Non-alcoholic fatty liver disease (NAFLD) has become a public health issue worldwide. Dietary polyphenols are naturally occurring plant active ingredients and are widely employed in the treatment of NAFLD. However, the therapeutic effect is still controversial. In this study, a network meta-analysis (NMA) was performed to appraise the effects of various polyphenols on metabolic indices of NAFLD.

PubMed, Embase, the Cochrane Library, and Web of Science were retrieved for English studies on dietary polyphenols in the treatment of NAFLD. Outcome measures were extracted from the included studies and compared using a Bayesian NMA model, encompassing body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and necrosis factor alpha (TNF-α).

In total, 54 randomized controlled trials (RCTs) were included in this study, including 3,132 participants. It involved 13 single (or combined) dietary polyphenols. Naringenin could reduce serum TC (surface under the cumulative ranking curve: 94.59%) and TG (99.00%) in NAFLD patients. Catechin could decrease BMI (77.74%) and serum ALT (94.21%), AST (93.56%), TC (92.26%), and increase HDL-C (93.72%). Dihydromyricetin (DHM) was effective in reducing serum LDL-C (73.22%), and quercetin decreased serum TNF-α (99.47%).

Catechin may be the most appropriate dietary polyphenol supplement for NAFLD. Future studies should incorporate more RCTs to further validate the efficacy of dietary polyphenols (like DHM and quercetin), which are limited in sample sizes, in treating NAFLD. On the other hand, it is essential to investigate improvements in the bioavailability of these dietary polyphenols and to clarify their safety profiles.

Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern, impacting approximately 32.4% of the worldwide population. As a disease linked to metabolic dysfunction, NAFLD continues to rise alongside global increases in obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. There is considerable evidence indicating that NAFLD disproportionately affects racial, ethnic, and minority groups, although the exact reasons for these disparities remain elusive. Contributing factors to this disease may include socioeconomic status, cultural influences, stress, genetic factors, and lifestyle choices. Emerging evidence suggests that these causal factors could influence epigenetic mechanisms, particularly DNA methylation and histone modifications, as well as the composition and diversity of gut microbiota. Nevertheless, there is a scarcity of research that comprehensively examines the interplay between epigenetic changes and gut microbiome variations in relation to NAFLD disparities across different racial and ethnic populations globally. This paper intends to (i) explore the connections between NAFLD, ethnic disparities, gut microbiota composition, and epigenetic alterations, while reviewing pertinent studies that illustrate how these factors contribute to health inequities among various ethnic groups impacted by this disease; (ii) explore potential therapeutic targets and biomarkers to advance the management of NAFLD; and (iii) provide insights to enhance our understanding of the mechanisms associated with this disease, thereby promoting further research in this field. Advancements in this area are anticipated to enhance our understanding of disease susceptibilities in at-risk groups and to provide new therapeutic options for NAFLD and its associated complications.

Cannabinoid receptor type-1 (CB1) signaling plays an important part in maintenance of energy homeostasis, and CB1 blockers have shown promise in the treatment of obesity-related metabolic dysfunction. Coffee peel contains abundant phytochemicals and possesses hypolipidemic and anti-inflammatory activities. The present study aimed to elucidate the preventive effect of coffee peel polyphenols (CPPs) on nonalcoholic fatty liver disease (NAFLD) from the perspective of CB1 signaling. Male C57BL/6J mice were fed a high-fat and high-cholesterol diet and CPPs (200/400 mg/kg/day) for 8 weeks. Serum biochemical indexes and liver pathological analysis were used to evaluate the effect of CPPs on NAFLD. Untargeted/targeted lipidomics analyses were used to evaluate the levels of endocannabinoid ligands and ceramides in serum and liver. The expression levels of proteins were detected by using Western blotting analysis. Administration of CPPs significantly improved hepatic steatosis, insulin resistance and biomarkers of liver function. Meanwhile, CPPs administration indicated reductions in endocannabinoid ligands, including anandamide and 2-arachidonoylglycerol levels, associated with blockade of CB1 overexpression. Blockage of CB1 signaling depleted hepatic C16:0- and C18:0-ceramide concentrations by enhancing ceramide metabolism. The reductions in hepatic ceramide concentrations contributed to down-regulating sterol regulatory element-binding protein-1c and up-regulating proliferator activated receptor alpha, leading to decrease de novo lipogenesis and increase fatty acid β-oxidation in the liver, respectively. This study demonstrated a novel mechanism that CPPs could ameliorate NAFLD through modulating CB1-ceramide axis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder which may progress from simple steatosis to liver failure. Patients with NAFLD have higher levels of systemic inflammation. Resveratrol, a natural polyphenolic compound, has been shown to have anti-inflammatory effects through various mechanisms. The aim of this study was to evaluate the effect of resveratrol supplementation on serum levels of plasminogen activator inhibitor-1 (PAI-1), adiponectin, fibroblast growth factor-21 (FGF-21) as well as high-sensitivity C-reactive protein (hs-CRP) in patients with NAFLD.

In this double-blind randomized controlled trial, 50 adults with NAFLD aged 20-60 years were allocated into two groups; the intervention and the placebo group received two capsules per day each containing 300 mg resveratrol and placebo, respectively. Fasting blood samples and anthropometric measurements were collected for all patients at baseline and at the end of the trial. Cges in the outcomes were analyzed using analysis of covariance (ANCOVA).

After 12 weeks of intervention, resveratrol supplementation did not cause significant changes in serum levels of liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) compared to the control group. No significant differences were observed in the serum levels of PAI-1, adiponectin, FGF-21, and hs-CRP between the two groups at the end of the study.

Resveratrol supplementation for 12 weeks did not show favorable effects on serum levels of liver enzymes, PAI-1, adiponectin, FGF-21, and hs-CRP.

Iranian Registry of Clinical Trials (IRCT201511233664N16) (2016-02-08).

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition affecting a broad population. This review aimed to identify and summarize the current evidence on bioactive-substance-based interventions for adults with MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), covering publications from 2000 to 2023. Methods: A search was conducted across six databases (MEDLINE, CINAHL, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Food Science Source, and SPORTDiscus) for randomized controlled trials and other study types (e.g., prospective cohort studies and systematic reviews), reflecting the scoping nature of this review. The search was limited to studies in adults (>18 years old), with an intervention of interest and at least one comparator group. Results: A total of 4572 articles were retrieved, with 201 full-text articles screened for eligibility. Of these, 131 primary studies and 49 systematic reviews were included in the scoping review. The most studied bioactive substances were Curcumin (Turmeric) (n = 25), Silymarin (Milk Thistle) (n = 17), Resveratrol (n = 10), Coffee (n = 7), Green Tea (n = 5), and Berberine (n = 5 each). Moreover, 46 studies reported on 36 other bioactive substances with 2 or fewer articles each. Among the included systematic reviews, 13 focused on Curcumin, 12 on Coffee or Tea, 10 on bioactive substance combinations, 6 on Resveratrol, and 2 each on Silymarin and Artichoke Leaf. The included studies showed substantial heterogeneity in reported outcomes, which primarily focused on hepatic health, body weight, adverse events, glycemic control, blood lipids, and body composition. Conclusions: This scoping review highlights a range of bioactive substances used in the treatment of MASLD. While evidence is abundant for bioactive substances like Curcumin and Silymarin, further research and synthesis of findings is necessary to establish the clinical efficacy of all bioactive substances.

Polyphenols, known for their potent antioxidant and anti-inflammatory properties, have emerged as promising, natural, and safe complementary treatment options for metabolic-associated steatotic liver disease (MASLD). Among these, curcumin, resveratrol, and silymarin are the most extensively studied; however, their differential effects on MASLD outcomes remain inconclusive. This systematic review and meta-analysis of RCTs aimed to evaluate the efficacy of curcumin, resveratrol, and silymarin in patients with MASLD. A comprehensive search of seven databases was conducted up to September 2024. Odds ratios (OR), mean differences (MD), and standardized MD (SMD) with 95% confidence intervals (CI) were used to assess treatment effects. Primary outcomes included improvement in hepatic steatosis and ALT activity, while secondary outcomes included changes in AST activity, blood lipids, glucose, BMI, blood pressure, and TNF-α. Twenty-seven studies involving 1691 participants were included. Curcumin significantly improved hepatic steatosis compared to placebo (OR: 4.39, 95% CI: 1.45 to 13.27, p = 0.009), followed by resveratrol (OR: 3.18, 95% CI: 1.20 to 8.42, p = 0.02). Silymarin exhibited the strongest effect in reducing ALT levels (MD: -6.44 U/L, 95% CI: -10.03 to -2.85, p = 0.0004), with curcumin (MD: -5.88 U/L, 95% CI: -9.05 to -2.72, p = 0.0003) also showing significant reductions. A marked reduction in AST was observed with silymarin (MD: -6.99 U/L, 95% CI: -8.56 to -5.42, p < 0.00001), followed by curcumin (MD: -3.36 U/L, 95% CI: -5.35 to -1.36, p = 0.001). Furthermore, curcumin intake significantly improved metabolic indicators (TG, FBG, HOMA-IR, and BMI). Resveratrol reduced FBG and DBP. Curcumin had the strongest effect on hepatic steatosis and improved both transaminase levels and metabolic markers. Silymarin demonstrated the greatest reduction in transaminase levels, while resveratrol showed modest benefits in steatosis and metabolic improvements. The three polyphenols appear as promising therapeutics for the treatment of MASLD.

Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a challenging metabolic disorder with a strong emphasis on its prevention and management. Polyphenols, a group of naturally occurring plant compounds, have been associated with a decreased risk of various metabolic disorders related to NAFLD. The current systematic review aims to critically assess evidence about the ameliorative effect of polyphenol supplementation on NAFLD patients. A PRISMA systematic search appraisal was conducted in PubMed, Scopus, Web of Science Core Collection, and all relevant studies published prior to April 2024 and met the inclusion criteria were included. Twenty-nine randomized clinical trials (RCTs) comprised 1840 NAFLD patients. The studies primarily examined eleven phenolic compounds, including turmeric, curcumin, resveratrol, genistein, catechin, green tea extract, hesperidin, and silymarin. Turmeric and curcumin decreased liver enzymes, inflammatory cytokines, lipid profile, insulin resistance, and NAFLD score, while resveratrol did not present consistent results across all the studies. Most studies on silymarin showed a reduction in liver enzymes and lipid profile; however, no changes were observed in inflammatory cytokine levels. The dietary supplementation of hesperidin and naringenin or green tea extract caused improvements in liver enzyme, lipid profile, and inflammatory cytokine, while genistein supplementation did not modulate blood lipid profile. In conclusion, dietary supplementation of polyphenols could potentially prevent and ameliorate NAFLD. Still, the inconsistent results across the included RCTs require further clinical research to establish optimal dosage and duration.

Resveratrol, a polyphenol found in grapes, has been studied extensively for its potential benefits on metabolic markers and inflammation. While promising results have been observed in animal studies and some human trials, the overall evidence is mixed. Moreover, elevated inflammatory markers have been closely linked to more severe symptoms of Multiple Sclerosis (MS). Therefore, strategies to reduce systemic inflammation could potentially improve outcomes for MS patients. So we aimed to examine the effectiveness of resveratrol supplementation on inflammatory markers in patients with Multiple sclerosis (MS), in a randomized placebo-controlled double-blinded parallel clinical trial.

A total of 55 subjects with MS were enrolled in this study and randomly assigned to the two groups who were supplemented with resveratrol at a dose of 500 mg/day or received placebo capsules for 8 weeks. Tumor necrosis factor-alpha (TNF-α), Malondialdehyde (MDA), fasting blood sugar (FBS), triglycerides, total cholesterol, low-density lipoprotein - cholesterol (LDL-C), high-density lipoprotein - cholesterol (HDL-C), and the degree of fatigue were measured at baseline and after the intervention.

Resveratrol treatment significantly decreased TNF-α (P < 0.001), and MDA (P < 0.001) compared to the placebo. The respective increase and decrease in FBS and HDL levels were seen in both groups, while the change in participants receiving resveratrol was significantly less pronounced. Changes in the levels of TG and fatigue scale remained unchanged.

This study showed that resveratrol supplementation exerted anti-inflammatory and anti-oxidant effects in patients with MS.Trial registration: Iranian Registry of Clinical Trials identifier: IRCT20230315057731N1.

Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most recent definition for steatotic liver disease associated with metabolic syndrome. The results of recent metabolic and observational studies suggest a potential beneficial effect of food-derived flavonoids in some chronic diseases, including MASLD. The study aims to evaluate the protective role of diet flavonoids in subjects with and without MASLD belonging to a cohort living in the South of Italy.

The study cohort comprised 1297 participants assessed in the NUTRIHEP cohort (2015-2018), divided into two groups, based on presence or absence of MASLD.

The results indicated statistically significant flavonoid consumption, showing a protective role against MASLD, at an optimal concentration of 165 mg/day, with an OR value of 0.63, (p = 0.001, 95% C.I.: 0.47; 0.83 t). The OR remained almost unchanged when the intake increased from 165 mg per day to 185 mg per day.

In conclusion, our study results show a protective role of flavonoids against MASLD. Consuming only 165 mg of flavonoids daily can activate this protective function, reducing the risk of MASLD.

Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical-pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of MAFLD can involve the interaction of genetics, hormones, and nutrition, lifestyle (diet and sedentary lifestyle) is the most influential factor in developing this condition. Polyphenols comprise many natural chemical compounds that can be helpful in managing metabolic diseases. Therefore, the aim of this review was to investigate the impact of oxidative stress, inflammation, mitochondrial dysfunction, and the role of polyphenols in managing MAFLD. Some polyphenols can reverse part of the liver damage related to inflammation, oxidative stress, or mitochondrial dysfunction, and among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, and silymarin. These compounds have actions in reducing plasma liver enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, and the HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, liver fat content, steatosis index, and fibrosis. On the other hand, they can improve HDL-c, adiponectin levels, and fibrogenesis markers. These results show that polyphenols are promising in the prevention and treatment of MAFLD.

Numerous studies highlight the potential of natural antioxidants, such as those found in foods and plants, to prevent or treat nonalcoholic fatty liver disease (NAFLD). Inflammation is a key factor in the progression from high-fat diet-induced NAFLD to nonalcoholic steatohepatitis (NASH). Injured liver cells and immune cells release inflammatory cytokines, activating hepatic stellate cells. These cells acquire a profibrogenic phenotype, leading to extracellular matrix accumulation and fibrosis. Persistent fibrosis can progress to cirrhosis. Fatty infiltration, oxidative stress, and inflammation exacerbate fatty liver diseases. Thus, many plant-derived antioxidants, like silymarin, silibinin, curcumin, resveratrol, berberine, and quercetin, have been extensively studied in experimental models and clinical patients with NAFLD. Experimentally, these compounds have shown beneficial effects in reducing lipid accumulation, oxidative stress, and inflammatory markers by modulating the ERK, NF-κB, AMPKα, and PPARγ pathways. They also help decrease metabolic endotoxemia, intestinal permeability, and gut inflammation. Clinically, silymarin and silibinin have been found to reduce transaminase levels, while resveratrol and curcumin help alleviate inflammation in NAFLD patients. However, these phytocompounds exhibit poor water solubility, leading to low oral bioavailability and hindering their biological efficacy. Additionally, inconclusive clinical results highlight the need for further trials with larger populations, longer durations, and standardized protocols.

The increasing scientific interest in antioxidants and naturally derived compounds as potential remedies for obesity and non-alcoholic fatty liver disease (NAFLD) has led to extensive research. The objective of this bibliometric analysis is to present an updated perspective on the topic of antioxidants, herbs, phytochemicals, and natural compounds, in the control of obesity and NAFLD, to identify new areas for future research. Publications from the years 2012-2022 were retrieved using the Scopus database. The research trends were analyzed using the Biblioshiny and VOSviewer tools. The field has seen a significant increase in research activity, as indicated by an annual growth rate of 10 % in the number of published manuscripts. China, Korea, and the USA emerged as the most prominent contributors in this specific field, supported by their notable volumes of publications and citations. The density analysis revealed that the most frequently occurring authors' keywords related to herbal species are, in rank order, Camelia sinensis, Momordica charantia, Curcuma longa, Ilex paraguariensis, Panax ginseng, Moringa oleifera, Garcinia cambogia, Garcinia mangostana, Zingiber officinale, and Cinnamomum verum. In the group of antioxidants, phytochemicals, and natural compounds, the top 10 were resveratrol, curcumin, quercetin, vitamin E, alpha-lipoic acid, vitamin C, chlorogenic acid, lycopene, fucoxanthin, and berberine. The co-occurrence analysis unveiled significant themes and potential trends, including a notable interest in the impact of herbal species, antioxidants, phytochemicals, and natural compounds on obesity and NAFLD through the modulation of the gut microbiome. Another recurring theme that arises, is the ongoing investigation of molecular targets that demonstrate anti-adipogenesis properties. The analysis presented in this study provides valuable insights for researchers investigating the efficacy of antioxidants, herbs, phytochemicals, and natural compounds in addressing obesity and NAFLD. Through the use of bibliometric methods, the study offers a comprehensive overview. Furthermore, the findings of this analysis can serve as a foundation for future research in this specific domain.

Metabolic-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, represents a growing global health concern. The intricate pathogenesis of MASLD, driven by genetic, metabolic, epigenetic, and environmental factors, leads to considerable clinical variability. Dysregulation of hepatic lipid metabolism, particularly cholesterol homeostasis, is a critical factor in the progression of MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). This review elucidates the multifaceted roles of cholesterol metabolism in MASLD, focusing on its absorption, transportation, biosynthesis, efflux, and conversion. We highlight recent advancements in understanding these processes and explore the therapeutic potential of natural products such as curcumin, berberine, and resveratrol in modulating cholesterol metabolism. By targeting key molecular pathways, these natural products offer promising strategies for MASLD management. Finally, this review also covers the clinical studies of natural products in MASLD, providing new insights for future research and clinical applications.

Since the effects of flaxseed supplementation on lipid profile and liver enzymes are still controversial, a meta-analysis of randomized controlled trials was conducted in the present study to assess the effect of flaxseed supplementation on lipid profile and liver enzymes. The study was designed, conducted, and reported according to the guidelines of the 2020 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. A systematic and comprehensive search was performed in several databases from inception up to January 10, 2024. The meta-analysis on the impact of flaxseed supplementation on lipid profile and liver enzymes indicates that the overall effect of flaxseed supplementation on triglycerides, combining different doses, revealed a significant reduction with a WMD of - 230.72 (-53.95, - 27.49) and a P-value of 0.010. High-density lipoprotein (HDL) demonstrated a positive effect, with an overall WMD of 1.82 (0.27, 3.38) and a P-value of 0.021, indicating an increase in HDL levels. The liver enzymes AST and ALT displayed reductions in their levels, with overall WMDs of - 21.18 (-2.95, 0.59) and - 24.83 (-8.74, - 20.91), respectively. Subgroup analysis based on dosage revealed more pronounced reductions in ALT levels for doses below 2000 mg/day. Findings from this study suggest that a flaxseed supplement might be beneficial to modulate the blood lipid profile and liver enzymes.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. Portulaca oleracea exhibits anti-oxidant, anti-inflammatory, and hepatoprotective effects. This clinical trial aimed to investigate the potential benefits of Portulaca oleracea in improving NAFLD.

This double-blind, randomized clinical trial enrolled 70 patients with NAFLD assigned to either the intervention group (n = 35) or placebo group (n = 35) using stratified block randomization. The intervention group received 700 mg Portulaca oleracea supplement for eight weeks, while the control group received placebo capsules. In addition, all participants received a calorie-restricted diet. Liver steatosis and fibrosis were assessed using elastography along with liver function and metabolic tests, blood pressure measurements, body composition analysis and dietary records pre-and post-intervention.

The average age of the participants was 44.01 ± 8.6 years, of which 34 (48.6%) were women. The group receiving Portulaca oleracea showed significant weight changes, body mass index, fat mass index, and waist circumference compared to the placebo (p < 0.001). In addition, blood sugar, lipid profile, liver enzymes aspartate and alanine transaminase, gamma-glutamyl transferase, and systolic blood pressure were significantly improved in the intervention group compared to those in the placebo (p < 0.05). During the study, inflammatory and oxidative stress indicators, improved significantly (p < 0.05). Based on the elastography results, the hepatorenal ultrasound index and liver stiffness decreased significantly in the Portulaca oleracea group compared to the placebo (p < 0.001).

The present clinical trial showed that receiving Portulaca oleracea supplement for eight weeks can improve the condition of liver steatosis and fibrosis in patients with NAFLD.

Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.

Non-alcoholic fatty liver disease (NAFLD) is a global public health problem that causes liver-related morbidity and mortality. It is also an independent risk factor for non-communicable diseases. In 2020, a proposal was made to refer to it as "metabolic dysfunction-associated fatty liver disease (MAFLD)", with concise diagnostic criteria. Given its widespread occurrence, its treatment is crucial. Increased levels of oxidative stress cause this disease. This review aims to evaluate various studies on antioxidant therapies for patients with MAFLD. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 87 studies that met the inclusion criteria. In total, 31.1% of human studies used natural antioxidants, 53.3% used synthetic antioxidants, and 15.5% used both natural and synthetic antioxidants. In human-based studies, natural antioxidants showed 100% efficacy in the treatment of MAFLD, while synthetic antioxidants showed effective results in only 91% of the investigations. In animal-based research, natural antioxidants were fully effective in the treatment of MAFLD, while synthetic antioxidants demonstrated effectiveness in only 87.8% of the evaluations. In conclusion, antioxidants in their natural form are more helpful for patients with MAFLD, and preserving the correct balance of pro-oxidants and antioxidants is a useful way to monitor antioxidant treatment.

Emerging treatment methods, including exercise, diet, and drugs, for nonalcoholic fatty liver disease have been proposed. However, the differences in their efficacy have not been determined. We aimed to compare the effects of these treatments excluding surgery via a systematic review and network meta-analysis of randomized controlled trials.

The data sources included PubMed, Embase, Web of Science and Cochrane up to February 1st, 2023. The endpoints consisted of body mass index (BMI), serum markers of metabolism and liver injury markers, liver fat content, and stiffness.

A total of 174 studies with 10,183 patients were included in this meta-analysis. In terms of improving BMI, Pan-agonist of peroxisome proliferator-activated receptors (PPAR) is the best treatment with the highest SUCRA (surface under the cumulative ranking) of 84.8% (mean = -3.40, 95% CI -5.55, -1.24) by the comparative effectiveness ranking. GLP-1 (glucagon-like peptide-1) has the best effect in improving the liver fat content based on the MRI-PDFF, steatosis score (SUCRA 99.7%, mean = -2.19, 95% CI -2.90, -1.48) and ballooning score (SUCRA 61.2%, mean = -0.82, 95% CI -4.46, 2.83).

Pan-agonist of PPAR was the most efficacious regimen in lowering BMIs, whereas GLP-1R agonists achieved the highest efficacy of steatosis improvement in this network meta-analysis.

Non-alcoholic fatty liver disease (NAFLD) accounts as a crucial health concern with a huge burden on health and economic systems. The aim of this study is to evaluate the effect of soy isoflavones supplementation on metabolic status in patients with NAFLD.

In this randomized clinical trial, 50 patients with NAFLD were randomly allocated to either soy isoflavone or placebo groups for 12 weeks. The soy isoflavone group took 100 mg/d soy isoflavone and the placebo group took the similar tablets containing starch. Anthropometric indices, blood lipids, glycemic parameters and blood pressure were measured at the beginning and at the end of the study.

At the end of week 12 the level of serum triglyceride (TG), low density lipoprotein (LDL) and total cholesterol (TC) was significantly decreased only in soy isoflavone group compared to baseline (P < 0.05). Although waist circumference (WC) decreased significantly in both groups after 12 weeks of intervention (P < 0.05), hip circumference (HC) decreased significantly only in soy isoflavone group (P = 0.001). No significant changes observed regarding high density lipoprotein (HDL) and blood pressure in both groups. At the end of the study, serum glucose level was significantly decreased in the placebo group compared to baseline (P = 0.047). No significant changes demonstrated in the soy isoflavone group in regard to glycemic parameters (P > 0.05).

This study revealed that soy isoflavones could significantly reduce TG, LDL TC, WC and HC in NAFLD patients.

The Ethics committee of Ahvaz Jundishapur University of Medical Sciences approved the protocol of the present clinical research (IR.AJUMS.REC.1401.155). The study was in accordance with the Declaration of Helsinki. This study's registered number and date are IRCT20220801055597N1 and 20.09.2022, respectively at https://fa.irct.ir .

Primary liver cancer is a type of cancer that develops in the liver. Hepatocellular carcinoma is a primary liver cancer that usually affects adults. Liver cancer is a fatal global condition that affects millions of people worldwide. Despite advances in technology, the mortality rate remains alarming. There is growing interest in researching alternative medicines to prevent or reduce the effects of liver cancer. Recent studies have shown growing interest in herbal products, nutraceuticals, and Chinese medicines as potential treatments for liver cancer. These substances contain unique bioactive compounds with anticancer properties. The causes of liver cancer and potential treatments are discussed in this review. This study reviews natural compounds, such as curcumin, resveratrol, green tea catechins, grape seed extracts, vitamin D, and selenium. Preclinical and clinical studies have shown that these medications reduce the risk of liver cancer through their antiviral, anti-inflammatory, antioxidant, anti-angiogenic, and antimetastatic properties. This article discusses the therapeutic properties of natural products, nutraceuticals, and Chinese compounds for the prevention and treatment of liver cancer.

Non-alcoholic fatty liver disease (NAFLD) encompasses hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. It is the primary cause of chronic liver disorders, with a high prevalence but no approved treatment. Therefore, it is indispensable to find a trustworthy therapy for NAFLD. Recently, mounting evidence illustrates that Sirtuin 1 (SIRT1) is strongly associated with NAFLD. SIRT1 activation or overexpression attenuate NAFLD, while SIRT1 deficiency aggravates NAFLD. Besides, an array of therapeutic agents, including natural compounds, synthetic compounds, traditional Chinese medicine formula, and stem cell transplantation, alleviates NALFD via SIRT1 activation or upregulation. Mechanically, SIRT1 alleviates NAFLD by reestablishing autophagy, enhancing mitochondrial function, suppressing oxidative stress, and coordinating lipid metabolism, as well as reducing hepatocyte apoptosis and inflammation. In this review, we introduced the structure and function of SIRT1 briefly, and summarized the effect of SIRT1 on NAFLD and its mechanism, along with the application of SIRT1 agonists in treating NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is influenced by a variety of factors, including environmental and genetic factors. The most significant outcome is the alteration of free fatty acid and triglyceride metabolism. Lipotoxicity, impaired autophagy, chronic inflammation, and oxidative stress, as well as coexisting insulin resistance, obesity, and changes in the composition of gut microbiota, are also considered crucial factors in the pathogenesis of MASLD. Resveratrol is a polyphenolic compound that belongs to the stilbene subgroup. This review summarises the available information on the therapeutic effects of resveratrol against MASLD. Resveratrol has demonstrated promising antisteatotic, antioxidant, and anti-inflammatory activities in liver cells in in vitro and animal studies. Resveratrol has been associated with inhibiting the NF-κB pathway, activating the SIRT-1 and AMPK pathways, normalizing the intestinal microbiome, and alleviating intestinal inflammation. However, clinical studies have yielded inconclusive results regarding the efficacy of resveratrol in alleviating hepatic steatosis or reducing any of the parameters found in MASLD in human patients. The lack of homogeneity between studies, low bioavailability of resveratrol, and population variability when compared to animal models could be the reasons for this.

A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Subjects were randomized to either receive two tablets of soy isoflavone (100 mg/day) or placebo. At week 12, the serum levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and controlled attenuation parameter (CAP) score were significantly decreased only in the soy isoflavone group (P < 0.05). A significant decline in the gamma glutamyl transferase (GGT) level was observed only in the placebo group (P = 0.017). A significant increase in the serum level of fetuin A was shown in both groups at the end of the trial with a significantly greater increment in the soy isoflavone group compared to the placebo group (P < 0.05). The changes in the serum level of FGF-21 were not significant in any of the two groups. Steatosis grade significantly improved only in the soy isoflavone group (P = 0.045). There was no significant change in the fibrosis grade in the groups. Soy isoflavone intake led to a decrease in ALT, AST, CAP score, steatosis grade and an increase in the level of fetuin A. However, no significant changes were observed in the fibrosis grade and serum levels of GGT and FGF-21.

Plants are a natural treasure trove; their secondary metabolites participate in several pharmacological processes, making them a crucial component in the synthesis of novel pharmaceuticals and serving as a reserve resource foundation in this process. Nonalcoholic fatty liver disease (NAFLD) is associated with the risk of progression to hepatitis and liver cancer. The "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions" have listed herbal remedies to treat liver diseases.

Chinese herbal medicines have been widely used for the prevention and treatment of NAFLD owing to their efficacy and low side effects. The production of reactive oxygen species (ROS) during NAFLD, and the impact and potential mechanism of ROS on the pathogenesis of NAFLD are discussed in this review. Furthermore, common foods and herbs that can be used to prevent NAFLD, as well as the structure-activity relationships and potential mechanisms, are discussed.

Web of Science, PubMed, CNKI database, Google Scholar, and WanFang database were searched for natural products that have been used to treat or prevent NAFLD in the past five years. The primary search was performed using the following keywords in different combinations in full articles: NAFLD, herb, natural products, medicine, and ROS. More than 400 research papers and review articles were found and analyzed in this review.

By classifying and discussing the literature, we obtained 86 herbaceous plants, 28 of which were derived from food and 58 from Chinese herbal medicines. The mechanism of NAFLD was proposed through experimental studies on thirteen natural compounds (quercetin, hesperidin, rutin, curcumin, resveratrol, epigallocatechin-3-gallate, salvianolic acid B, paeoniflorin, ginsenoside Rg1, ursolic acid, berberine, honokiol, emodin). The occurrence and progression of NAFLD could be prevented by natural antioxidants through several pathways to prevent ROS accumulation and reduce hepatic cell injuries caused by excessive ROS.

This review summarizes the natural products and routinely used herbs (prescription) in the prevention and treatment of NAFLD. Firstly, the mechanisms by which natural products improve NAFLD through antioxidant pathways are elucidated. Secondly, the potential of traditional Chinese medicine theory in improving NAFLD is discussed, highlighting the safety of food-medicine homology and the broader clinical potential of multi-component formulations in improving NAFLD. Aiming to provide theoretical basis for the prevention and treatment of NAFLD.

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide+ precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.

Reactive oxygen species are a group of cellular molecules that stand as double-edged swords, their good and bad being discriminated by a precise balance. Several metabolic reactions in the biological system generate these molecules that interact with cellular atoms to regulate functions ranging from cell homeostasis to cell death. A prooxidative state of the cell concomitant with decreased clearance of such molecules leads to oxidative stress, which contributes as a prime pathophysiological mechanism in various diseases including renal disorders, such as acute kidney injury. However, targeting the generation of oxidative stress in renal disorders by an antioxidant, resveratrol, is gaining considerable therapeutic importance and is known to improve the condition in preclinical studies. This review aims to discuss molecular mechanisms of oxidative stress in acute kidney injury and its amelioration by resveratrol. The major sources of data were PubMed and Google Scholar, with studies from the last five years primarily included, with significant earlier data also considered. Mitochondrial dysfunction, various enzymatic reactions, and protein misfolding are the major sources of reactive oxygen species in acute kidney injury, and interrupting these loci of generation or intersection with other cellular components by resveratrol can mitigate the severity of the condition.

Garcinol is a naturally occurring compound from the fruit rind of the Garcinia indica, with antioxidant, anti-inflammatory, and anticancer properties. Curcuminoids are the active molecule from the rhizome of Curcuma longa, studied extensively for its health benefits as an anti-inflammatory and antioxidant activities. Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic steatohepatitis characterized by liver fat and inflammation.

To evaluate the clinical efficacy and safety of Garcinol, Curcuminoids and piperine (GCP) combination in patients with mild to moderate NASH in a randomized, double-blind, placebo-controlled study.

The patients received one tablet (450 mg) of GCP containing garcinol-50 mg, curcuminoids -250 mg and piperine 5 mg or a placebo (450 mg of microcrystalline cellulose) twice daily for 90 days. Changes in circulating aspartate aminotransferase (AST), alanine transaminase (ALT) levels, liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) using Fibroscan were compared from baseline to day 90. Anthropometric parameters, serum levels of lipids, Interleukin (IL-6), hsCRP, and adiponectin were estimated. Safety was evaluated by laboratory parameters and by monitoring adverse events.

Seventy-two patients were randomized and 63 (GCP = 32, Placebo = 31) completed the study. The mean age of the patients was 48.3 ± 8.7 years (36 males and 27 females). The mean reduction in AST (U/L) was 9.53 in GCP and 3.16 in placebo (p < 0.001) and that of ALT (U/L) was 13.47 in GCP and 7.43 in Placebo (p = 0.002). The liver stiffness and CAP scores showed a better reduction in GCP (0.56 kPa and 12.38 db/m) compared to placebo (0.064 kPa and 10.42 db/m) p < 0.05. Consequently, the noninvasive Fibroscan-AST (FAST) score reduction was also found to be significant in GCP compared to placebo. Additionally, body weight, lipid levels, hsCRP, and IL-6 in serum decreased, while adiponectin levels increased in GCP-supplemented participants compared to placebo. The combination of garcinol and curcuminoids was well tolerated with no significant changes in hematological and clinical laboratory parameters during the 90-day supplementation.

Our results suggest that GCP could be a possible supplement for the management of NASH.Clinical trial registration: https://clinicaltrials.gov/, identifier CTRI/2019/11/022147.

Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.

Sirtuins are Nicotinamide Adenine Dinucleotide (NAD+) dependent class ІΙΙ histone deacetylases enzymes (HDACs) present from lower to higher organisms such as bacteria (Sulfolobus solfataricus L. major), yeasts (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), humans (Homo sapiens sapiens), even in plants such as rice (Oryza sativa), thale cress (Arabidopsis thaliana), vine (Vitis vinifera L.) tomato (Solanum lycopersicum). Sirtuins play an important role in the regulation of various vital cellular functions during metabolism and ageing. It also plays a neuroprotective role by modulating several biological pathways such as apoptosis, DNA repair, protein aggregation, and inflammatory processes associated with ageing and neurodegenerative diseases. In this review, we have presented an updated Sirtuins and its role in ageing and age-related neurodegenerative diseases (NDDs). Further, this review also describes the therapeutic potential of Sirtuins and the use of Sirtuins inhibitor/activator for altering the NDDs disease pathology.

Long-term liver injuries lead to hepatic fibrosis, often progressing into cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. There is currently no effective therapy available for liver fibrosis. Thus, continuous investigations for anti-fibrotic therapy are ongoing. The main theme of anti-fibrotic investigation during recent years is the rationale-based selection of treatment molecules according to the current understanding of the pathology of the disease. The research efforts are mainly toward repurposing current FDA-approved drugs targeting etiological molecular factors involved in developing liver fibrosis. In parallel, investigations also focus on experimental small molecules with evidence to hinder or reverse the fibrosis. Natural compounds, immunological, and genetic approaches have shown significant encouraging effects. This review summarizes the efficacy and safety of current under-investigation antifibrosis medications targeting various molecular targets, as well as the properties of antifibrosis medications, mainly in phase II and III clinical trials.

Chronic liver disease (CLD) affects a significant portion of the global population, leading to a substantial number of deaths each year. Distinct forms like non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD), though they have different etiologies, highlight shared pathologies rooted in oxidative stress. Central to liver metabolism, mitochondria are essential for ATP production, gluconeogenesis, fatty acid oxidation, and heme synthesis. However, in diseases like NAFLD, ALD, and liver fibrosis, mitochondrial function is compromised by inflammatory cytokines, hepatotoxins, and metabolic irregularities. This dysfunction, especially electron leakage, exacerbates the production of reactive oxygen species (ROS), augmenting liver damage. Amidst this, nuclear factor erythroid 2-related factor 2 (NRF2) emerges as a cellular protector. It not only counters oxidative stress by regulating antioxidant genes but also maintains mitochondrial health by overseeing autophagy and biogenesis. The synergy between NRF2 modulation and mitochondrial function introduces new therapeutic potentials for CLD, focusing on preserving mitochondrial integrity against oxidative threats. This review delves into the intricate role of oxidative stress in CLD, shedding light on innovative strategies for its prevention and treatment, especially through the modulation of the NRF2 and mitochondrial pathways.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise globally. It is currently one of the most prevalent liver diseases and one of the world's important public health problems. At present, there is no consensus on a pharmacological treatment for MAFLD. By contrast, lifestyle interventions based on exercise and a balanced diet are considered to be the cornerstone of MAFLD management. Mediterranean diet (MD) have a large content of polyphenols, polyunsaturated fatty acids, oleic acid, carotenoids and fiber, which carry out antioxidant, anti-inflammatory and antibacterial benefits. It has been considered to reduce the incidence rate of cardiovascular disease and type 2 diabetes. The purpose of this narrative review is therefore to summarize and analyze the evidence for the effect of MD on metabolic outcomes in MAFLD patients.

Lifestyle modification with regular exercise can improve metabolic diseases by reducing lipid profile and inflammation. Probiotics have been recently recommended not only for gastrointestinal diseases but also for metabolic and even degenerative diseases. Therefore, in the present study, the effect of high-intensity interval training (HIIT) and Lacticaseibacillus rhamnosus strain GG (LGG) as a probiotic on tetracycline-induced hepatic steatosis in an animal model was evaluated. Eighty male Wistar rats were randomly divided into eight groups (n = 10 in each group): control, LGG, HIIT, LGG + HIIT, tetracycline-induced (TTC), TTC + LGG, TTC + HIIT, and TTC + LGG + HIIT. The rats are treated by intraperitoneal injection (IP) with 140 mg kg-1 tetracycline, an antibiotic previously known to induce steatosis. The exercise training groups performed HIIT 5 days/week for 5 weeks, and 107 CFU/ml of Lacticaseibacillus rhamnosus GG was gavaged for the LGG groups 5 days/week for 5 weeks. Fatty droplets in the hepatocyte were considered with Oil Red staining. TTC-receiving rats have more lipid accumulation and larger lipid droplets in the liver compared to healthy animals. The two-way ANOVA showed that the interaction of LGG and HIIT significantly decreased LDL, cholesterol, and triglyceride in the healthy rats (p < 0.05). In TTC-receiving rats, the interaction of LGG and HIIT significantly increased HDL and SOD and significantly decreased triglyceride, ALP, AST, and ALT (p < 0.05). The consumption of probiotic LGG, along with HIIT with control of lipid profile and liver enzymes and improvement of the oxidative capacity, neutralizes the damage of TTC to liver tissue. Therefore, this protocol can be recommended for people with hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is a progressive condition that encompasses a spectrum of liver disorders, beginning with the simple steatosis, progressing to nonalcoholic steatohepatitis (NASH), and possibly leading to more severe diseases, including liver cirrhosis and hepatocellular carcinoma (HCC). In recent years, the prevalence of NAFLD has increased due to a shift towards energy-dense dietary patterns and a sedentary lifestyle. NAFLD is also strongly associated with metabolic disorders such as obesity and hyperlipidemia. The progression of NAFLD could be influenced by a variety of factors, such as diet, genetic factors, and even epigenetic factors. In contrast to genetic factors, epigenetic factors, including histone modifications, exhibit dynamic and reversible features. Therefore, the epigenetic regulation of the initiation and progression of NAFLD is one of the directions under intensive investigation in terms of pathogenic mechanisms and possible therapeutic interventions. This review aims to discuss the possible mechanisms and the crucial role of histone modifications in the framework of epigenetic regulation in NAFLD, which may provide potential therapeutic targets and a scientific basis for the treatment of NAFLD.

Background: Resveratrol, a polyphenol found in various plants, is known for its diverse bioactivities and has been explored in relation to nonalcoholic fatty liver disease (NAFLD). However, no high-quality evidence exists regarding its efficacy. Objective: a meta-analysis was conducted to evaluate the potential efficacy of resveratrol in treating nonalcoholic fatty liver disease by analyzing both preclinical studies and clinical trials. Method: PubMed, Embase and Web of Science were searched for the included literature with the criteria for screening. Quantitative synthesis and meta-analyses were performed by STATA 16.0. Results: Twenty-seven studies were included, and the results indicated that resveratrol effectively improved liver function, reduced fatty liver indicators, and affected other indices in preclinical studies. The effective dosage ranged from 50 mg/kg-200 mg/kg, administered over a period of 4-8 weeks. While there were inconsistencies between clinical trials and preclinical research, both study types revealed that resveratrol significantly reduced tumor necrosis factor-α levels, further supporting its protective effect against nonalcoholic fatty liver disease. Additionally, resveratrol alleviated nonalcoholic fatty liver disease primarily via AMPK/Sirt1 and anti-inflammatory signaling pathways. Conclusion: Current meta-analysis could not consistently verify the efficacy of resveratrol in treating nonalcoholic fatty liver disease, but demonstrated the liver-protective effects on nonalcoholic fatty liver disease. The large-sample scale and single region RCTs were further needed to investigate the efficacy.

Liver fibrosis is a major challenge to global health because of its various complications, including cirrhosis and hepatocarcinoma, while no effective treatment is available for it. Sappanone A (SA) is a homoisoflavonoid extracted from the heartwood of Caesalpinia sappan Linn. with anti-inflammatory and antioxidant properties. However, the effects of SA on hepatic fibrosis remain unknown. This study aimed to investigate the protective effects of SA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. To establish a liver fibrosis model, mice were treated intraperitoneally (i.p.) with CCl4 for 4 weeks. SA (25, 50, and 100 mg/kg body weight) was i.p. injected every other day during the same period. Our data indicated that SA decreased liver injury, fibrotic responses, and inflammation due to CCl4 exposure. Consistently, SA reduced oxidative stress and its-mediated hepatocyte death in fibrotic livers. Of note, SA could not directly affect the activation of hepatic stellate cells. Mechanistically, SA treatment lessened oxidative stress-triggered cell death in hepatocytes after CCl4 exposure. SA down-regulated the expression of M1 macrophage polarization markers (CD86 and iNOS) and up-regulated the expression of M2 macrophage polarization markers (CD163, IL-10, and Arg1) in livers and macrophages. Meanwhile, SA induced the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, decreased inflammatory responses and the trend of M2 macrophage polarization provided by SA were substantially abolished by SR202 (a PPARγ inhibitor) treatment in macrophages. Additionally, SA treatment promoted fibrosis regression. Taken together, our findings revealed that treatment with SA alleviated CCl4-induced fibrotic liver in mice through suppression of oxidative stress-mediated hepatocyte death and promotion of M2 macrophage polarization via PPARγ. Thus, SA might pave the way for a new hepatoprotective agent to treat liver fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is a common condition that is prevalent in patients who consume little or no alcohol, and is characterized by excessive fat accumulation in the liver. The disease is becoming increasingly common with the rapid economic development of countries. Long-term accumulation of excess fat can lead to NAFLD, which represents a global health problem with no effective therapeutic approach. NAFLD is a complex, multifaceted pathological process that has been the subject of extensive research over the past few decades. Herbal medicines have gained attention as potential therapeutic agents to prevent and treat NAFLD due to their high efficacy and low risk of side effects. Our overview is based on a PubMed and Web of Science database search as of Dec 22 with the keywords: NAFLD/NASH Natural products and NAFLD/NASH Herbal extract. In this review, we evaluate the use of herbal medicines in the treatment of NAFLD. These natural resources have the potential to inform innovative drug research and the development of treatments for NAFLD in the future.

The flexibility between the wide array of hepatic functions relies on calcium (Ca2+) signalling. Indeed, Ca2+ is implicated in the control of many intracellular functions as well as intercellular communication. Thus, hepatocytes adapt their Ca2+ signalling depending on their nutritional and hormonal environment, leading to opposite cellular functions, such as glucose storage or synthesis. Interestingly, hepatic metabolic diseases, such as obesity, type 2 diabetes and non-alcoholic fatty liver diseases, are associated with impaired Ca2+ signalling. Here, we present the hepatocytes' toolkit for Ca2+ signalling, complete with regulation systems and signalling pathways activated by nutrients and hormones. We further discuss the current knowledge on the molecular mechanisms leading to alterations of Ca2+ signalling in hepatic metabolic diseases, and review the literature on the clinical impact of Ca2+-targeting therapeutics.