This study was performed by Cano Contreras et al, who explored the effects of alpha-lipoic acid (ALA) and Silybum marianum (SM) supplementation combined with a mediterranean diet (MD) on metabolic dysfunction-associated steatotic liver disease (MASLD). The randomized controlled design and use of transient elastography provide methodological strengths, whereas the focus on a Mexican cohort addresses a critical gap in regional MASLD research. Although improvements in visceral fat and controlled attenuation parameters (CAP) were observed, key metabolic markers, including transaminases and lipid profiles, showed no significant changes, raising concerns about the intervention's comprehensive metabolic impact. The reliance on CAP and the absence of mechanistic biomarker analysis limit insights into the antioxidant and anti-inflammatory pathways of ALA and SM. Future research should explore synergistic effects with other nutraceuticals, such as vitamin E and polyphenols, and include extended follow-up and patient stratification to assess long-term benefits and personalized therapeutic outcomes. Addressing these limitations could solidify the role of nutraceuticals in MASLD management and enable the development of more effective and sustainable interventions.

Background: Despite the well-established liver-protective efficacy of monoammonium glycyrrhizinate (MONO), diammonium glycyrrhizinate (DIAM), and magnesium isoglycyrrhizinate (MAGN), which has been translated into clinical practice, their clinical differentiation remains elusive owing to their structural similarities and overlapping therapeutic effects. Methods: The present study delves into the pharmacokinetics, cellular-level liver-protective potencies, and underlying mechanisms of action of these three compounds through a comprehensive analysis. Results: The findings reveal that both DIAM and MAGN exhibit superior bioavailability and hepatoprotective profiles compared to MONO. Notably, an investigation of the metabolic pathways mediating liver protection in normal human liver cells (LO2), utilizing an ultra-performance liquid chromatography-time of flight tandem mass spectrometry (UPLC-TOF-MS/MSe) platform, demonstrated that MAGN augments antioxidant components, thereby favoring its application in drug-induced liver injury (DILI). Conversely, DIAM appears to be a more suitable candidate for addressing non-alcoholic fatty liver disease (NAFLD) and viral hepatitis. Conclusion: This study contributes novel perspectives on the mechanisms of action and potential clinical utilities of DIAM and MAGN in liver disease prevention and management.

Luffa acutangula var. amara (Roxb.) C.B. Clarke, known as 'Katu Koshataki' in Ayurveda, is a traditional medicinal plant in India. The juice of these fruits is recommended for chronic alcohol-induced liver diseases.

This study aimed to validate the hepatoprotective and antioxidant properties of Luffa acutangula var. amara fruit pericarp ethanolic extract (EOLA) against ethanol-induced chronic hepatotoxicity in rats, isolate bioactive phytochemicals and in silico evaluation.

Ethanolic extract of L. acutangula var. amara fruit pericarp was evaluated in chronic alcohol-induced hepatitis (20% ethanol orally twice daily for 28 days) at doses of 100 and 200 mg/kg p.o. Additionally, in vivo anti-inflammatory and antioxidant potential were assessed. Luteolin and gallic acid were isolated using bioactivity guided fractionation. Furthermore, these phytochemicals were assessed for hepatoprotective potential using molecular docking and molecular dynamics studies against different targets.

The EOLA demonstrated efficacy in stabilizing elevated biochemical markers and antioxidant levels associated with ethanol-induced hepatotoxicity in rats, and it preserved the normal architecture of hepatocytes in histological analyses compared to the ethanol control group. The EOLA was subjected to fractionation using hexane: chloroform (8:2 → 2:8), followed by chloroform: methanol (8:2 → 2:8) to yield a total eight fractions. The fractions 1, 2, and 3 showed potent antioxidant potential, yielding luteolin and gallic acid as LAC-1 and LAC-3 from fractions 1 and 8, respectively. Gallic acid and luteolin were investigated using molecular docking and molecular dynamic simulation techniques to assess their interactions with key proteins such as Cytochrome P450 2C9, Superoxide Dismutase, Glutathione Peroxidase, Glutathione S-Transferase, Catalase, Peroxisome Proliferator-Activated Receptor-ϒ, Vanin-1, and Cannabinoid Receptor CB2. The metabolites exhibit strong binding stability, with a root mean square deviation range of less than 2.8 Å.

It can be concluded that the fruit pericarp of L. acutangula var. amara could be used as a functional food for reducing the liver damage caused by alcohol and other factors.

Background: Estrogen depletion alters bone mineralization and oxidative stress. Antioxidants like humic acids (HA) may help mitigate bone demineralization and redox imbalances. Thus, this study evaluated the effects of HA on bone mineral composition and oxidative stress markers in an experimental menopause model. Methods: Twenty-four female C57BL/6 mice were divided into four groups (n = 6/group): Sham; Sham + HA; Ovariectomized (OVX); and OVX + HA. The menopause model was induced by bilateral ovariectomy at the beginning of the experiment. HA derived from biomass vermicompost was administered daily by gavage for 28 days. After euthanasia, femurs and fragments of the gastrocnemius muscle, liver, and kidney were collected. Bone elemental composition was analyzed using scanning electron microscopy (SEM) coupled with energy dispersive spectroscopy (EDS). Superoxide dismutase (SOD), catalase (CAT), and hydrogen peroxide (H2O2) activities were assessed in muscle, renal, and hepatic tissues. Data were analyzed using two-way ANOVA and Bonferroni's post hoc test. Results: Untreated OVX mice exhibited a significant reduction in femoral calcium content (p < 0.05). However, HA treatment increased calcium levels and improved the Ca/P ratio (p < 0.05). H2O2 activity was reduced in the liver and kidney of OVX + HA mice compared to untreated animals (p < 0.05). CAT activity in muscle increased in the OVX + HA group compared to the OVX (p < 0.05). Conclusions: HA treatment improved femoral elemental composition and modulated oxidative stress markers in an experimental menopause model.

Exposure to ionizing radiation is inevitable due to its extensive use in industrial and medical applications. The search for effective and safe natural therapeutic agents as alternatives to chemical drugs is crucial to mitigate their side effects. This study aimed to evaluate the effects of citicoline as a standalone treatment or in combination with the anti-hepatotoxic drug silymarin in protecting against liver injury caused by γ-radiation in rats.

The rats were exposed to γ-radiation (7 Gy) and treated with citicoline (300 mg/kg/day) and/or silymarin (50 mg/kg/day). The results showed that citicoline alleviated liver damage in irradiated rats by reducing hepatic malondialdehyde levels, serum aspartate aminotransferase activity, and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and nuclear factor-kappa B (NF-κB). It also increased acetylcholine (ACh) levels and the gene expression of the anti-inflammatory protein α7 nicotinic acetylcholine receptor (α7nAChR). Additionally, citicoline improved serum triiodothyronine (T3) levels, thyroid hormone receptor beta (TRβ) gene expression, and iodothyronine deiodinase type 1 activity in hepatic tissues of irradiated rats. Furthermore, citicoline enhanced the effects of silymarin on thyroxine (T4), TRβ, ACh, and α7nAChR when co-administered in irradiated rats. Histopathological analysis confirmed these findings, demonstrating improved liver tissue structure.

Citicoline mitigates γ-radiation-induced liver damage by reducing oxidative stress, activating the cholinergic anti-inflammatory pathway, and modulating thyroid hormone metabolism. These findings support the use of citicoline as a safe standalone treatment or as an adjuvant with silymarin for managing liver damage and thyroid hormone disturbances caused by γ-irradiation.

Trimethylamine N-oxide (TMAO) is a metabolite produced by gut microbiota, and its potential impact on lipid metabolism in mammals has garnered widespread attention in the scientific community. Bovine fatty liver disease, a metabolic disorder that severely affects the health and productivity of dairy cows, poses a significant economic burden on the global dairy industry. However, the specific role and pathogenesis of TMAO in bovine fatty liver disease remain unclear, limiting our understanding and treatment of the condition. This study aims to construct a bovine fatty liver cell model using an integrated approach that combines transcriptomic, proteomic, and metabolomic data. The objective is to investigate the impact of TMAO on lipid metabolism at the molecular level and explore its potential regulatory mechanisms.

We established an in vitro bovine fatty liver cell model and conducted a comprehensive analysis of cells treated with TMAO using high-throughput omics sequencing technologies. Bioinformatics methods were employed to delve into the regulatory effects on lipid metabolism, and several key genes were validated through RT-qPCR. Treatment with TMAO significantly affected 4790 genes, 397 proteins, and 137 metabolites. KEGG enrichment analysis revealed that the significantly altered molecules were primarily involved in pathways related to the pathology of fatty liver disease, such as metabolic pathways, insulin resistance, hepatitis B, and the AMPK signaling pathway. Moreover, through joint analysis, we further uncovered that the interaction between TMAO-mediated AMPK signaling and oxidative phosphorylation pathways might be a key mechanism promoting lipid accumulation in the liver.

Our study provides new insights into the role of TMAO in the pathogenesis of bovine fatty liver disease and offers a scientific basis for developing more effective treatment strategies.

Insulin resistance is a primary feature of type 2 diabetes. This study compared the effects of curcumin and its nanoformulation on insulin resistance, fasting blood sugar, liver function, GLUT4, lipid profile, and oxidative stress in the liver and pancreas in a diabetic model.

Thirty male Wistar rats were divided into five groups: a control group, a diabetic group, a diabetic group treated with metformin (40 mg/kg), a diabetic group treated with curcumin (100 mg/kg), and a diabetic group treated with curcumin NPs (100 mg/kg). Diabetes was induced by injecting dexamethasone daily for 14 days. Treatment with curcumin and curcumin NPs was administered by gavage for 14 days. Body weight and fasting blood sugar levels were measured on days 1, 14, and 28.

The metformin, curcumin, and curcumin NPs groups showed significantly greater body weight gain than the untreated diabetic group (P < 0.001). In diabetic rats treated with curcumin and curcumin NPs, insulin resistance decreased by approximately 40 %, while fasting blood sugar levels dropped by 35-40 % (P < 0.001). The levels of liver enzymes (AST, ALT), cholesterol, triglycerides, LDL, and the oxidative stress marker MDA in liver and pancreatic tissues were reduced by 30-50 %. Additionally, beneficial markers such as albumin, HDL, antioxidants (GSH, SOD), and GLUT4 levels were increased by 25-45 % (P < 0.001). Nano-curcumin consistently showed greater improvements than curcumin, especially in reducing oxidative stress and supporting liver and pancreatic health.

This study demonstrates that curcumin NPs has a superior effect on reducing oxidative stress and improving metabolic parameters in diabetes compared to curcumin. by enhancing the bioavailability and stability of curcumin, the nanoformulation showed stronger therapeutic potential for managing high blood sugar, cholesterol issues, and liver health, positioning curcumin NPs as a promising alternative to conventional treatments for diabetes and its complications.

Nonalcoholic fatty liver disease (NAFLD) is increasingly concerning due to its rising prevalence. It encompasses conditions from simple steatosis to severe nonalcoholic steatohepatitis (NASH), posing risks such as fibrosis, cirrhosis, or hepatocellular carcinoma if untreated. This systematic review and meta-analysis aims to assess aldafermin, an FGF19 analog, for efficacy and safety in NASH patients.

Eligible studies were identified by searching PubMed, Cochrane Library, and Google Scholar, resulting in 1115 studies. Three RCTs were included. The risk of bias was assessed using the Cochrane Risk of Bias tool, and data synthesis utilized Review Manager software. The certainty of evidence was evaluated with the GRADE approach.

In the 3 mg dose group, aldafermin significantly improved various parameters. The ELF score decreased notably (pooled MD: -0.46, 95% CI: -0.64 to -0.28; P<0.00001). Additionally, fibrosis improvement without NASH worsening showed a pooled MD of 8.15 (95% CI: -3.62 to 19.93; P<0.17), and fibrosis improvement with NASH resolution displayed a pooled MD of 10.16 (95% CI: 1.68-18.64; P=0.02). Furthermore, significant reductions were noted in absolute AST levels (pooled MD: -13.40, 95% CI: -18.66 to -8.14; P<0.00001) and absolute ALT levels (pooled MD: -19.92, 95% CI: -27.08 to -12.75; P<0.00001), suggesting improved liver function.

The meta-analysis indicates that aldafermin, particularly, the 3 mg dose, shows significant efficacy in improving liver histology and biochemical markers in NASH patients compared to placebo, along with a satisfactory safety profile.

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.

Liver cancer represents a multifactorial, multistage, and intricately progressive malignancy. Over the past decade, artesunate (ART), initially renowned for its anti-malarial efficacy, has been the focus of over 3000 studies uncovering its diverse pharmacological actions, including anti-inflammatory, immunoregulatory, metabolic regulatory, anti-fibrotic, and anti-cancer properties. This review highlights ART's role in the multistep progression from hepatitis to cancer and its underlying regulatory mechanisms, revealing signal transducer and activator of transcription 3 (STAT3) and ferroptosis (a novel form of programmed cell death) as promising therapeutic targets. ART demonstrates efficacy in inhibiting hepatitis virus infections, modulating inflammation, and facilitating recovery from inflammatory processes. During stages of hepatic fibrosis or cirrhosis, ART reverses fibrotic and cirrhotic changes by suppressing hepatic stellate cell activity, regulating inflammatory pathways, inhibiting hematopoietic stem cell proliferation, and inducing ferroptosis. Additionally, ART hinders hepatocellular carcinoma (HCC) cell proliferation, invasion, and metastasis, induces apoptosis and autophagy, combats drug resistance, and enhances chemosensitivity. Collectively, ART exhibits multi-step actions across multiple targets and signaling pathways, highlighting its potential as a clinical candidate for the prevention and treatment of liver cancer, from hepatitis and hepatic fibrosis to advanced HCC.

Non-alcoholic fatty liver disease (NAFLD) not only could cause abnormal lipid metabolism in the liver, but also could cause liver inflammation. Previous studies have shown that Polysaccharide of Atractylodes macrocephala Koidz (PAMK) could alleviate animal liver inflammatory damage and alleviate NAFLD in mice caused by high-fat diet(HFD), but regulation of liver inflammation caused by NAFLD has rarely been reported. In this study, an animal model of non-alcoholic fatty liver inflammation in the liver of mice was established to explore the protective effect of PAMK on the liver of mice. The results showed that PAMK could alleviate the abnormal increase of body weight and liver weight of mice caused by HFD, alleviate the abnormal liver structure of mice, reduce the level of oxidative stress and cytokine secretion in the liver of mice, and downregulate the mRNA expression of TLR4, MyD88, NF-κB and protein expression of P-IκB, P-NF-κB-P65, TLR4, MyD88, NF-κB in the liver. These results indicate that PAMK could alleviate hepatocyte fatty degeneration and damage, oxidative stress and inflammatory response of the liver caused by NAFLD in mice.

The relationship between dietary antioxidants and fatty liver disease remains a topic of debate. This study aimed to examine the association between the Composite Dietary Antioxidant Index (CDAI) and nonalcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD).

The study analyzed data from the 2003-2018 cycles of the National Health and Nutrition Examination Survey. The study included 16,321 individuals aged 20-85 years. Food and nutrient intake data were based on the 24-h recall method. Multivariate logistic regression models were employed to examine the relationship between CDAI and NAFLD/MAFLD.

In the fully adjusted multivariate logistic regression model, CDAI demonstrated a significant negative correlation with NAFLD and MAFLD. Mediation analysis showed that inflammatory factors partially mediated the relationship between CDAI and NAFLD/MAFLD prevalence. The combination of high CDAI levels with effective physical activity was associated with a greater reduction in NAFLD/MAFLD prevalence than high CDAI levels alone.

Our study highlighted a negative association between CDAI and NAFLD/MAFLD, mediated by inflammatory factors. Additionally, participants with characteristics of active physical activity and high levels of CDAI were more strongly correlated with the reduced prevalence of NAFLD/MAFLD. Further research in clinical cohorts should be conducted to comprehensively investigate the impact of CDAI on NAFLD/MAFLD prevalence.

Background/Objectives: Alzheimer's disease (AD) is the most common form of dementia and affects approximately 50 million individuals worldwide. Interest in coconut oil (CO) as a potential dietary intervention has surged owing to its substantial medium-chain triglyceride (MCT) content. Therefore, sustaining cognitive function and potentially slowing the progression of AD are crucial. This systematic review and meta-analysis evaluated the effects of CO and its bioactive metabolites on AD and dementia. Methods: The review protocol is registered in PROSPERO (CRD42023450435). Relevant research articles published between January 2015 and June 2023 were systematically searched. Seven studies met the predetermined eligibility criteria. Thematic analysis was utilized to synthesis the data about the qualitative features, while meta-analysis was employed for the quantitative findings. A meta-analysis was conducted to assess the standardized mean difference (SMD) and the corresponding 95% confidence interval (CI). Forest plots were generated using Review Manager 5.3 (RevMan 5.3). Results: The analysis revealed that all studies showed consistent results regarding the effects of CO on cognitive scores, with little variability in the true effects of CO on cognitive scores across the studies included in the meta-analysis. Conclusions: CO improved cognitive scores in patients with AD compared with those in the control group (p < 0.05). The results of this study add to the increasing amount of evidence indicating that MCTs found in CO might be a way to improve abilities and potentially slow the advancement of AD. The findings of this study may encourage the development of targeted dietary strategies and interventions for individuals at risk of or diagnosed with AD.

With the increasing prevalence and serious health consequences of metabolic-associated fatty liver disease (MAFLD), early diagnosis and intervention are key to effective treatment. Recent studies highlight the important role of dietary factors, including the use of flavonoids, in improving liver health. These compounds possess anti-inflammatory, antioxidant, and liver-protective properties. Flavonoids have been shown to affect the gut microbiota, which plays a key role in liver function and disease progression. Therefore, their role in preventing the development and progression of MAFLD through modulation of the microbiome seems to be of interest. This narrative review aims to consolidate the current evidence on the effects of selected flavonoids on MAFLD progression, their potential mechanisms of action, and the implications for the development of personalized dietary interventions for the management of liver disease.

Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl4-induced murine model.

A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson's trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR.

SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl4 via activating Farnesoid X receptor.

These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a growing public health concern characterized by fat accumulation and severe disorders like nonalcoholic steatohepatitis (NASH), which are influenced by obesity, inflammatory processes, and metabolic pathways. This research investigates the potential of silymarin-supplemented cookies in managing NAFLD by evaluating their impact on liver enzyme activity, inflammatory markers, and lipid profiles. A clinical trial in Lahore, Pakistan, involved 64 NAFLD patients. Participants were divided into placebo and three treatment groups, with the latter receiving silymarin-supplemented cookies for 3 months. The study assessed liver enzyme levels and inflammatory markers, at baseline and after the intervention, utilizing statistical analyses to evaluate differences. The lipid profile and renal function test (RFT) were also measured at baseline and after 3 months in each group for safety assessment. After 3 months, the treatment groups indicated more significant decreases in liver enzymes compared to the placebo group (p ≤ .05). Treatment 3 showed significant reductions in alanine aminotransferase (ALT) (64.39-49.38 U/L) and aspartate aminotransferase (AST) (61.53-45.38 U/L). Treatment 3 also showed improvements in alkaline phosphatase (ALP) levels and the AST/ALT ratio. Additionally, the treatment group demonstrated a significant reduction in inflammatory markers. Treatment 3 showed a significant decrease in C-reactive protein (CRP) (6.32-3.39 mg/L) and erythrocyte sedimentation rate (ESR) (38.72-23.86 mm/h), indicating that individuals with NAFLD may benefit from the intervention's potential benefits in lowering inflammation. The study revealed that an intervention significantly improved the inflammatory markers, liver enzymes, and lipid profiles of NAFLD participants, suggesting potential benefits for liver health.

Due to the pathological production of liver disease in utility particularly complexity, the morbidity and mortality of liver disease including viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. Considering its insidious onset, rapid progression and drug resistance, finding an effective therapy is particularly worthwhile. Phyllanthus urinaria L. (P. urinaria), an ethnic medicine, can be applied at the stages of viral hepatitis, liver fibrosis/cirrhosis and HCC, which demonstrates great potential in the treatment of liver disease. Currently, there are numerous reports on the application of P. urinaria in treating liver diseases, but a detailed analysis of its metabolites and a complete summary of its pharmacological mechanism are still scarce. In this review, the phytochemical metabolites and ethnopharmacological applications of P. urinaria are summarized. Briefly, P. urinaria mainly contains flavonoids, lignans, tannins, phenolic acids, terpenoids and other metabolites. The mechanisms of P. urinaria are mainly reflected in reducing surface antigen secretion and interfering with DNA polymerase synthesis for anti-viral hepatitis activity, reducing hepatic stellate cells activity, inflammation and oxidative stress for anti-liver fibrosis/cirrhosis activity, as well as preventing tumor proliferation, invasion and angiogenesis for anti-HCC activity via relevant signaling pathways. Accordingly, this review provides insights into the future application of natural products in the trilogy of liver diseases and will provide a scientific basis for further research and rational utilization of P. urinaria.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a predominant liver disease worldwide, lacking approved drugs for clinical intervention at present. The composite dietary antioxidant index (CDAI) is used to assess the anti-inflammatory properties of diets, with higher CDAI indicating greater exposure to antioxidants. Therefore, our study aimed to explore the relationship between CDAI and MASLD in order to identify potential therapeutic approaches. We collected data from 12,286 participants in the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2020 for analysis. The correlation between CDAI and MASLD status, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was evaluated by adjusting for confounding variables using weighted binary logistic regression model, linear regression model, and restricted cubic spline (RCS) regression. The median CDAI in this study was - 0.3055 (interquartile range [IQR], - 2.299 to 2.290). The CDAI was higher in the population characterized by being young, female, higher income, absence of diabetes, and non-MASLD. After multivariable adjustment, the results of the weighted linear regression model suggested that higher CDAI may be associated with a decrease in CAP values; the results of the RCS regression model indicated significant non-linear relationships between MASLD status, CAP, LSM, and CDAI. The CDAI corresponding to the inflection points of the relationship curves between MASLD status, CAP, LSM, and CDAI were 0.349, 0.699, and 0.174, respectively. After further stratification by gender, we found that the relationship between MASLD status, CAP, and CDAI was significantly linear for females, whereas for males, it was non-linear, and the CDAI values corresponding to the inflection points in the curves for males were 1.325 and 0.985, respectively. We found that higher CDAI may be associated with decreased CAP values, particularly significant in females, suggesting that the intake of complex dietary antioxidants may ameliorate hepatic steatosis and reduce the occurrence of MASLD. Therefore, promoting dietary patterns rich in antioxidants may be an appropriate strategy to reduce the incidence of MASLD.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.

Long-term hepatic damage is associated with human morbidity and mortality owing to numerous pathogenic factors. A variety of studies have focused on improving liver health using natural products and herbal medicines. We aimed to investigate the effect of enzyme-treated Zizania latifolia ethanol extract (ETZL), which increases the content of tricin via enzymatic hydrolysis, for 8 weeks on liver-related outcomes, lipid metabolism, antioxidant activity, and fatigue compared to a placebo. Healthy Korean adult males aged 19-60 years were randomized into ETZL treatment and placebo groups, and alcohol consumption was 24.96 and 28.64 units/week, respectively. Alanine transaminase, a blood marker associated with liver cell injury, significantly decreased after 8 weeks compared to the baseline in the ETZL treatment group (p = 0.004). After 8 weeks, the treatment group showed significant changes in the levels of high-density lipoprotein and hepatic steatosis index compared to the baseline (p = 0.028 and p = 0.004, respectively). ETZL treatment tended to reduce antioxidant-activity-related factors, total antioxidant status, and malondialdehyde, but there was no significant difference. In the multidimensional fatigue scale, ETZL treatment showed a significant reduction in general fatigue and total-fatigue-related values after 8 weeks compared to the baseline (p = 0.012 and p = 0.032, respectively). Taken together, the 8-week treatment of enzyme-treated Zizania latifolia ethanol extract demonstrated positive effects on liver-related outcomes, lipid metabolism, and mental fatigue without adverse effects on safety-related parameters.

Reactive oxygen species (ROS) are highly reactive oxygen derivatives that include free radicals such as superoxide anion radical (O2•-) and hydroxyl radical (HO•), as well as non-radical molecules hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hypochlorous acid (HOCl) [...].

Curcumin (CUR) is a compound extracted from turmeric that has a variety of functions including antioxidant and anti-inflammatory. As an estrogen-like mycotoxin, zearalenone (ZEN) not only attacks the reproductive system, but also has toxic effects on the liver. However, whether CUR can alleviate ZEN-induced liver injury remains unclear. This paper aims to investigate the protective effect of CUR against ZEN-induced liver injury in mice and explore the molecular mechanism involved. BALB/c mice were randomly divided into control (CON) group, CUR group (200 mg/kg b. w. CUR), ZEN group (40 mg/kg b. w. ZEN) and CUR+ZEN group (200 mg/kg b. w. CUR+40 mg/kg b. w. ZEN). 28 d after ZEN exposure and CUR treatment, blood and liver samples were collected for subsequent testing. The results showed that CUR reversed ZEN-induced hepatocyte swelling and necrosis in mice. It significantly reduced the serum alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice (p < 0.05). In addition, CUR significantly reduced hepatic ROS, malondialdehyde, hydrogen peroxide and apoptosis levels in mice (p < 0.05). Quantitative RT-PCR and Western blot results showed that CUR significantly reduced the expression of Bax and Caspase3, and reversed the increase of Nrf2, HO-1 and NQO1 expression in the liver of mice induced by ZEN (p < 0.05). In conclusion, CUR alleviated ZEN-induced liver injury in mice by scavenging ROS and inhibiting the mitochondrial apoptotic pathway.

Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox homeostasis is especially crucial in liver pathology, as disturbances at this level have been linked to a variety of chronic diseases. Hepatitis is an umbrella term used to describe liver inflammation, which is the foundation of this disease regardless of its cause. Chronic hepatitis produces both oxidative stress generated by hepatocyte inflammation and viral inoculation. The majority of hepatitis in children is caused by a virus, and current studies reveal that 60-80% of cases become chronic, with many young patients still at risk of advancing liver damage. This review intends to emphasize the relevance of understanding these pathological redox pathways, as well as the need to update therapeutic strategies in chronic liver pathology, considering the beneficial effects of antioxidants.

Lately, liver diseases were categorized as one of the most prevalent health problems globally as it causes a severe threat to mankind all over the world due to the wide range of occurrence. There are multiple factors causing hepatic disorders, such as alcohol, virus, poisons, adverse effects of drugs, poor diet, inherited conditions and obesity. Liver diseases have various types including alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, liver cancer, hepatocellular carcinoma, liver fibrosis and hepatic inflammation. Therefore, it is imperative to find effective and efficacious agents in managing liver diseases. Fusarium oxysporum, an endophytic fungus and containing many bioactive compounds, could be served as a forked medication for enormous number and types of maladies. It was characterized by producing biochemical compounds which had rare pharmacological properties as it may be found in a limit number of other medicinal plants. The majority of the past researches related to Fusarium oxysporum recited the fungal negative field either on the pathogenic effects of the fungus on economical crops or on the fungal chemical components to know how to resist it. The present review will highlight on the bright side of Fusarium oxysporum and introduce the functional activities of its chemical compounds for treating its target diseases. The key point of illustrated studies in this article is displaying wide range of detected bioactive compounds isolated from Fusarium oxysporum and in other illustrated studies it was elucidated the therapeutical and pharmacological potency of these biologically active compounds (isolated from medicinal plants sources) against different types of liver diseases including non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and others. It was demonstrated that F. oxysporum contains unique types of isoflavones, flavonoids, phenols and another active chemical compounds, and these compounds showed recently a fabulous clinical contribution in the therapy of liver injury diseases, which opens new and unprecedented way for evaluating the maintaining efficacy of Fusarium oxysporum bioactive compounds in dealing with hepatic complications and its remedy impacting on liver diseases and injured hepatocytes through recommending implement a practical study.

Constipation is a prevalent gastrointestinal disorder, with its prevalence showing an annual upward trend. There are many factors involved in the occurrence of constipation, such as abnormal smooth muscle contraction and disorders of gastrointestinal hormone secretion. Amomum villosum (A. villosum) has been proven to be effective in improving digestive system diseases, but there is no report on improving constipation. Therefore, we used network pharmacology prediction combined with animal experiments to explore the key active components of A. villosum and their pharmacological mechanisms. The results of network pharmacological prediction showed that β-sitosterol was the key laxative compound of A. villosum, which may play a laxative role by activating the adrenoceptor alpha 1 A-myosin light chain (ADRA1A-MLC) pathway. Further animal experiments showed that β-sitosterol could significantly shorten the time to first black stool; increase faecal weight, faecal number, and faecal water content; and promote gastrointestinal motility. β-sitosterol may promote intestinal motility by upregulating the expression of ADRA1A and myosin light chain 9 (Myl9) mRNA and protein in the colon, thereby activating the ADRA1A-MLC signalling pathway. In addition, it is possible to improve constipation symptoms by regulating serum neurotransmitters and gastrointestinal motility-related factors, such as the serum content of 5-hydroxytryptamine (5-HT) and acetylcholinesterase (AchE) and the mRNA expression of 5-hydroxytryptamine receptor 4 (5-HT4), stem cell factor (SCF), stem cell factor receptor (c-Kit) and smooth muscle myosin light chain kinase (smMLCK) in the colon. These results lay a foundation for the application of A. villosum and β-sitosterol in constipation.

Background: Neutrophils are thought to play a pivotal role in the pathogenesis of many inflammatory diseases, such as hepatitis, liver cirrhosis, etc. Activated human neutrophils release human neutrophil peptides (HNP1-3) or alpha-defensins that are antimicrobial peptides in azurophil granules. Furthermore, HNP1-3 build a scaffold of neutrophil extracellular traps (NETs) and promote the process of programmed cell death called NETosis. Our study aimed to investigate the role of alpha-defensins in the pathogenesis of alcohol-related liver cirrhosis (ALC). Methods: The concentrations of alpha-defensins in the plasma of 62 patients with ALC and 24 healthy subjects were measured by ELISA. The patients with ALC were prospectively recruited based on the severity of liver dysfunction according to the Child-Pugh and Model of End-Stage Liver Disease-Natrium (MELD-Na) scores, modified Maddrey's Discriminant Function (mDF), and the presence of ALC complications. Results: The concentrations of alpha-defensins in plasma were significantly higher in the ALC patients than in the controls. The plasma levels of HNP1-3 correlated with the MELD and mDF scores. ALC subgroups with MELD > 20 and mDF > 32 displayed significantly higher HNP1-3 concentrations. The plasma levels of HNP1-3 revealed a good predictive AUC for hepatic encephalopathy and ascites development (0.81 and 0.74, respectively) and for patient survival (0.87) in those over 40 years of age. Conclusion: These findings suggest that alpha-defensins play an important role in the assessment of ALC.

Immunologic and metabolic signals regulated by gut microbiota and relevant metabolites mediate bidirectional interaction between the gut and liver. Gut microbiota dysbiosis, due to diet, lifestyle, bile acids, and genetic and environmental factors, can advance the progression of chronic liver disease. Commensal gut bacteria have both pro- and anti-inflammatory effects depending on their species and relative abundance in the intestine. Components and metabolites derived from gut microbiota-diet interaction can regulate hepatic innate and adaptive immune cells, as well as liver parenchymal cells, significantly impacting liver inflammation. In this mini review, recent findings of specific bacterial species and metabolites with functions in regulating liver inflammation are first reviewed. In addition, socioeconomic and environmental factors, hormones, and genetics that shape the profile of gut microbiota and microbial metabolites and components with the function of priming or dampening liver inflammation are discussed. Finally, current clinical trials evaluating the factors that manipulate gut microbiota to treat liver inflammation and chronic liver disease are reviewed. Overall, the discussion of microbial and metabolic mediators contributing to liver inflammation will help direct our future studies on liver disease.

Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.

Background: Liver fibrosis represents an intermediate stage in the progression of liver disease, and as of now, there exists no established clinical therapy for effective antifibrotic treatment. Purpose: Our aim is to explore the impact of Carbon dots derived from Vaccaria Semen Carbonisata (VSC-CDs) on carbon tetrachloride-induced liver fibrosis in mice. Methods: VSC-CDs were synthesized employing a modified pyrolysis process. Comprehensive characterization was performed utilizing various techniques, including transmission electron microscopy (TEM), multiple spectroscopies, X-ray photoelectron spectroscopy (XPS), and high-performance liquid chromatography (HPLC). A hepatic fibrosis model induced by carbon tetrachloride was utilized to evaluate the anti-hepatic fibrosis effects of VSC-CDs. Results: VSC-CDs, exhibiting a quantum yield (QY) of approximately 2.08%, were nearly spherical with diameters ranging from 1.0 to 5.5 nm. The VSC-CDs prepared in this study featured a negative charge and abundant chemical functional groups. Furthermore, these particles demonstrated outstanding dispersibility in the aqueous phase and high biocompatibility. Moreover, VSC-CDs not only enhanced liver function and alleviated liver damage in pathomorphology but also mitigated the extent of liver fibrosis. Additionally, this study marks the inaugural demonstration of the pronounced activity of VSC-CDs in inhibiting inflammatory reactions, reducing oxidative damage, and modulating the TGF-β/Smad signaling pathway. Conclusion: VSC-CDs exerted significant potential for application in nanodrugs aimed at treating liver fibrosis.

Metabolic syndrome (MetS) has become an increasing global health problem, which leads to cardiovascular diseases and type 2 diabetes. Silybum marianum extracts have been reported to possess several biological activities. In this study, an ethyl acetate extract prepared from S. marianum seeds of the Iraqi Kurdistan region was analyzed to identify its chemical constituents. Subsequently, its potential for the prevention and treatment of MetS was studied in a rat model induced by a high-fat/high-fructose diet (HFD/F). Silydianin and silychristin were the most abundant flavonolignan constituents (39.4%) identified in the S. marianum extract (SMEE). HFD/F-induced rats treated with SMEE exhibited preventive effects including reduced serum triglyceride levels (TG), decreased glucose levels in an oral glucose tolerance test (p < 0.001), attenuated weight gain, and reduced blood pressure compared to the untreated control group. Therapeutic application of SMEE after inducing MetS led to lowering of TG (p < 0.001) and glucose levels, in addition to reducing weight gain and normalizing blood pressure (p < 0.005). Thus, S. marianum extract rich in silydianin and silychristin may be useful for preventing and attenuating MetS, and further research and clinical trials are warranted.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection drove the global coronavirus disease 2019 (COVID-19) pandemic, causing a huge loss of human life and a negative impact on economic development. It is an urgent necessity to explore potential drugs against viruses, such as SARS-CoV-2. Silymarin, a mixture of herb-derived polyphenolic flavonoids extracted from the milk thistle, possesses potent antioxidative, anti-apoptotic, and anti-inflammatory properties. Accumulating research studies have demonstrated the killing activity of silymarin against viruses, such as dengue virus, chikungunya virus, and hepatitis C virus. However, the anti-COVID-19 mechanisms of silymarin remain unclear. In this study, multiple disciplinary approaches and methodologies were applied to evaluate the potential mechanisms of silymarin as an anti-viral agent against SARS-CoV-2 infection. In silico approaches such as molecular docking, network pharmacology, and bioinformatic methods were incorporated to assess the ligand-protein binding properties and analyze the protein-protein interaction network. The DAVID database was used to analyze gene functions, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment. TCMSP and GeneCards were used to identify drug target genes and COVID-19-related genes. Our results revealed that silymarin compounds, such as silybin A/B and silymonin, displayed triplicate functions against SARS-CoV-2 infection, including directly binding with human angiotensin-converting enzyme 2 (ACE2) to inhibit SARS-CoV-2 entry into the host cells, directly binding with viral proteins RdRp and helicase to inhibit viral replication and proliferation, and regulating host immune response to indirectly inhibit viral infection. Specifically, the targets of silymarin molecules in immune regulation were screened out, such as proinflammatory cytokines TNF and IL-6 and cell growth factors VEGFA and EGF. In addition, the molecular mechanism of drug-target protein interaction was investigated, including the binding pockets of drug molecules in human ACE2 and viral proteins, the formation of hydrogen bonds, hydrophobic interactions, and other drug-protein ligand interactions. Finally, the drug-likeness results of candidate molecules passed the criteria for drug screening. Overall, this study demonstrates the molecular mechanism of silymarin molecules against SARS-CoV-2 infection.

Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by inflammatory responses and oxidative stress. Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-γ, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition.

Non-alcoholic fatty liver disease (NAFLD) is a prevailing health challenge that requires urgent innovative interventions. This review explores the role of nanotechnology as a promising potential in the treatment of NAFLD. It delineates the limitations of the current management strategies for NAFLD and highlights the new nanotechnology-based treatments including nanoemulsions, liposomes, micelles, polymeric nanoparticles, nanogels, inorganic nanoparticles, and zinc oxide nanoparticles. Despite the optimism surrounding the nanotechnological approach, the review underscores the need to address the limitations such as technical challenges, potential toxicity, and ethical considerations that impede the practical application of nanotechnology in NAFLD management. It advocates for collaborative efforts from researchers, clinicians, ethicists, and policymakers to achieve safe, effective, and equitable nanotechnology-based treatments for NAFLD. See also Figure 1(Fig. 1).

Chronic inflammation, in general, refers to systemic immune abnormalities most often caused by the environment or lifestyle, which is the basis for various skin diseases, autoimmune diseases, cardiovascular diseases, liver diseases, digestive diseases, cancer, and so on. Therapeutic strategies have focused on immunosuppression and anti-inflammation, but conventional approaches have been poor in enhancing the substantive therapeutic effect of drugs. Nanomaterials continue to attract attention for their high flexibility, durability and simplicity of preparation, as well as high profitability. Nanotechnology is used in various areas of clinical medicine, such as medical diagnosis, monitoring and treatment. However, some related problems cannot be ignored, including various cytotoxic and worsening inflammation caused by the nanomaterials themselves. This paper provides an overview of functional nanomaterial formulations for the prevention, diagnosis and treatment of chronic inflammation-related diseases, with the intention of providing some reference for the enhancement and optimization of existing therapeutic approaches.

Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty liver disease. It is commonly associated with liver injury, inflammation, and cell death. Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins. Activated hepatic stellate cells contribute to the major population of myofibroblasts. Many treatments for liver fibrosis have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment (e.g., simtuzumab), drug (e.g., pegbelfermin and natural herbs), genetic regulation (e.g., non-coding RNAs), and transplantation of stem cells (e.g., hematopoietic stem cells). However, none of these treatments has been approved by Food and Drug Administration. The treatment efficacy can be evaluated by histological staining methods, imaging methods, and serum biomarkers, as well as fibrosis scoring systems, such as fibrosis-4 index, aspartate aminotransferase to platelet ratio, and non-alcoholic fatty liver disease fibrosis score. Furthermore, the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis. To avoid the life-threatening stage of liver fibrosis, anti-fibrotic treatments, especially for combined behavior prevention, biological treatment, drugs or herb medicines, and dietary regulation are needed. This review summarizes the past studies and current and future treatments for liver fibrosis.

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2-5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.