Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form NAFL, can be progressive and more susceptible to developing cirrhosis hepatocellular carcinoma. Currently, lifestyle interventions are most essential effective strategies for preventing controlling NAFL without development fibrosis. While there still limited appropriate drugs specifically treat NAFL/NASH, growing progress is being seen in elucidating pathogenesis identifying therapeutic targets. In this review, we discussed recent developments etiology prospective targets, as well pharmacological candidates pre/clinical trials patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, Importantly, evidence elucidates that disruption gut-liver axis microbe-derived metabolites drive NAFL/NASH. Extracellular vesicles (EVs) act signaling mediator, resulting accumulation, macrophage stellate cell activation, further promoting inflammation fibrosis progression during Targeting gut microbiota or EVs may serve new treatment Finally, other mechanisms, such therapy genetic approaches, also have enormous potential. Incorporating different mechanisms personalized medicine improve efficacy better benefit patients

Language: Английский

---

The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(20), P. 11128 - 11128

Published: Oct. 15, 2021

One of the most common chronic liver disorders, affecting mainly people in Western countries, is nonalcoholic fatty disease (NAFLD). Unfortunately, its pathophysiological mechanism not fully understood, and no dedicated treatment available. Simple steatosis can lead to steatohepatitis even fibrosis, cancer, cirrhosis liver. NAFLD very often occurs parallel with type 2 diabetes mellitus obese people. Furthermore, it much more likely develop patients metabolic syndrome (MS), whose criteria include abdominal obesity, elevated blood triacylglycerol level, reduced high-density lipoprotein cholesterol increased pressure, high fasting glucose. An important phenomenon MS also insulin resistance (IR), which NAFLD. Liver IR development are linked through an interaction between accumulation free acids, hepatic inflammation, oxidative stress. The particularly exposed levels reactive oxygen species due a large number mitochondria hepatocytes. In these organelles, main DNA repair pathway base excision (BER). present article will illustrate how impairment BER may be related

Language: Английский

---

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

---

Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(3), P. 454 - 499

Published: Jan. 30, 2024

Steatotic liver disease (SLD) displays a dynamic and complex phenotype. Consequently, the metabolic dysfunction-associated steatotic (MASLD)/metabolic steatohepatitis (MASH) therapeutic pipeline is expanding rapidly in multiple directions. In parallel, non-invasive tools for diagnosing monitoring responses to interventions are being studied, clinically feasible findings explored as primary outcomes interventional trials. The realization that distinct subgroups exist under umbrella of SLD should guide more precise personalized treatment recommendations facilitate advancements pharmacotherapeutics. This review summarizes recent updates pathophysiology-based nomenclature outlines both effective pharmacotherapeutics those MASLD/MASH, detailing their mode action current status phase 2 3 clinical Of extensive arsenal MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, shown only marginal benefits now tested part combination therapies, yet others still development monotherapies. Although successful drug candidate (or combinations) remains elusive, such approaches will ideally target MASH fibrosis while improving cardiometabolic risk factors. Due urgent need novel strategies potential availability safety tolerability data, repurposing existing approved drugs an appealing option. Finally, it essential highlight and, by extension, MASLD be recognized approached systemic affecting organs, with vigorous implementation interdisciplinary coordinated plans. Significance Statement SLD, including, among others, MASH, considered most prevalent chronic condition than one-fourth global population. aims provide information regarding pathophysiology, diagnosis, management line guidelines Collectively, hoped provided furthers understanding state direct implications stimulates additional research initiatives.

Language: Английский

---

Association between the cardiometabolic index and NAFLD and fibrosis

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 8, 2024

Abstract Composed of obesity and lipid parameters, the cardiometabolic index (CMI) has emerged as a novel diagnostic tool. Originally developed for diabetes diagnosis, its application expanded to identifying patients with cardiovascular diseases, such atherosclerosis hypertension. However, relationship between CMI non-alcoholic fatty liver disease (NAFLD) fibrosis in US population remains unclear. This cross-sectional study analyzed data from National Health Nutrition Examination Survey (NHANES) spanning 2017–2020, involving 2996 participants aged 20 years or older. Vibration controlled transient elastography using FibroScan® system (model 502, V2 Touch) attenuation parameter measurements identified NAFLD at threshold ≥ 274 dB/m, while stiffness measurement (LSM) results (median, 8.2 kPa) indicated fibrosis. A multifactorial logistic regression model explored The effectiveness detecting was assessed through receiver operating characteristic curve analysis. Controlling potential confounders, showed significant positive association (adjusted OR = 1.44, 95% CI 1.44–1.45) 1.84, 1.84–1.85). Areas Under Curve predicting were 0.762 (95% 0.745 ~ 0.779) 0.664(95% 0.633 0.696), respectively, optimal cut-off values 0.462 0.527. There is correlation fibrosis, which suitable simple predictor

Language: Английский

---

Antioxidant Peptides from Miiuy Croaker Swim Bladders: Ameliorating Effect and Mechanism in NAFLD Cell Model through Regulation of Hypolipidemic and Antioxidant Capacity

Marine Drugs, Journal Year: 2025, Volume and Issue: 23(2), P. 63 - 63

Published: Feb. 1, 2025

In this work, the hypolipidemic and antioxidative capacity of FSGLR (S7) GIEWA (S10) from miiuy croaker swim bladders was explored systematically in an oleic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model HepG2 cells. Moreover, activity S7 S10 their abilities were preliminarily investigated combination with molecular docking technology. The results indicated that could decrease amount lipid accumulation content triglycerides (TG) total cholesterol (TC) OA-induced NAFLD cell a dose-dependent manner. addition, exhibited better bile salt binding, pancreatic lipase (PL) inhibition, esterase (CE) inhibition capacities. mechanisms connected downregulation mRNA expression levels adipogenic factors, including sterol-regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), protein (SREBP)-2, hydroxymethylglutaryl-CoA reductase (HMGR), synthase (FAS) (p < 0.01), upregulation β-oxidation-related carnitine palmitoyltransferase 1 (CPT-1), acyl-CoA oxidase (ACOX-1), peroxisome proliferator-activated receptor α (PPARα). significantly protect cells against oxidative damage, antioxidant related to increased intracellular proteases (superoxide dismutase, SOD; glutathione peroxidase, GSH-PX; catalase, CAT) remove excess reactive oxygen species (ROS) production malondialdehyde (MDA). presented findings indicate functions make them potential candidates for treatment NAFLD.

Language: Английский

---

Diet and Risk of Non-Alcoholic Fatty Liver Disease, Cirrhosis, and Liver Cancer: A Large Prospective Cohort Study in UK Biobank

Nutrients, Journal Year: 2022, Volume and Issue: 14(24), P. 5335 - 5335

Published: Dec. 15, 2022

Background and Aims: Epidemiological evidence has shown the association between nutritional habits liver disease. However, results remain conflicting. This study investigated influence of dietary factors on risk incident non-alcoholic fatty disease (NAFLD), cirrhosis, cancer. Methods: Data from UK Biobank database were analyzed (n = 372,492). According to baseline data food frequency questionnaire, two main patterns (Western prudent) identified using principal component analysis. We used cox proportional hazards models explore associations individual groups with NAFLD, Results: During a median follow-up 12 years, 3527 hospitalized 1643 669 cancer cases recorded among 372,492 participants without prior history or chronic diseases at baseline. In multivariable adjusted analysis, in high tertile Western pattern score had an 18% (95%CI 1.09–1.29), 21% 1.07–1.37), 24% 1.02–1.50) higher cancer, respectively, compared low tertile. Participants prudent scores 15% 0.75–0.96) lower as those addition, consumption red meat fruit, cereal, tea, fiber significantly associated (ptrend < 0.05). Conclusions: large prospective cohort showed that increased intake could be correlated diseases, while was only reduced cirrhosis risk. These may provide new insights into lifestyle interventions for prevention chronical diseases.

Language: Английский

---

The brain-gut-microbiota interplay in depression: A key to design innovative therapeutic approaches

Pharmacological Research, Journal Year: 2023, Volume and Issue: 192, P. 106799 - 106799

Published: May 19, 2023

Depression is the most prevalent mental disorder in world associated with huge socio-economic consequences. While depressive-related symptoms are well known, molecular mechanisms underlying disease pathophysiology and progression remain largely unknown. The gut microbiota (GM) emerging as a key regulator of central nervous system homeostasis by exerting fundamental immune metabolic functions. In turn, brain influences intestinal microbial composition through neuroendocrine signals, within so-called microbiota-brain axis. balance this bidirectional crosstalk important to ensure neurogenesis, preserve integrity blood-brain barrier avoid neuroinflammation. Conversely, dysbiosis permeability negatively affect development, behavior, cognition. Furthermore, although not fully defined yet, changes GM depressed patients reported influence pharmacokinetics common antidepressants affecting their absorption, metabolism, activity. Similarly, neuropsychiatric drugs may shape turn an impact on efficacy toxicity pharmacological intervention itself. Consequently, strategies aimed at re-establishing correct homeostatic (i.e., prebiotics, probiotics, fecal transplantation, dietary interventions) represent innovative approach improve pharmacotherapy depression. Among these, probiotics Mediterranean diet, alone or combination standard care, hold promise for clinical application. Therefore, disclosure intricate network between depression will give precious insights diagnostic therapeutic approaches towards depression, profound implications drug development practice.

Language: Английский

---

The Gut–Organ Axis within the Human Body: Gut Dysbiosis and the Role of Prebiotics

Life, Journal Year: 2023, Volume and Issue: 13(10), P. 2023 - 2023

Published: Oct. 8, 2023

The human gut microbiota (GM) is a complex microbial ecosystem that colonises the gastrointestinal tract (GIT) and comprised of bacteria, viruses, fungi, protozoa. GM has symbiotic relationship with its host fundamental for body homeostasis. not limited to scope GIT, but there are bidirectional interactions between other organs, highlighting concept "gut-organ axis". Any deviation from normal composition GM, termed "microbial dysbiosis", implicated in pathogenesis various diseases. Only few studies have demonstrated modifications disease phenotypes, it still unknown whether an altered contributes or simply reflects status. Restoration probiotics prebiotics been postulated, evidence effects limited. Prebiotics substrates "selectively utilized by microorganisms, conferring health benefit". This study highlights vital organs demonstrates dysbiosis emergence certain representative Finally, this article focuses on potential as target therapy manipulate presents gaps literature research.

Language: Английский

---

Small Intestinal Bacterial Overgrowth and Non-Alcoholic Fatty Liver Disease: What Do We Know in 2023?

Nutrients, Journal Year: 2023, Volume and Issue: 15(6), P. 1323 - 1323

Published: March 8, 2023

Non-alcoholic fatty liver disease (NAFLD) is a chronic associated with the pathological accumulation of lipids inside hepatocytes. Untreated NAFL can progress to non-alcoholic hepatitis (NASH), followed by fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The common denominator above-mentioned metabolic disorders seems be insulin resistance, which occurs in NAFLD patients. Obesity greatest risk factor for lipid hepatocytes, but part patient population has normal body weight according BMI index. Obese people or without have higher incidence small intestinal bacterial overgrowth (SIBO), those suffering from show increased permeability, including more frequent presence intestine (SIBO). health consequences SIBO are primarily malabsorption (vitamin B12, iron, choline, fats, carbohydrates proteins) bile salt deconjugation. Undetected untreated may lead nutrient and/or energy malnutrition, thus directly impairing function (e.g., folic acid choline deficiency). However, whether contributes dysfunction, decreased barrier integrity, inflammation, endotoxemia translocation not yet clear. In this review, we focus on gut–liver axis discuss critical points, novel insights role nutrition, lifestyle, pre- probiotics, medication supplements therapy prevention both NAFLD.

Language: Английский

---