An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 552 - 566

Published: April 14, 2023

Language: Английский

---

Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 95, P. 101231 - 101231

Published: Dec. 5, 2023

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury well persistent activation inflammatory response and fibrogenesis. fibrosis is a major determinant for disease (CLD) progression in the last two decades our understanding on molecular cellular mechanisms underlying fibrogenic CLD has dramatically improved, boosting pre-clinical studies clinical trials designed to find novel therapeutic approaches. From these several critical concepts have emerged, starting reveal complexity pro-fibrotic microenvironment which involves very complex, dynamic interrelated interactions between different hepatic extrahepatic cell populations. This review will offer first recapitulation established pathophysiological basic principles by intentionally focus attention NAFLD/NASH, metabolic-related form with high impact general population emerging leading cause worldwide. NAFLD/NASH-related pro-inflammatory profibrogenic be analysed information cells, mediators signalling pathways taken advantage methodological approaches techniques (single genomics, imaging mass cytometry, vitro two- three-dimensional models, etc.). We next overview recent advancement diagnostic prognostic tools, including serum biomarkers polygenic scores, support analysis biopsies. Finally, this provide current therapies treatment NAFLD/NASH patients.

Language: Английский

---

Global burden of cardiovascular diseases: projections from 2025 to 2050

European Journal of Preventive Cardiology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

Abstract Aims The prediction of future trends in cardiovascular disease (CVD) mortality and their risk factors can assist policy-makers healthcare planning. This study aims to project geospatial CVDs underlying from 2025 2050. Methods results Using historical data on disability-adjusted life years (DALYs) the Global Burden Disease (GBD) 2019 study, encompassing period 1990 2019, Poisson regression was performed model DALYs associated with CVD its Subgroup analysis based GBD super-regions. Between 2050, a 90.0% increase prevalence, 73.4% crude mortality, 54.7% are projected, an expected 35.6 million deaths 2050 (from 20.5 2025). However, age-standardized prevalence will be relatively constant (−3.6%), decreasing (−30.5%) (−29.6%). In ischaemic heart remain leading cause (20 deaths) while high systolic blood pressure main factor driving (18.9 deaths). Central Europe, Eastern Asia super-region is set incur highest rate (305 per 100 000 population). Conclusion coming decades, global suggests that net effect summative preventative efforts likely continue unchanged. fall reflects improvement medical care following diagnosis. systems expect rapid rise driven by ageing populace. continued burden largely attributed atherosclerotic diseases. Registration Not applicable.

Language: Английский

---

Epicardial Adipose Tissue Assessed by Computed Tomography and Echocardiography Are Associated With Adverse Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Circulation Cardiovascular Imaging, Journal Year: 2023, Volume and Issue: 16(5)

Published: May 1, 2023

Epicardial adipose tissue (EAT) has garnered attention as a prognostic and risk stratification factor for cardiovascular disease. This study, via meta-analyses, evaluates the associations between EAT outcomes stratified across imaging modalities, ethnic groups, study protocols.Medline Embase databases were searched without date restriction on May 2022 articles that examined outcomes. The inclusion criteria (1) studies measuring of adult patients at baseline (2) reporting follow-up data interest. primary outcome was major adverse events. Secondary included cardiac death, myocardial infarction, coronary revascularization, atrial fibrillation.Twenty-nine published 2012 2022, comprising 19 709 patients, in our analysis. Increased thickness volume associated with higher risks death (odds ratio, 2.53 [95% CI, 1.17-5.44]; P=0.020; n=4), infarction 2.63 1.39-4.96]; P=0.003; n=5), revascularization 2.99 1.64-5.44]; P<0.001; fibrillation (adjusted odds 4.04 3.06-5.32]; n=3). For 1 unit increment continuous measure EAT, computed tomography volumetric quantification hazard 1.74 1.42-2.13]; P<0.001) echocardiographic 1.20 1.09-1.32]; conferred an increased events.The utility biomarker predicting prognosticating disease is promising, being identified independent predictors events.URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42022338075.

Language: Английский

---

Type 2 diabetes mellitus and cardiometabolic outcomes in metabolic dysfunction-associated steatotic liver disease population

Diabetes Research and Clinical Practice, Journal Year: 2024, Volume and Issue: 211, P. 111652 - 111652

Published: April 2, 2024

Language: Английский

---

Oligonucleotide therapies for nonalcoholic steatohepatitis

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(2), P. 102184 - 102184

Published: March 30, 2024

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It characterized by series substantial damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage NASH, in some cases, may result cirrhosis carcinoma (HCC). Nowadays large number investigations are actively under way test various therapeutic strategies, emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor activating RNA) have shown high potential treating this fatal disease. This article systematically reviews the pathogenesis NASH/NAFLD, promising druggable targets proven current studies chemical compounds or biological drug development, feasibility limitations oligonucleotide-based approaches clinical pre-clinical studies.

Language: Английский

---

The Beneficial Effects of Geniposide on Glucose and Lipid Metabolism: A Review

Drug Design Development and Therapy, Journal Year: 2022, Volume and Issue: Volume 16, P. 3365 - 3383

Published: Sept. 1, 2022

Abstract: Geniposide is a naturally sourced active ingredient that has diverse pharmacological effects and great potential in improving or treating different kinds of diseases. In recent years, more studies have confirmed geniposide can improve glucose lipid metabolism disorder, which an increasingly prevalent health problem causing various metabolic diseases globally. Our review aims to summarize basic information on the glucolipid metabolism. increases utilization insulin production, protects pancreatic islet β cells, inhibits resistance hepatic suppresses gluconeogenesis. While aspect metabolism, promote lipolysis, inhibit lipogenesis, regulate transport. ameliorates disorders, entire glycolipid network three-dimensional manner at level molecular mechanism. Growing evidence revealed may serve as effective drug combat for time come. Keywords: geniposide, Gardenia Jasminoides Ellis, disease, ingredient,

Language: Английский

---

Efruxifermin, an investigational treatment for fibrotic or cirrhotic nonalcoholic steatohepatitis (NASH)

Expert Opinion on Investigational Drugs, Journal Year: 2023, Volume and Issue: 32(6), P. 451 - 461

Published: June 3, 2023

ABSTRACTIntroduction Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic and strongly associated with metabolic disorders: obesity, type 2 diabetes (T2D), cardiovascular disease. Persistent injury results in inflammatory processes leading to nonalcoholic steatohepatitis (NASH), fibrosis, ultimately cirrhosis. To date, no pharmacologic agent approved for treatment of NASH. Fibroblast growth factor 21 (FGF21) agonism has been linked beneficial effects ameliorating steatosis, insulin resistance, supporting its potential as a therapeutic target NAFLD.Areas covered Efruxifermin (EFX, also AKR-001 or AMG876) an engineered Fc-FGF21 fusion protein optimized pharmacokinetic pharmacodynamic profile, which currently tested several phase clinical trials NASH, fibrosis compensated EFX improved disturbances including glycemic control, showed favorable safety tolerability, demonstrated antifibrotic efficacy according FDA requirements 3 trials.Expert opinion While some other FGF-21 agonists (e.g. pegbelfermin) are not further investigated, available evidence supports development promising anti-NASH drug fibrotic cirrhotic populations. However, efficacy, long-term benefits (i.e. risk, decompensation events, progression, transplantation, mortality) remain be determined.KEYWORDS: AMG876)Fibroblast (FGF21)liver fibrosisliver cirrhosisNon-alcoholic (NAFLD)Nonalcoholic (NASH) Declaration interestThe authors have relevant affiliations financial involvement any organization entity interest conflict subject matter materials discussed manuscript. This includes employment, consultancies, honoraria, stock ownership options, expert testimony, grants patents received pending, royalties. declares interests. Outside submitted work, FT's lab research funding from Allergan, Bristol-Myers Squibb, Gilead Inventiva. FT honoraria consulting lectures Astra Zeneca, Gilead, AbbVie, BMS, Boehringer, Madrigal, Intercept, Falk, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis.Reviewer disclosuresPeer reviewers on this manuscript relationships disclose.Additional informationFundingTP supported by BIH clinician scientist program interest. German Research Foundation (DFG SFB/TRR 296 CRC1382, Project-ID 403224013) Ministry Education (BMBF DEEP-HCC consortium, BMBF Immun Avatar consortium).

Language: Английский

---

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Livers, Journal Year: 2023, Volume and Issue: 3(1), P. 33 - 53

Published: Jan. 12, 2023

The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk adverse events including injury. For more than 30 years, a series experimental clinical investigations reported or suggested that common pain reliever acetaminophen (APAP) could be hepatotoxic in obesity related metabolic diseases, at least after an overdose. Nonetheless, several did not reproduce these data. This discrepancy might come from extent steatosis, accumulation specific lipid species, mitochondrial dysfunction diabetes-related parameters such as ketonemia hyperglycemia. Among factors, some them seem pivotal for induction cytochrome P450 2E1 (CYP2E1), conversion APAP to toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors explain why NAFLD are always associated with frequent severe APAP-induced acute hepatotoxicity, increased volume distribution body, higher hepatic glucuronidation reduced CYP3A4 activity. Accordingly, occurrence outcome injury obese individual would depend on delicate balance between augment generation NAPQI others can mitigate hepatotoxicity.

Language: Английский

---

Metabolic dysfunction-associated steatotic liver disease: A silent pandemic

World Journal of Hepatology, Journal Year: 2024, Volume and Issue: 16(4), P. 511 - 516

Published: April 24, 2024

The worldwide epidemiology of non-alcoholic fatty liver disease (NAFLD) is showing an upward trend, parallel to the rising trend metabolic syndrome, owing lifestyle changes. pathogenesis NAFLD has not been fully understood yet. Therefore, emerged as a public health concern in field hepatology and metabolisms worldwide. Recent changes nomenclature from dysfunction-associated steatotic have brought positive outlook understanding process doctor-patient communication. Lifestyle are main treatment modality. Recently, clinical trial using drugs that target ‘insulin resistance’ which driving force behind NAFLD, shown promising results. Further translational research needed better understand underlying pathophysiological mechanism may open newer avenues therapeutic targets. role gut dysbiosis etiopathogenesis use fecal microbiota modification should be studied extensively. Prevention this silent epidemic by spreading awareness early intervention our priority.

Language: Английский

---