatic Stellate Cells; Hepatocytes; Humans; Immunity, Cellular; Liver; Liver Cirrhosis; Macrophage Activation; Macrophages; Metalloproteases
PubMed: 28201843
DOI: 10.1055/s-0036-1597816 -
Biochemia Medica Oct 2022Hepatic cirrhosis is a major health problem across the world, causing high morbidity and mortality. This disease has many etiologies, yet the result of chronic hepatic... (Review)
Review
Hepatic cirrhosis is a major health problem across the world, causing high morbidity and mortality. This disease has many etiologies, yet the result of chronic hepatic injury is hepatic fibrosis causing cirrhosis and hepatocellular carcinoma, as the liver's architecture is progressively destroyed. While liver biopsy is currently the gold standard for fibrosis staging, it has significant disadvantages, leading to a growing interest in non-invasive markers. Direct biomarkers - hyaluronic acid, laminin, collagen type III N-peptide, type IV collagen and cholylglycine - are new and rarely applied in routine clinical practice. This is the case primarily because there is no general consensus regarding the clinical application and effectiveness of the individual biomarkers. The usage of these markers in routine clinical practice could be advantageous for patients with liver fibrosis, requiring a simple blood test instead of a biopsy. The former option would be especially attractive for patients who are contraindicated for the latter. This review summarizes recent findings on direct biomarkers of liver fibrosis and highlights their possible applications and potential benefit for liver fibrosis diagnostics and/or staging.
Topics: Humans; Collagen Type IV; Laminin; Collagen Type III; Hyaluronic Acid; Liver Cirrhosis; Biomarkers; Glycocholic Acid
PubMed: 36277426
DOI: 10.11613/BM.2022.030501 -
Metabolism: Clinical and Experimental Oct 2022Liver fibrosis caused by hepatic stellate cells (HSCs) activation is implicated in the pathogenesis of liver diseases. To date, there has been no effective intervention...
INTRODUCTION
Liver fibrosis caused by hepatic stellate cells (HSCs) activation is implicated in the pathogenesis of liver diseases. To date, there has been no effective intervention means for this process. S100 proteins are calcium-binding proteins that regulate cell growth and differentiation. This study aimed to investigate whether S100A16 induces HSCs activation and participates in liver fibrosis progression.
METHODS
HSCs were isolated, and the relationship between S100A16 expression and HSCs activation was studied. S100a16 knockdown and transgenic mice were generated and subjected to HSCs activation and liver fibrosis stimulated by different models. Clinical samples were collected for further confirmation. Alterations in gene expression in HSCs were investigated, using transcriptome sequencing to determine the underlying mechanisms.
RESULTS
We observed increased S100A16 levels during HSCs activation. Genetic silencing of S100a16 prevented HSCs activation in vitro. Furthermore, S100a16 silencing exhibited obvious protective effects against HSCs activation and fibrosis progression in mice. In contrast, S100a16 transgenic mice exhibited spontaneous liver fibrosis. S100A16 was also upregulated in the HSCs of patients with fibrotic liver diseases. RNA sequencing revealed that C-X-C motif chemokine receptor 4 (Cxcr4) gene was a crucial regulator of S100A16 induction during HSCs activation. Mechanistically, S100A16 bound to P53 to induce its degradation; this augmented CXCR4 expression to activate ERK 1/2 and AKT signaling, which then promoted HSCs activation and liver fibrosis.
CONCLUSIONS
These data indicate that S100a16 deficiency prevents liver fibrosis by inhibiting Cxcr4 expression. Targeting S100A16 may provide insight into the pathogenesis of liver fibrosis and pave way for the design of novel clinical therapeutic strategies.
Topics: Animals; Fibrosis; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Liver Diseases; Mice; Mice, Transgenic; Signal Transduction
PubMed: 35914619
DOI: 10.1016/j.metabol.2022.155271 -
Planta Medica Dec 2018Liver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation... (Review)
Review
Liver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation of the normal liver architecture and the development of liver cirrhosis and even hepatocellular carcinoma. Numerous and studies indicated that oxidative stress mediates the initiation and progression of liver fibrosis. Overaccumulation of reactive oxygen species disrupts macromolecules, induces necrosis and apoptosis of hepatocytes, stimulates the production of pro-fibrogenic mediators, and directly activates hepatic stellate cells, thereby resulting in liver damage and initiating liver fibrosis. Ameliorating oxidative stress is a potential therapeutic strategy for the treatment of liver fibrosis. Natural antioxidants have attracted increasing attention in treating liver fibrosis due to their safety and efficacy. In this review, the pathogenesis of liver fibrosis and the role of oxidative stress in liver fibrosis were discussed. Naturally occurring antioxidants that can treat and prevent liver fibrosis were summarized. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of oxidative stress in liver fibrosis to representative antioxidants for treating liver fibrosis. Naturally occurring antioxidants show a potential for further investigations as lead compounds in fighting liver fibrosis.
Topics: Alkaloids; Animals; Antioxidants; Biological Products; Clinical Trials as Topic; Flavonoids; Humans; Liver Cirrhosis; Oxidative Stress; Terpenes
PubMed: 30312974
DOI: 10.1055/a-0757-0008 -
Postgraduate Medical Journal Apr 1998Liver fibrosis and its related complications continue to represent a significant worldwide healthcare burden. Over the past decade there has been considerable... (Review)
Review
Liver fibrosis and its related complications continue to represent a significant worldwide healthcare burden. Over the past decade there has been considerable improvement in our understanding of the cellular mechanisms and pathophysiology underlying hepatic fibrosis. This greater insight into the relevant basic sciences may lead to the development of novel treatment strategies designed to block the fibrogenic cascade or even enhance matrix degradation. In addition, there have been significant advances in the management of the complications of cirrhosis, with specific treatments now available for some conditions. Perhaps most notably, liver transplantation is now a highly successful treatment for end-stage liver disease and should be considered in all patients with chronic liver disease.
Topics: Esophageal and Gastric Varices; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Liver Transplantation
PubMed: 9683971
DOI: 10.1136/pgmj.74.870.193 -
American Family Physician Dec 2019Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may...
Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may be reversible. Only one in three people with cirrhosis knows they have it. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. When clinical signs, symptoms, or abnormal liver function tests are discovered, further evaluation should be pursued promptly. The most common causes of cirrhosis are viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Initial workup includes viral hepatitis serologies, ferritin, transferrin saturation, and abdominal ultrasonography as well as complete blood count, liver function tests, and prothrombin time/international normalized ratio, if not already ordered. Additional testing is based on demographics and risk factors. Common serum and ultrasound-based screening tests to assess fibrosis include the aspartate transaminase to platelet ratio index score, Fibrosis 4 score, FibroTest/FibroSure, nonalcoholic fatty liver fibrosis score, standard ultrasonography, and transient elastography. Generally, noninvasive tests are most useful in identifying patients with no to minimal fibrosis or advanced fibrosis. Chronic liver disease management includes directed counseling, laboratory testing, and ultrasound monitoring. Treatment goals are preventing cirrhosis, decompensation, and death. Varices are monitored with endoscopy and often require prophylaxis with nonselective beta blockers. Ascites treatment includes diuresis, salt restriction, and antibiotic prophylaxis for spontaneous bacterial peritonitis, when indicated. Hepatic encephalopathy is managed with lifestyle and nutritional modifications and, as needed, with lactulose and rifaximin. Hepatocellular carcinoma screening includes ultrasound screening every six months for patients with cirrhosis.
Topics: Chronic Disease; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 31845776
DOI: No ID Found -
Free Radical Biology & Medicine Jan 2021Liver fibrosis is a reversible wound-healing response to acute or chronic liver injury that can progress to cirrhosis and liver cancer. Finding new strategies for...
Liver fibrosis is a reversible wound-healing response to acute or chronic liver injury that can progress to cirrhosis and liver cancer. Finding new strategies for prevention and management of liver fibrosis is urgently needed. It is known that hepatic stellate cell (HSC) is the primary source of extracellular matrix that drives liver fibrosis progression. Herein, we carried out a comprehensive secretome profiling to identify NMN-induced changes in secretory proteins and found that NMN suppressed the secretion of profibrotic protein and oxidoreductase in activated HSC (LX-2) cells, while real-time quantitative PCR analysis revealed that NMN downregulated profibrotic gene expression, resulting in HSC inactivation. Next, we demonstrated that nicotinamide mononucleotide (NMN) reduced the accumulation of liver extracellular matrix in thioacetamide (TAA) and carbon tetrachloride (CCl) induced mouse models for liver fibrosis. Furthermore, we determined that NMN inhibited oxidation-mediated 15-PGDH degradation to promote prostaglandin E degradation and suppress HSC activation. In summary, our results propose that NMN supplementation is a new therapeutic approach for liver fibrosis prevention.
Topics: Animals; Dinoprostone; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Mice; Nicotinamide Mononucleotide; Thioacetamide
PubMed: 33220424
DOI: 10.1016/j.freeradbiomed.2020.11.014 -
Nature Reviews. Gastroenterology &... Feb 2022
Review
Topics: Deep Learning; Hepatocytes; Humans; Liver Cirrhosis; Phenotype; Sequence Analysis; Signal Transduction
PubMed: 34903888
DOI: 10.1038/s41575-021-00567-6 -
PeerJ 2022Liver fibrosis develops as a result of severe liver damage and is considered a major clinical concern throughout the world. Many factors are crucial for liver fibrosis... (Review)
Review
Liver fibrosis develops as a result of severe liver damage and is considered a major clinical concern throughout the world. Many factors are crucial for liver fibrosis progression. While advancements have been made to understand this disease, no effective pharmacological drug and treatment strategies have been established that can effectively prevent liver fibrosis or even could halt the fibrotic process. Most of those advances in curing liver fibrosis have been aimed towards mitigating the causes of fibrosis, including the development of potent antivirals to inhibit the hepatitis virus. It is not practicable for many individuals; however, a liver transplant becomes the only suitable alternative. A liver transplant is an expensive procedure. Thus, there is a significant need to identify potential targets of liver fibrosis and the development of such agents that can effectively treat or reverse liver fibrosis by targeting them. Researchers have identified hypoxia-inducible factors (HIFs) in the last 16 years as important transcription factors driving several facets of liver fibrosis, making them possible therapeutic targets. The latest knowledge on HIFs and their possible role in liver fibrosis, along with the cell-specific activities of such transcription factors that how they play role in liver fibrosis progression, is discussed in this review.
Topics: Humans; Cell Hypoxia; Hypoxia; Liver Cirrhosis; Liver Diseases; Transcription Factors
PubMed: 36523459
DOI: 10.7717/peerj.14299