Search Results (2,438)

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterised by hepatic steatosis in the absence of significant alcohol consumption or other specific causes of liver injury. It has become one of the leading causes of liver dysfunction worldwide. However, the precise pathophysiological mechanisms underlying NAFLD remain unclear, and effective therapeutic strategies are still under investigation. Autophagy, a vital intracellular process in eukaryotic cells, enables the degradation and recycling of cytoplasmic components through a membrane trafficking pathway. Recent studies have demonstrated a strong association between impaired or deficient autophagy and the development and progression of NAFLD. Restoring autophagic function may represent a key approach to mitigating hepatocellular injury. Nevertheless, due to the complexity of autophagy regulation and its context-dependent effects on cellular function, therapeutic strategies targeting autophagy in NAFLD remain limited. This review aims to summarise the relationship between autophagy and NAFLD, focusing on autophagy as a central mechanism. We discuss the latest research advances regarding interventions such as diet and exercise, pharmacological therapies (including modern pharmacological therapy and plant-derived compounds), and other approaches (such as hormones, nanoparticles, gut microbiota, and vitamins). Furthermore, we briefly highlight potential autophagy-related molecular targets that may offer novel therapeutic insights for NAFLD management. Full article

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver conditions globally. This study aimed to assess the long non-coding RNAs (lncRNAs) growth arrest-specific 5 (GAS5), miR-29a-3p, and neurogenic locus notch homolog protein 2 (NOTCH2) as biomarkers in patients with NAFLD and find out if they are related to any clinical factors. Subjects and Methods: Thirty-eight age-matched healthy persons and thirty-eight NAFLD patients were enrolled. Patients were split into the following three groups: non-alcoholic steatohepatitis (NASH) (n = 12), patients with NAFLD-related cirrhosis (n = 8), and patients with NAFLD-related simple steatosis (n = 18). Real-time PCR was utilized to examine the expression. Results: The lncRNA GAS5 and NOTCH2 were higher in NAFLD cases in comparison to controls. On the other hand, microRNA-29a-3p was underexpressed in NAFLD cases in comparison to controls. Regarding NAFLD diagnosis, lncRNA GAS5 was the best single marker with a sensitivity of 100% and a specificity of 94.7% at the cutoff values of ≥1.16-fold change. Regarding different stages of the disease, the highest level of lncRNA GAS5 was in cirrhosis. lncRNA GAS5 expression, among other studied parameters, is still a significant predictor of NAFLD (adjusted odds ratio of 162, C.I. = 5.7–4629) (p = 0.003). LncRNA GAS5 has a positive correlation with NOTCH2 and a negative correlation with miR-29a-3p. LncRNA GAS5, NOTCH2, and RNA-29a-3p were significantly different in NAFLD cases compared to controls. Conclusions: lncRNA GAS5 appears to be the most effective single marker for detecting NAFLD. LncRNA GAS5 expression is a significant independent predictor of NAFLD. LncRNA GAS5 can differentiate different NAFLD stages. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent, multisystem disease affecting approximately 30% of adults worldwide. Obesity, along with dyslipidemia, type 2 diabetes mellitus, and hypertension, are closely intertwined with MASLD. In people with obesity, MASLD prevalence is estimated to be about 75%. Despite various approaches to MASLD treatment, dietary changes remain the most accessible and safe interventions in MASLD, especially in obese and overweight patients. Whey proteins are rich in bioactive compounds, essential amino acids with antioxidant properties, offering potential benefits for MASLD prevention and management. This state-of-the-art review summarizes whey protein impacts on a spectrum of MASLD-related manifestations, such as obesity, impaired glucose and lipid metabolism, hypertension, liver injury, oxidative stress, and inflammation. The results obtained in clinical environments, with a focus on meta-analysis, propose whey protein supplementation as a promising strategy aimed at managing multifaced MASLD disorders. Well-designed cohort studies are needed for validation of the efficacy and long-term safety of whey proteins in MASLD patients. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders. Full article

Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15–25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences. Full article

Background/Objectives: The liver, the body’s primary detoxifying organ, is often affected by various inflammatory diseases, including hepatitis, cirrhosis, and non-alcoholic fatty liver disease (NAFLD), many of which can be exacerbated by secondary infections such as spontaneous bacterial peritonitis, bacteremia, and sepsis—particularly in patients with advanced liver dysfunction. The global rise in these conditions underscores the need for effective interventions. Natural products have attracted attention for their potential to support liver health, particularly through synergistic combinations of plant extracts. Epavin, a dietary supplement from Erbenobili S.r.l., formulated with plant extracts like Taraxacum officinale (L.), Silybum marianum (L.) Gaertn., and Cynara scolymus (L.), known for their liver-supporting properties, has been proposed as adjuvant for liver functions. The aim of this work was to evaluate of Epavin’s antioxidant, anti-inflammatory, and protective effects against heavy metal-induced toxicity. In addition, the antibacterial effect of Epavin against a panel of bacterial strains responsible for infections associated with liver injuries has been evaluated. Methods: The protection against oxidative stress induced by H₂O₂ was evaluated in HepG2 and BALB/3T3 cells using the dichlorofluorescein diacetate (DCFH-DA) assay. Its anti-inflammatory activity was investigated by measuring the reduction in nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages using the Griess assay. Additionally, the cytoprotecting of Epavin against heavy metal-induced toxicity and oxidative stress were evaluated in HepG2 cells using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) and DCFH-DA assays. The antibacterial activity of Epavin was assessed by determining the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) against Gram-positive (Enterococcus faecalis ATCC 29212, and BS, Staphylococcus aureus 25923, 29213, 43300, and BS) and Gram-negative (Escherichia coli 25922, and BS, Klebsiella pneumoniae 13883, 70063, and BS) bacterial strains using the microdilution method in broth, following the Clinical and Laboratory Standards Institute’s (CLSI) guidelines. Results: Epavin effectively reduced oxidative stress in HepG2 and BALB/3T3 cells and decreased NO production in LPS-stimulated RAW 264.7 macrophages. Moreover, Epavin demonstrated a protective effect against heavy metal-induced toxicity and oxidative damage in HepG2 cells. Finally, it exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains, with MIC values ranging from 1.5 to 6.0 mg/mL. Conclusions: The interesting results obtained suggest that Epavin may serve as a valuable natural adjuvant for liver health by enhancing detoxification processes, reducing inflammation, and exerting antibacterial effects that could be beneficial in the context of liver-associated infections. Full article

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition worldwide and represents a major global health challenge. Pharmacological and pharmacodynamic results indicate that aspirin eugenol ester (AEE) performs various pharmacological activities. However, it is unclear whether AEE can ameliorate the NAFLD. This study investigated the ameliorative effects of AEE on glucose and lipid metabolism disorders by in vitro and in vivo experiments. In the cellular model, TC increased to 0.104 μmol/mg and TG increased to 0.152 μmol/mg in the model group, while TC decreased to 0.043 μmol/mg and TG decreased to 0.058 μmol/mg in the AEE group. In the model group, the area occupied by lipid droplets within the visual field was significantly elevated to 17.338%. However, the administration of AEE resulted in a substantial reduction in this area to 10.064%. AEE significantly reduced the lipid droplet area and TC and TG levels (p < 0.05), increased bile acids in the cells and in the medium supernatant (p < 0.05), and significantly up-regulated the expression of LRH-1, PPARα, CYP7A1, and BSEP mRNA levels (p < 0.05) compared to the model group. In the animal model, different doses of AEE administration significantly down-regulated the levels of TC, TG, LDL, GSP, and FBG (p < 0.05) compared to the high-fat-diet (HFD) group, and 216 mg/kg of AEE significantly improved hepatocellular steatosis, attenuated liver injury, and reduced the area of glycogen staining (p < 0.05). In the HFD group, the glycogen area within the visual field exhibited a significant increase to 18.250%. However, the administration of AEE resulted in a notable reduction in the glycogen area to 13.314%. Liver and serum metabolomics results show that AEE can reverse the metabolite changes caused by a HFD. The major metabolites were involved in seven pathways, including riboflavin metabolism, glycerophospholipid metabolism, tryptophan metabolism, primary bile acid biosynthesis, biosynthesis of unsaturated fatty acids, nicotinate and nicotinamide metabolism, and tryptophan metabolism. In conclusion, AEE had a positive regulatory effect on NAFLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25–30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways—such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy—are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR’s essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Aim: The frontal QRS-T (fQRS-T) angle serves as an electrocardiography indicator that visually represents the disparity between the frontal QRS axis and the T axis. The heterogeneity between cardiac depolarization and repolarization rises with an increase in the fQRS-T angle. Prior research has demonstrated a relationship between the fQRS-T angle and the extent of atherosclerosis, along with the risk of cardiovascular mortality. The non-alcoholic fatty liver disease fibrosis score (NFS) is a non-invasive scoring tool used to quantify the degree of liver fibrosis in individuals with non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease increases the risk of atherosclerotic cardiovascular disease, which can be predicted using the NFS. The objective of this study is to examine the potential correlation between the fQRS-T angle and NFS in patients with stable angina pectoris. Materials and Methods: This cross-sectional study included 177 (48 women) non-alcoholic patients who underwent coronary angiography due to stable angina pectoris. Individual NFS values were calculated using clinical and laboratory data. Patients were categorized into two groups based on a NFS threshold value of 0.67. Following a minimum fasting period of 12 h, biochemical laboratory parameters were acquired using a peripheral venous sample, and electrocardiographic data were recorded. Results: The univariate logistic regression analysis revealed significant associations between hypertension (p = 0.018), coronary artery disease (p = 0.014), neutrophil (p = 0.024), hemoglobin (p = 0.038), and low-density lipoprotein (LDL, p = 0.007) with the NFS. The electrocardiographic variables related to the score included the QRS duration (p = 0.015), Pmax (p = 0.026), QTC interval (p = 0.02), and fQRS-T angle (p < 0.001). In the multivariate logistic regression analysis, NFS was independently associated with LDL (OR: 0.984, 95% CI: 0.970–0.998, p = 0.024) and fQRS-T angle (OR: 3.472, 95% CI: 1.886–6.395, p < 0.001). Conclusions: The FQRS-T angle may exhibit a distinct correlation with NAFLD. Extensive investigations should validate this link, since the fibrosis score can serve as an effective tool for monitoring patients prior to the onset of clinical symptoms associated with liver fibrosis. Full article

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) represents significant health challenges, especially among patients with chronic hepatitis B (CHB). This study uses machine learning models to predict NAFLD in patients with inactive CHB. It builds on previous research by employing classification algorithms to analyze demographic, clinical, and laboratory data to identify NAFLD predictors. Methods: A single-center cross-sectional study was conducted, including 450 inactive CHB patients from Sultan Qaboos University Hospital. Five ML models were developed: Logistic Regression, Random Forest, Extreme Gradient Boosting (XGBoost), Support Vector Machine (SVM), and Multi-Layer Perceptron (MLP). Results: The prevalence of NAFLD was 50.22%. Among the machine learning models, Random Forest achieved the highest performance with an ROC AUC of 0.983 (95% CI: 0.952–0.999), followed by XGBoost at 0.977 (95% CI: 0.938–0.999) and MLP at 0.963 (95% CI: 0.915–0.995). SVM also showed strong performance with an AUC of 0.949 (95% CI: 0.897–0.985), while Logistic Regression demonstrated comparatively lower discrimination with an AUC of 0.886 (95% CI: 0.799–0.952). Key predictive features identified included platelet count, low-density lipoprotein (LDL), hemoglobin, and alanine aminotransferase (ALT). Logistic Regression highlighted platelet count as the most significant negative predictor, while LDL and ALT were positive contributors. Conclusions: This study shows the utility of ML in improving the identification and management of NAFLD in CHB patients, enabling targeted interventions. Future research should expand on these findings, integrating genetic and lifestyle factors to enhance predictive accuracy across diverse populations. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading cause of chronic liver disease worldwide, driven by the global epidemics of obesity, type 2 diabetes, and metabolic syndrome. In this evolving nosological landscape, alcohol consumption—traditionally excluded from the diagnostic criteria of non-alcoholic fatty liver disease (NAFLD)—has regained central clinical importance. The recently defined MetALD phenotype acknowledges the co-existence of metabolic dysfunction and a significant alcohol intake, highlighting the synergistic nature of their pathogenic interactions. This narrative review provides a comprehensive analysis of the biochemical, mitochondrial, immunometabolic, and nutritional mechanisms through which alcohol exacerbates liver injury in MASLD. Central to this interaction is cytochrome P450 2E1 (CYP2E1), whose induction by both ethanol and insulin resistance enhances oxidative stress, lipid peroxidation, and fibrogenesis. Alcohol also promotes mitochondrial dysfunction, intestinal barrier disruption, and micronutrient depletion, thereby aggravating metabolic and inflammatory derangements. Furthermore, alcohol contributes to sarcopenia and insulin resistance, establishing a bidirectional link between hepatic and muscular impairment. While some observational studies have suggested a cardiometabolic benefit of a moderate alcohol intake, emerging evidence challenges the safety of any threshold in patients with MASLD. Accordingly, current international guidelines recommend alcohol restriction or abstinence in all individuals with steatotic liver disease and metabolic risk. The review concludes by proposing an integrative clinical model and a visual cascade framework for the assessment and management of alcohol consumption in MASLD, integrating counseling, non-invasive fibrosis screening, and personalized lifestyle interventions. Future research should aim to define safe thresholds, validate MetALD-specific biomarkers, and explore the efficacy of multidisciplinary interventions targeting both metabolic and alcohol-related liver injury. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) causes progressive liver fibrosis. Although erythrocyte mean corpuscular volume (MCV) has been shown to have a positive correlation with all-cause mortality, the association between MCV and the development of MASLD has not been fully elucidated. Here, we examined the clinical significance of the association between MCV and MASLD. Methods: A cross-sectional study was carried out in 1009 Japanese individuals (including 186 individuals aged < 60 years and 823 individuals aged ≥ 60 years) with metabolic disorders. The relationships between MCV and noninvasive clinical markers of liver fibrosis, including fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS), were statistically evaluated. Results: Using multiple and logistic regression analyses in overall subjects, it was found that MCV was positively and independently associated with the values of FIB-4 index, APRI, NFS, and the prevalence of liver fibrosis defined by each index. However, the associations between the MCV value and MASLD indices were found to be positive in subjects aged ≥ 60 years but not in those aged < 60 years. Conclusions: MCV might be a simple and useful biomarker for the development of MASLD in the elderly. Full article