Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension

Gastroenterology, Journal Year: 2019, Volume and Issue: 158(5), P. 1334 - 1345.e5

Published: Dec. 5, 2019

Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor that reduces portal hypertension rats was safe well tolerated phase 1 studies. We performed a 2b, randomized trial the safety efficacy patients NASH, cirrhosis, hypertension.Patients (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, double-blind manner, groups received biweekly infusions belapectin 2 mg/kg (n = 54), 8 or placebo 54) for 52 weeks. The primary endpoint change HVPG (Δ HVPG) at end 52-week period compared baseline. Secondary endpoints included changes histology development liver-related outcomes.We found no significant difference ΔHVPG between group (-0.28 HG vs 0.10 HG, P 1.0) (-0.25 1.0). Belapectin had effect on fatty disease activity score, outcomes did not differ significantly among groups. In analysis subgroup without esophageal varices baseline 81), reduction weeks (P .02) reduced new .03). (2 mg/kg) produced signals.In 2b study 162 hypertension, year infusion but placebo. However, varices, reduce varices. ClinicalTrials.gov number: NCT02462967.

Language: Английский

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Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: April 14, 2021

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis steatohepatitis (NASH). NASH is a chronic state inflammation that leads the transformation hepatic stellate cells myofibroblasts. These produce extra-cellular matrix results in fibrosis. In normal situation, fibrogenesis wound healing process preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This takes many years often asymptomatic. Therefore, patients usually present themselves with end-stage e.g., cirrhosis, decompensated even hepatocellular carcinoma. Fibrosis has also been identified as most important predictor prognosis NAFLD. Currently, only minority be hence referred for treatment. not because largely asymptomatic, but due fact currently biopsy still golden standard accurate detection performing harbors some risks requires resources expertise, applicable every clinical setting unsuitable screening. Consequently, non-invasive diagnostic tools, mainly based on analysis blood other specimens imaging developed development. this review, we will first give an overview pathogenic mechanisms evolution serves basis subsequent discussion current future biomarkers anti-fibrotic drugs.

Language: Английский

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Oxidative Stress in Liver Pathophysiology and Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(9), P. 1653 - 1653

Published: Aug. 22, 2023

The liver is an organ that particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also the biotransformation of xenobiotics. disruption redox balance causes oxidative stress, affects function, modulates inflammatory pathways and contributes disease. Thus, stress implicated in acute injury pathogenesis prevalent infectious or chronic diseases such as viral hepatitis B C, alcoholic fatty disease, non-alcoholic disease (NAFLD) steatohepatitis (NASH). Moreover, plays a crucial role progression fibrosis, cirrhosis hepatocellular carcinoma (HCC). Herein, we provide overview on effects pathophysiology mechanisms by promotes

Language: Английский

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Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Sept. 21, 2021

Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which characterized over-deposition diffuse extracellular matrix (ECM) and anomalous hyperplasia connective tissue, it may further develop into cirrhosis, failure or cancer. To date, diseases accompanied with have significant morbidity mortality in the world increasing tendency. However, although early has been reported to be reversible, detailed mechanism reversing still unclear there lack effective treatment for fibrosis. Thus, top priority research development anti-fibrosis drugs. In recent years, many strategies emerged as crucial means inhibit occurrence including anti-inflammation protection, inhibition hepatic stellate cells (HSCs) activation proliferation, reduction ECM overproduction acceleration degradation. Moreover, gene therapy proved promising method. Here, we provide overview relevant targets drugs under development. We aim classify summarize their potential roles fibrosis, discuss challenges

Language: Английский

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Transforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities

Chemico-Biological Interactions, Journal Year: 2022, Volume and Issue: 369, P. 110289 - 110289

Published: Nov. 29, 2022

Language: Английский

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Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 18, 2022

Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course development fibrosis, certain parts intestine become narrowed, significantly destroying structure and function affecting quality life patients. Chronic inflammation initiating factor fibrosis. Unfortunately, existing anti-inflammatory drugs cannot effectively prevent alleviate there no effective anti-fibrotic drug, which makes surgical treatment mainstream for intestinal stenosis. Mesenchymal stem cells (MSCs) are capable tissue regeneration repair through their self-differentiation, secretion cytokines, extracellular vesicles. MSCs have been shown to play therapeutic role in many organs. However, MSC largely remained unexplored. This review summarizes mechanism including immune cells, TGF-β, gut microbiome metabolites. Available options particularly, also discussed.

Language: Английский

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Breaking the barriers: the role of gut homeostasis in Metabolic-Associated Steatotic Liver Disease (MASLD)

Gut Microbes, Journal Year: 2024, Volume and Issue: 16(1)

Published: March 21, 2024

Obesity, insulin resistance (IR), and the gut microbiome intricately interplay in Metabolic-associated Steatotic Liver Disease (MASLD), previously known as Non-Alcoholic Fatty (NAFLD), a growing health concern. The complex progression of MASLD extends beyond liver, driven by "gut-liver axis," where diet, genetics, gut-liver interactions influence disease development. pathophysiology involves excessive liver fat accumulation, hepatocyte dysfunction, inflammation, fibrosis, with subsequent risk hepatocellular carcinoma (HCC). gut, tripartite barrier, mechanical, immune, microbial components, engages constant communication liver. Recent evidence links dysbiosis disrupted barriers to systemic inflammation progression. Toll-like receptors (TLRs) mediate immunological crosstalk between recognizing structures triggering immune responses. "multiple hit model" development factors like resistance, dysbiosis, genetics/environmental elements disrupting axis, leading impaired intestinal barrier function increased permeability. Clinical management strategies encompass dietary interventions, physical exercise, pharmacotherapy targeting bile acid (BA) metabolism, modulation approaches through prebiotics, probiotics, symbiotics, fecal microbiota transplantation (FMT). This review underscores microbiome, their impact on therapeutic prospects.

Language: Английский

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Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9671 - 9671

Published: June 2, 2023

The liver is a critical system for metabolism in human beings, which plays an essential role abundance of physiological processes and vulnerable to endogenous or exogenous injuries. After the damage liver, type aberrant wound healing response known as fibrosis may happen, can result excessive accumulation extracellular matrix (ECM) then cause cirrhosis hepatocellular carcinoma (HCC), seriously endangering health causing great economic burden. However, few effective anti-fibrotic medications are clinically available treat fibrosis. most efficient approach prevention treatment currently eliminate its causes, but this approach’s efficiency too slow, some causes cannot be fully eliminated, worsen. In cases advanced fibrosis, only transplantation. Therefore, new treatments therapeutic agents need explored stop further development early reverse process achieve resolution. Understanding mechanisms that lead necessary find targets drugs. complex regulated by variety cells cytokines, among hepatic stellate (HSCs) cells, their continued activation will progression It has been found inhibiting HSC activation, inducing apoptosis, inactivating activated (aHSCs) thus regression. Hence, review concentrate on how HSCs become during including intercellular interactions related signaling pathways, well targeting pathways resolution Finally, compounds summarized provide more options therapy

Language: Английский

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Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114472 - 114472

Published: March 2, 2023

Liver fibrosis is the common consequence of various chronic liver injuries and mainly characterized by imbalance between production degradation extracellular matrix, which leads to accumulation interstitial collagen other matrix components. Matrix metalloproteinases (MMPs) their specific inhibitors, that is, tissue inhibitors (TIMPs), play a crucial role in synthesis lysis. Previous vivo vitro studies our laboratory found repressing (ECM) restoring balance MMPs TIMPs can alleviate fibrosis. We conducted review articles published PubMed Science Direct last decade until February 1, 2023, were searched for using these words "MMPs/TIMPs" "Hepatic Fibrosis." Through literature review, this article reviews experimental based on MMPs/TIMPs, summarizes components may exert an anti-liver effect affecting expression or activity attempts clarify mechanism MMPs/TIMPs regulating homeostasis, so as provide support development drugs. MMP-TIMP-ECM interaction result better understanding pathogenesis progression hepatic from different angle, targeting be promising therapeutic strategy Additionally, we summarized analyzed drugs have been reduce changing ratio including medicine natural products.

Language: Английский

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Macrophage in liver Fibrosis: Identities and mechanisms

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 120, P. 110357 - 110357

Published: May 22, 2023

Liver fibrosis is a chronic disease characterized by the deposition of extracellular matrix and continuous loss tissues that perform liver functions. Macrophages are crucial modulators innate immunity play important roles in fibrogenesis. comprise heterogeneous subpopulations exhibit different cellular Understanding identity function these cells essential for understanding mechanisms According to definitions, macrophages divided into M1/M2 or monocyte-derived macrophages/Kupffer cells. Classic phenotyping corresponds pro- anti-inflammatory effects, and, therefore, influences degree later phases. In contrast, origin closely associated with their replenishment activation during fibrosis. These two classifications depict dynamics liver-infiltrating macrophages. However, neither description properly elucidates positive negative role Critical tissue mediating include hepatic stellate fibroblasts, being particular interest because close association molecular biological descriptions inconsistent between mice humans, warranting further investigations. fibrosis, can secrete various pro-fibrotic cytokines, such as TGF-β, Galectin-3 interleukins (ILs), fibrosis-inhibiting IL10. secretions may be specific spatiotemporal characteristics Furthermore, dissipation, degrade secreting metalloproteinases (MMPs). Notably, using therapeutic targets has been explored. The current approaches categorized follows: treatment macrophage-related molecules macrophage infusion therapy. Although there have limited studies, shown reliable potential treatment. this review, we focu on relationship progression regression

Language: Английский

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