The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.

The primary aim of the study was to analyze novel long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) to assess their roles as potential oncogenes and tumor suppressors and to develop a survival prediction model based on their expression levels. Data from The Cancer Genome Atlas, GSE135631, and GSE214846, were utilized to evaluate changes in lncRNA expression in HCC and their associations with patient prognosis. A risk model was created based on lncRNA expression to predict patient mortality. The co-expression network was employed to identify associated pathways, and the results were subsequently validated using the RT-qPCR method. The findings indicated that 14 lncRNAs were down-regulated in HCC, and their increased expression was associated with a favorable prognosis. Additionally, eight lncRNAs were overexpressed and correlated with poorer patient outcomes. The multivariate Cox regression analysis demonstrated that overexpression of AKR1B10P1, RP11-465B22.3, WASH8P, and the downregulation of NPM1P25 could independently predict patient survival, irrespective of clinical variables. The risk score model based on these lncRNAs effectively stratified patients by their mortality risk. Furthermore, the co-expression network analysis revealed that the identified lncRNAs might be involved in various pathways, including fatty acid metabolism, mTOR signaling, glycolysis, angiogenesis, Wnt-β-catenin pathway, and DNA repair. RT-qPCR results validated the significant increase in the expression level of WASH8P in cancer specimens compared to normal tissues. Our results unveiled that changes in the expression levels of AKR1B10P1, RP11-465B22.3, WASH8P, and NPM1P25 were significantly and independently associated with prognosis. Moreover, the patient mortality risk model constructed using these four lncRNAs exhibited a robust capacity to accurately predict patients' survival rates.

New approach methodologies (NAMs) are promising for refining, reducing, and replacing animal experiments for hazard characterization. Quantitative in vitro-in vivo extrapolation (qIVIVE) is essential to extrapolate an in vitro-based point of departure to an in vitro-based human equivalent dose and subsequently to an in vitro-based health-based guidance or threshold value. The use of NAMs for hazard characterization leads to the need for various new extrapolations and linked uncertainties that preferably are quantified. Currently, qIVIVE is often performed without addressing these uncertainties. A clear description and, if possible, quantification of extrapolations and uncertainties when using NAMs for risk assessment will aid the regulatory implementation of NAMs for risk assessment. A case study of a qIVIVE-based assessment on the risk of liver steatosis from dietary exposure to imazalil is reported, using a human cell line in vitro test method as an example of a NAM to replace animal experiments. We consider the uncertainties related to the extrapolations from in vitro to in vivo effects, from in vitro nominal concentrations to in vitro intracellular concentrations, from in vitro concentrations to external doses (reverse dosimetry), from in vitro exposure durations to in vivo exposure situations, and from the average human to a sensitive individual. The case study addresses these uncertainties in a mainly quantitative approach, using available data and the Monte Carlo Risk Assessment platform.

Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition affecting both metabolic and reproductive health in women. The impact of vitamin D on metabolic regulation has attracted growing interest. The purpose of this study is to investigate the impact of vitamin D supplementation on key metabolic parameters-namely blood glucose, insulin, and lipid levels-in individuals with PCOS.

A systematic review was conducted to identify relevant studies in PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov. The search focused on randomized controlled trials (RCTs) evaluating the impact of vitamin D supplementation in patients with PCOS. Meta-analysis was performed using RevMan 5.3 software, and study quality was evaluated with the Cochrane Risk of Bias Tool. In addition, outcome-related evidence was graded using the GRADE system, and TSA was performed to determine if the number of participants met the required threshold.

A total of 691 individuals with PCOS from 13 RCTs were evaluated. The meta-analysis indicated that the supplementation of vitamin D led to a notable reduction in the subsequent metabolic parameters: fasting blood glucose[MD=-2.91 mg/dL, 95% CI (-4.78, -1.04) mg/dL, P = 0.002], insulin levels[MD=-1.98 µIU/mL, 95% CI (-3.32, -0.64) µIU/mL, P = 0.004], triglycerides[MD=-11.01 mg/dL, 95% CI (-16.42, -5.61) mg/dL, P < 0.0001], total cholesterol [MD=-11.69 mg/dL, 95% CI (-15.56, -7.82) mg/dL, P < 0.00001], very low-density lipoprotein cholesterol (VLDL-cholesterol) [MD=-2.64 mg/dL, 95% CI (-4.50, -0.79) mg/dL, P = 0.005], and low-density lipoprotein cholesterol (LDL-cholesterol) [MD=-5.85 mg/dL, 95% CI (-10.28, -1.42) mg/dL, P = 0.010]. Nevertheless, the supplementation of vitamin D did not exert a significant impact on high - density lipoprotein cholesterol (HDL - cholesterol) [MD=-0.21 mg/dL, 95% CI (-0.81, 1.22) mg/dL, P = 0.69]. Begg's and Egger's tests suggested a minimal probability of publication bias, and the TSA confirmed that the optimal sample size for major outcomes had been reached, supporting the robustness of the meta-analysis results.

Vitamin D supplementation shows significant benefits in improving metabolic parameters in PCOS patients, particularly in reducing fasting blood glucose, insulin, and lipid levels, suggesting a potential role of vitamin D in PCOS management. The long-term outcomes and most effective dose of vitamin D warrant further investigation in future research.

Not applicable.

Obesity is associated with a higher risk of severe diseases such as atherosclerotic cardiovascular disease, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Polyunsaturated fatty acids, of the omega-3 family (n-3 PUFA), have been shown to reduce adipose tissue inflammation in obesity, as well as to have lipid-lowering effects and improve insulin sensitivity. However, direct effects on liver transcriptome in humans have not been described. Our aim was to understand the impact of n-3 PUFA on gene expression in obese human liver.

Patients with obesity (BMI ≥ 40 kg/m2) were treated for eight weeks with 3.36 g n-3 PUFAs (1.84 g eicosapentaenoic acid (EPA) and 1.53 g docosahexaenoic acid (DHA)), or with 5 g of butter as a control (n = 15 per group) before undergoing bariatric surgery where liver biopsies were taken. Liver samples were used for mRNA microarray analyses and subsequently Gene Set Enrichment Analysis (GSEA) was performed. This bioinformatic approach led us to identify 80 significantly dysregulated pathways that were divided into 9 different clusters including insulin and lipid metabolism, and immunity. N-3 PUFA treatment significantly affected pathways related to immunity, metabolism, and inflammation. Specifically, it upregulated pathways involved in T-cell and B-cell functions and lipid metabolism, while downregulating glucagon signalling. These findings highlight the impact of n-3 PUFAs on key metabolic and immune processes in the liver of patients with obesity.

This study provides further insights into the impact on n-3 PUFA on human liver gene expression, particularly in pathways associated with immunity, lipid metabolism, and inflammation, setting basis for further clinical research.

Obesity increases the risk of diseases like atherosclerotic- cardiovascular disease, type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD). Omega-3 polyunsaturated fatty acids (n-3 PUFA) are known for their anti-inflammatory and metabolic benefits, but their direct impact on liver gene expression in people with obesity, remains unclear. In this study, patients with obesity (BMI ≥ 40 kg/m2) were administered either n-3 PUFAs or butter before bariatric surgery. Liver biopsies were analysed for gene expression via Gene Set Enrichment Analysis (GSEA). The results revealed 80 dysregulated pathways across 9 clusters, including those related to insulin and lipid metabolism, and immunity. This sheds light on how n-3 PUFAs influence gene expression in the liver of patients with obesity, setting the groundwork for further clinical exploration.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, bone and cartilage damage, musculoskeletal pain, swelling, and stiffness. Inflammation is one of the key factors that induce RA. Jingfang Granule (JFG) is a traditional Chinese medicine (TCM) with significant anti-inflammatory effects. Clinical studies have confirmed that JFG can be used to treat RA, but the mechanism is still vague.

This study was designed to evaluate the protective function and the mechanism of JFG on rats with RA.

Complete Freud's Adjuvant (CFA) was used to establish a rat RA model, and JFG or Diclofenac Sodium (Dic) was orally administered. Foot swelling and hematoxylin eosin (H&E) staining were used to test the therapeutic effect of JFG on RA treatment, while ELISA kits were used to detect serum cytokines. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) were used to evaluate oxidative stress levels. The integration of label-free proteomics, fecal short chain fatty acid (SCFA) targeted metabolomics, peripheral blood SCFA, medium and long chain fatty acid targeted metabolomics, and 16S rDNA sequencing of gut microbiota were used to screen the mechanism. Western blot technology was used to validate the results of multiple omics studies. Serum D-Lactic acid, lipopolysaccharide specific IgA antibody (LPS IgA), diamine oxidase (DAO), and colon Claudin 5 and ZO-1 were used to evaluate the intestinal barrier.

The results confirmed that JFG effectively protected rats from RA injury, which was confirmed by improved foot swelling and synovial pathology. At the same time, JFG reduced the levels of TNF-α, IL-1β, and IL-6 in serum by inhibiting the NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway in synovial tissue. Multiple omics studies indicated that JFG increased the abundance of gut microbiota and regulated the number of gut bacteria, thereby increased the levels of Acetic acid, Propionic acid, and Butyric acid in the gut and serum of RA rats, which activated AMPK to regulate fatty acid metabolism and fatty acid biosynthesis, thereby inhibited lipid oxidative stress induced ferroptosis to improve tissue damage caused by RA. Meanwhile, JFG improved the intestinal barrier by upregulating the expresses of Claudin 5 and ZO-1, which was confirmed by low concentrations of D-Lactic acid, LPS-SIgA and DAO in serum.

This study confirmed that JFG improved the disturbance of fatty acid metabolism by modulating gut microbiota and the production of fecal SCFAs to activate AMPK, and then inhibited ferroptosis caused by lipid oxidative stress in synovium tissue and prevented AR injury. This study proposes for the first time to investigate the mechanism of JFG treatment for RA from the perspective of the "Gut-joint" axis, and provides a promising approach for the treatment of RA.

Non-alcoholic fatty liver disease (NAFLD) is the prevalent liver disease. Ovarian tumor domain-containing 7B (OTUD7B) is a deubiquitinating enzyme and its role in NAFLD remains unclear. In high-fat diet (HFD)-induced NAFLD mouse model and palmitic acid (PA)-treated HepG2 cells, OTUD7B expression was decreased. Adenoviral overexpression of OTUD7B in mice resulted in reduced body weight and liver injury, with decreased serum aminotransferase (ALT) and aspartate aminotransferase (AST) levels. OTUD7B overexpression attenuated hepatic lipid deposition (serum TG, TC, LDL-C, HDLC, and FFA levels), which might be through the suppression of lipogenesis and β-oxidation-related genes. The contents of hepatic inflammatory factors (TNF-α, IL-6, and IL-1β) were decreased following OTUD7B overexpression in NAFLD mice. A mechanism study indicated that the protective effect of OTUD7B overexpression might be associated with β-catenin signal activation. OTUD7B overexpression promoted PA-induced β-catenin activity in TopFlash assay, and increased total β-catenin and c-myc levels in cells. The increase in β-catenin levels was contributed to the stabilization via inhibiting K48-linked ubiquitination and proteasomal degradation by OTUD7B. NR4A2 role in NASH has been proved. NR4A2 ChIP-seq and RNA-seq data excluded transcriptional regulation of NR4A2 to OTUD7B, and it was experimentally evidenced that NR4A2 bound to OTUD7B promoter region and positively transcriptionally regulate OTUD7B expression. In summary, OTUD7B overexpression ameliorated hepatic inflammation and steatosis in NAFLD. The possible mechanism of OTUD7B might be through the inhibition of β-catenin degradation by removing K48-linked ubiquitination, which might be regulated by NR4A2.

The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression.

THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH.

USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency.

Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.

Alcoholic liver disease (ALD) is a prevalent liver condition that arises from prolonged and excessive alcohol intake. Bergenin (BER) is an effective phytotherapeutic agent that exhibits pharmacological properties, including anti-inflammatory and anti-oxidative effects. To establish an in vivo model of ALD, C57BL/6 mice were continuously fed a high-fat diet (HFD) and administered alcohol gavage for 8 weeks, while concurrently administering BER and evaluated for therapeutic effects. After modeling, the therapeutic effects of BER were evaluated by observing histopathological changes and the detection of relevant biochemical indicators in mice. In addition, RNA sequencing of liver tissues was performed to analyze differentially expressed genes and to investigate the associated signaling pathways in order to elucidate the protective mechanisms of BER. These differentially expressed genes were mainly enriched in lipid metabolism pathways and the cytochrome P450 metabolism of exogenous substances. Subsequently, HepG2 was co-treated with sodium oleate (NaOA) and ethanol to establish an in vitro model, and the specific mechanism by which BER ameliorates ALD was further analyzed in depth. AMPK inhibitor, Compound C (CC), was demonstrated to significantly inhibit the regulation of lipid metabolism by BER in vitro. Finally, the differentially expressed genes selected were validated through qRT-PCR and Western blot analysis. Collectively, our findings revealed that BER effectively alleviated liver injury caused by alcohol and HFD in mice, significantly suppressing lipid deposition in ALD, enhancing alcohol metabolism, and mitigating oxidative stress.

Apolipoprotein A4 (APOA4) is synthesized by the small intestine in response to dietary lipids. Chronic exposure to a high-fat diet (HFD) desensitizes lipid-induced APOA4 production and attenuates brown adipose tissue (BAT) thermogenesis. We hypothesized that exogenous APOA4 could increase BAT thermogenesis and energy expenditure in HFD-fed mice, resulting in decreased obesity and improved glucose tolerance.

BAT and inguinal white adipose tissue (IWAT) thermogenesis, body composition, energy intake and expenditure, and locomotor activity were measured using an infrared camera, immunoblots, quantitative magnetic resonance imaging, and a comprehensive lab animal monitoring system. An intraperitoneal glucose tolerance test and hepatic lipid accumulation and steatosis were assayed.

Mice receiving continuous infusion of APOA4 for the last 4 weeks of 10 weeks of HFD feeding gained no additional body weight and had reduced fat mass but enhanced BAT and IWAT thermogenesis and energy expenditure, despite unaltered food intake and locomotor activity. Additionally, APOA4 infusion elevated fatty acid β oxidation; decreased lipogenesis, lipid accumulation, and steatosis in liver; and improved glucose tolerance.

Maintenance of plasma APOA4 via exogenous APOA4 protein parallels elevation of BAT and IWAT thermogenesis, hepatic fatty acid β oxidation, and overall energy expenditure, with subsequent prevention of additional weight gain in HFD-fed obese mice.

Previous studies have shown a positive correlation between the non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol(non-HDLc/HDLc ratio) and metabolism-associated steatohepatitis (MASLD), suggesting it is a superior predictor of MASLD.The aim of this study is to assess the predictive value of the non-HDLc/HDLc ratio for MASLD.

In this study, we retrospectively analyzed data from 4,498 adult patients at the Health Management Centre of Guangdong Provincial Hospital of Integrative Medicine, regardless of gender, and the diagnostic criteria for MASLD were derived from guidelines. We used univariate and multivariate logistic regression to verify the relationship between the non-HDLc/HDLc ratio and MASLD and assessed the stability of the results through interaction tests. ROC curve analysis was then employed to compare the diagnostic efficacy of several lipid indices, including the non-HDLc/HDLc ratio, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), and the composite lipid profile in diagnosing MASLD.

These data suggested that non-HDLc/HDLc, LDL-C, TG, and TC were positively correlated with MASLD, while HDL-C was inversely correlated, even after adjusting for confounders such as gender, age, body mass index, ALT, AST, uric acid, blood glucose, and hypertension. Among them, non-HDLc/HDLc ratio(OR: 2.709, 95% CI: 2.316-3.169, p < 0.001), LDL-C (OR: 1.294, 95% CI: 1.125-1.489, p < 0.001), TG (OR: 2.854, 95% CI: 2.473-3.293, p < 0.001), TC (OR: 1.242, 95% CI: 1.122-1.374, p < 0.001), and HDL-C (OR: 0.074, 95% CI: 0.044-0.123, p < 0.001) were identified. The interaction results showed that gender did not affect lipid levels in MASLD (p > 0.05). ROC analysis confirmed the validity of the non-HDL cholesterol/HDL cholesterol ratio in predicting MASLD incidence, with an AUC of 0.801. Moreover, the composite lipid indices demonstrated greater predictive power for MASLD compared to individual indices (AUC: 0.857), and validation set results were consistent with those of the training set.

The present study revealed that the non-HDLc/HDLc ratio was positively correlated with the development of MASLD, and the ratio was also effective in predicting MASLD.

This study aimed to ascertain the potential benefits of green radish polysaccharide (GRP) in treating alcoholic liver disease (ALD) in mice and explore its mechanism of action. Using biochemical analysis, high-throughput sequencing of gut microbiota, and gas chromatography-mass spectrometry to measure short-chain fatty acids (SCFAs) in feces, we found that GRP intervention significantly improved lipid metabolism and hepatic function in mice subjected to excessive alcohol intake. The GRP intervention reduced malondialdehyde levels by 66% and increased total superoxide dismutase levels by 22%, thereby mitigating alcohol-induced oxidative stress. Furthermore, GRP intervention in mice with alcohol consumption resulted in a reduction in tumor necrosis factor, interleukin 6, and lipopolysaccharide levels by 12%, 9%, and 25%, respectively, effectively attenuating alcoholic liver inflammation. 16S rRNA amplicon sequencing demonstrated that excessive alcohol consumption markedly altered the gut microbiota composition in mice. The GRP treatment resulted in a significant reduction in the number of beneficial bacteria (Lactobacillus and Lachnospiraceae_NK4A136_group) and an increase in the proportion of harmful bacteria (Muribaculaceae and Verrucomicrobiota). The metabolomic analyses of the SCFAs demonstrated an increase in the contents of SCFAs, acetic acid, propionic acid, and butyric acid, following GRP supplementation. Furthermore, the metabolic levels of cholinergic synapses and glycolysis/gluconeogenesis were found to be modulated. In conclusion, these findings suggest that GRP may attenuate alcohol-induced oxidative damage in the liver by modulating the gut microbiota and hepatic metabolic pathways. This may position GRP as a potential functional component for ALD prevention.

Background: Polygonum multiflorum shows dual hepatoprotective and hepatotoxic effects. The bioactive components responsible for these effects are unknown. This study investigates whether cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (cis-TSG), a stilbene glycoside, has hepatoprotective and/or hepatotoxic effects in a liver injury model. Methods: C57BL/6J mice were administered α-naphthylisothiocyanate (ANIT) to induce cholestasis, followed by treatment with cis-TSG. Hepatoprotective and hepatotoxic effects were assessed using serum biomarkers, liver histology, and metabolomic and lipidomic profiling. Transcriptomic analysis were conducted to explore gene expression changes associated with lipid and bile acid metabolism, inflammation, and oxidative stress. Results and Discussion: ANIT administration caused significant liver injury, evident from elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and dysregulated lipid metabolism. cis-TSG treatment markedly reduced ALT and AST levels, normalized lipid profiles, and ameliorated liver damage, as seen histologically. Metabolomic and lipidomic analyses revealed that cis-TSG influenced key pathways, notably glycerophospholipid metabolism, sphingolipid metabolism, and bile acid biosynthesis. The treatment with cis-TSG increased monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs), enhancing peroxisome proliferator-activated receptor alpha (PPARα) activity. Transcriptomic data confirmed these findings, showing the downregulation of genes linked to lipid metabolism, inflammation, and oxidative stress in the cis-TSG-treated group. The findings suggest that cis-TSG has a hepatoprotective effect through modulation of lipid metabolism and PPARα activation.

There is an increasing incidence and prevalence of fatty liver disease in the western world, with steatosis as the most prevalent variant. Known causes of steatosis include exposure to food-borne chemicals, and overconsumption of alcohol, carbohydrates and fat, and it is a well-known side effect of certain pharmaceuticals such as tetracycline, amiodarone and tamoxifen (drug-induced hepatic steatosis). Mechanistic knowledge on chemical-induced steatosis has greatly evolved and has been organized into adverse outcome pathways (AOPs) describing the chain of events from first molecular interaction of a substance with a biological system to the adverse outcome, intrahepatic lipid accumulation. In this study, three known steatosis-inducing pesticides (imazalil, clothianidin, and thiacloprid) were tested for their ability to induce hepatic triglyceride accumulation in the zebrafish (Danio rerio) embryo (ZFE) at 5 days post fertilization, both as single compounds and equipotent binary mixtures. The results indicate that the ZFE is very well applicable as a higher tier testing model to confirm effects in downstream key events in AOPs, that is, chemically-induced triglyceride accumulation in the whole organism and production of visible steatosis. Moreover, dose addition could be concluded for binary mixtures of substances with similar and with dissimilar modes of action.

Mitigating steatosis is essential for delaying the progression of alcoholic liver disease. The effect and mechanism of Lactiplantibacillus plantarum P101 (LP.P101) on alleviating alcohol-induced hepatic lipid accumulation were investigated in our study. The mouse model was constructed by a short-term (10-day)-plus-binge ethanol feeding and gavaged with 108 CFU/mL of LP.P101 daily. Lipid droplet in the liver was significantly reduced by LP.101 intervention on AMPK activation. However, when AMPK was inhibited by dorsomorphin, the levels of related indicators (ALT, TG, etc.) and the expression levels of AMPK and relevant genes in the liver converged to that of the alcohol-fed group. Compared with the alcohol-fed group, LP.P101 reduced the relative abundance of Firmicutes and increased that of Bacteroidetes. Parabacteroides merdae was negatively correlated with lipid accumulation, and unclassified Negativibacillus was negatively associated with AMPK activation. Importantly, LP.P101 modified the compositions of the serum metabolites. The potential biomarker stercobilinogen was positively correlated with AMPK activation and negatively associated with lipid accumulation. This work confirmed that LP.P101 attenuated alcohol-induced hepatic lipid accumulation in mice through AMPK activation, and the alterations in gut microbiota and metabolites may play a significant role on AMPK activation.

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half-fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients.

Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. Unlike murine models, to which various standardized high lipid diets such as a high-cholesterol diet (HCD) are available, there has yet to be a uniformly adopted zebrafish HCD protocol. In this study, we have developed an improved HCD protocol and thoroughly tested its impact on zebrafish lipid deposition and lipoprotein regulation in a dose- and time-dependent manner. The diet stability, reproducibility, and fish palatability were also validated. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LPs) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae for 8 days produced hepatic steatosis that became more stable and sever after 1 day of fasting and was associated with an opaque liver phenotype (dark under transmitted light). Unlike larvae, adult fish fed HCD for 14 days followed by a 3-day fast did not develop a stable fatty liver phenotype, though the fish had higher ApoB-LP levels in plasma and an upregulated lipogenesis gene fasn in adipose tissue. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease.

Milk fat globules (MFGs) are produced by mammary epithelial cells (MECs) and originate from intracellular lipid droplets with a wide size distribution. In the mammary gland and milk, bacteria can thrive on MFGs. Herein, we aimed to investigate whether the response of MECs to the bacterial secretome is dependent on the MFG size used as a substrate for the bacteria, and whether the response differs between pathogenic and commensal bacteria. We used secretomes from both Bacillus subtilis and E. coli. Proinflammatory gene expression in MECs was elevated by the bacteria secretomes from both bacteria sources, while higher expression was found in cells exposed to the secretome of bacteria grown on large MFGs. The secretome of B. subtilis reduced lipid droplet size in MECs. When the secretome originated from E. coli, lipid droplet size in MEC cytoplasm was elevated with a stronger response to the secretome from bacteria grown on large compared with small MFGs. These results indicate that MEC response to bacterial output is modulated by bacteria type and the size of MFGs used by the bacteria, which can modulate the stress response of the milk-producing cells, their lipid output, and consequently milk quality.

Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH). In vitro liver cell models were used to investigate the fate and mechanistic effects of CLD and CLDOH using multiomics. A 3D-cell model was used to investigate whether CLD and CLDOH can affect susceptibility to the metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively metabolized into a glucuronide conjugate, whereas CLD was sequestered. CLD but not CLDOH induced a depletion of Septin-2,- 7,- 9,- 10,- 11 due to proteasomal degradation. Septin binding with CLD and CLDOH was confirmed by surface plasmon resonance. CLD disrupted lipid droplet size and increased saturated long-chain dicarboxylic acid production by inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in the 3D model of MASLD. To conclude, CLD hepatoxicity is specifically driven by the degradation of septins. CLDOH, was too rapidly metabolized to induce septin degradation. We show that the conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. This suggests that protective strategies could be explored to reduce the hepatotoxicity of CLD.

Tamoxifen is an estrogen receptor modulator that has been reported to alleviate hepatic lipid accumulation in mice, but the mechanism is still unclear. Peroxisome fatty acid β-oxidation is the main metabolic pathway for the overload of long-chain fatty acids. As long-chain fatty acids are a cause of hepatic lipid accumulation, the activation of peroxisome fatty acid β-oxidation might be a novel therapeutic strategy for metabolic associated fatty liver disease. In this study, we investigated the mechanism of tamoxifen against hepatic lipid accumulation based on the activation of peroxisome fatty acid β-oxidation. Tamoxifen reduced liver long-chain fatty acids and relieved hepatic lipid accumulation in high fat diet mice without sex difference. In vitro, tamoxifen protected primary hepatocytes against palmitic acid-induced lipotoxicity. Mechanistically, the RNA-sequence of hepatocytes isolated from the liver revealed that peroxisome fatty acid β-oxidation was activated by tamoxifen. Protein and mRNA expression of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase were significantly increased in vivo and in vitro. Small interfering RNA enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase in primary hepatocytes abolished the therapeutic effects of tamoxifen in lipid accumulation. In conclusion, our results indicated that tamoxifen could relieve hepatic lipid accumulation in high fat diet mice based on the activation of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase-mediated peroxisome fatty acids β-oxidation.

Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in adipose tissue and have been linked to cardiometabolic disorders, including fatty liver disease. The toxicity of these compounds is associated with activation of the aryl hydrocarbon receptor (Ahr), leading to the induction of phase I metabolizing enzyme cytochrome P4501a1 (Cyp1a1) and the subsequent production of reactive oxygen species (ROS). Recent research has shown that DLPs can also induce the xenobiotic detoxification enzyme flavin-containing monooxygenase 3 (FMO3), which plays a role in metabolic homeostasis. We hypothesized whether genetic deletion of Fmo3 could protect mice, particularly in the liver, where Fmo3 is most inducible, against PCB 126 toxicity. To test this hypothesis, male C57BL/6 wild-type (WT) mice and Fmo3 knockout (Fmo3 KO) mice were exposed to PCB 126 or vehicle (safflower oil) during a 12-week study, at weeks 2 and 4. Various analyses were performed, including hepatic histology, RNA-sequencing, and quantitation of PCB 126 and F2-isoprostane concentrations. The results showed that PCB 126 exposure caused macro and microvesicular fat deposition in WT mice, but this macrovesicular fatty change was absent in Fmo3 KO mice. Moreover, at the pathway level, the hepatic oxidative stress response was significantly different between the two genotypes, with the induction of specific genes observed only in WT mice. Notably, the most abundant F2-isoprostane, 8-iso-15-keto PGE2, increased in WT mice in response to PCB 126 exposure. The study's findings also demonstrated that hepatic tissue concentrations of PCB 126 were higher in WT mice compared to Fmo3 KO mice. In summary, the absence of FMO3 in mice led to a distinctive response to dioxin-like pollutant exposure in the liver, likely due to alterations in lipid metabolism and storage, underscoring the complex interplay of genetic factors in the response to environmental toxins.

To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n = 68) and validation (n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.

The intake of high-fat diets (HFD) has been shown to diminish the muscle quality of aquatic animals. Sanguinarine, as an excellent additive, exhibits the capability to reduce fat deposition and alleviate inflammation. However, its role in the muscle quality reduction caused by HFD remains unclear. An eight-week trial was conducted to investigate the impacts of dietary supplementation of sanguinarine at 1200 μg/kg (HFDS; crude fat = 10%) on the muscle quality of grass carp (Ctenopharyngodon idellus) in comparison to a basic diet (CON, crude fat = 5%). Each group had 3 replicates, with 40 fish per replicate. This experiment employed one-way ANOVA and Duncan's multiple comparisons of the means. The results showed that the HFD exhibited lower growth performance, reduced protein deposition, myofiber diameter, and muscle hardness, coupled with higher levels of fat deposition and inflammation when compared with the CON. However, HFDS improved growth performance (P < 0.05), fat metabolism (ppar-α ( P = 0.001), lpl (P < 0.001), atgl (P < 0.001), and cpt1 (P = 0.001) expression exhibited a significant elevation), protein deposition (the protein and mRNA levels of AKT (P = 0.004), PI3K (P = 0.027), TOR (P = 0.005), and P70S6K (P = 0.007) demonstrated a marked increase), myofiber diameter, muscle hardness, and the total content of eicosapentaenoic acid and docosahexaenoic acid. Furthermore, the HFDS reduced oxidative damage caused by fat deposition by significantly downregulating nf-κb (P < 0.001), il-1β (P < 0.001), il-6 (P < 0.001), il-8 (P = 0.003), and tnf-α (P < 0.001) expression and markedly upregulated nrf2 (P < 0.001), gpx4 (P < 0.001), cat (P < 0.001), sod (P < 0.001), and gr (P = 0.003) expression. The findings from this study suggest that sanguinarine has the potential to alleviate the adverse effects of HFD on growth and muscle quality, providing a theoretical foundation for its practical implementation.

The disruption of circadian rhythms (CRs) has been linked to metabolic disorders, yet the role of hepatic BMAL1, a key circadian regulator, in the whole-body metabolism and the associated lipid metabolic phenotype in the liver remains unclear. Bmal1 floxed (Bmal1f/f) and hepatocyte-specific Bmal1 knockout (Bmal1hep-/-) C57BL/6J mice underwent a regular feeding regimen. Hepatic CR, lipid content, mitochondrial function, and systemic metabolism were assessed at zeitgeber time (ZT) 0 and ZT12. Relevant molecules were examined to elucidate the metabolic phenotype. Hepatocyte-specific knockout of Bmal1 disrupted the expression of rhythmic genes in the liver. Bmal1hep-/- mice exhibited decreased hepatic TG content at ZT0, primarily due to enhanced lipolysis, reduced lipogenesis, and diminished lipid uptake. The β-oxidation function of liver mitochondria decreased at both ZT0 and ZT12. Our findings on the metabolic profile and associated hepatic lipid metabolism in the absence of Bmal1 in hepatocytes provides new insights into metabolic syndromes from the perspective of liver CR disturbances.

Previous studies have shown that feeding mice with food containing mantle tissue from Japanese scallops results in aggravated liver and kidney damage, ultimately resulting in mortality within weeks. The aim of this study is to evaluate the toxicity of scallop mantle in China's coastal areas and explore the impact of scallop mantle toxins (SMT) on intestinal barrier integrity and gut microbiota in mice. The Illumina MiSeq sequencing of V3-V4 hypervariable regions of 16S ribosomal RNA was employed to study the alterations in gut microbiota in the feces of SMT mice. The results showed that intestinal flora abundance and diversity in the SMT group were decreased. Compared with the control group, significant increases were observed in serum indexes related to liver, intestine, inflammation, and kidney functions among SMT-exposed mice. Accompanied by varying degrees of tissue damage observed within these organs, the beneficial bacteria of Muribaculaceae and Marinifilaceae significantly reduced, while the harmful bacteria of Enterobacteriaceae and Helicobacter were significantly increased. Taken together, this article elucidates the inflammation and glucose metabolism disorder caused by scallop mantle toxin in mice from the angle of gut microbiota and metabolism. SMT can destroy the equilibrium of intestinal flora and damage the intestinal mucosal barrier, which leads to glucose metabolism disorder and intestinal dysfunction and may ultimately bring about systemic toxicity.

In this study, we investigated the hepatoprotective effects of an ethanol extract of Sophora flavescens Aiton (ESF) on an alcohol-induced liver disease mouse model. Alcoholic liver disease (ALD) was caused by the administration of ethanol to male C57/BL6 mice who were given a Lieber-DeCarli liquid diet, including ethanol. The alcoholic fatty liver disease mice were orally administered ESF (100 and 200 mg/kg bw/day) or silymarin (50 mg/kg bw/day), which served as a positive control every day for 16 days. The findings suggest that ESF enhances hepatoprotective benefits by significantly decreasing serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), markers for liver injury. Furthermore, ESF alleviated the accumulation of triglyceride (TG) and total cholesterol (TC), increased serum levels of superoxide dismutase (SOD) and glutathione (GSH), and improved serum alcohol dehydrogenase (ADH) activity in the alcoholic fatty liver disease mice model. Cells and organisms rely on the Kelch-like ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system as a critical defensive mechanism in response to oxidative stress. Therefore, Nrf2 plays an important role in ALD antioxidant responses, and its level is decreased by increased reactive oxidation stress (ROS) in the liver. ESF increased Nrf2, which was decreased in ethanol-damaged livers. Additionally, four polyphenol compounds were identified through a qualitative analysis of the ESF using LC-MS/MS. This study confirmed ESF's antioxidative and hangover-elimination effects and suggested the possibility of using Sophora flavescens Aiton (SF) to treat ALD.

Scutellaria baicalensis Georgi (SBG) and Coptis chinensis Franch (CCF) are traditional herbal medicine pairs used for clearing heat and eliminating dampness, stopping diarrhea, and detoxification. Traditionally, these two herbs are combined and decocted together, but the modern preparation procedures separate them to avoid the large amount of precipitation generated from co-decoction. Thus, a conflict lies between the traditional and modern extraction processes of Scutellaria baicalensis Georgi - Coptis chinensis Franch (SBG-CCF).

There is a conflict between traditional medical practices of SBG-CCF and the modern formulation industry. In this study, we investigated the differences in the effects and mechanisms of SBG-CCF extracted by decocting separately and combining decoctions, as well as the scientific effectiveness of traditional and modern treatment methods on both. Acute alcoholic liver injury (ALI) rats were used as the pathological model.

SD rats were divided into 8 groups, including blank group, model group, low, medium, and high dose groups of SBG-CCF separated decoction, low, medium, and high dose groups of SBG-CCF combined decoction. Acute alcoholic liver injury model was induced in rats by gradually increasing the dose of alcohol through gavage everyday using white wine with an alcohol content 52%. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were used as indicators to assess the intervention effect of SBG-CCF. And the potential active ingredients of SBG-CCF and the targets related to ALI were screened using network pharmacology, and the prediction results of network pharmacology were verified by quantitative real-time fluorescence PCR (qRT-PCR).

SBG-CCF decoction alone and six combinations of decoctions have different degrees of improvement on alcoholic liver injury, with significant efficacy in the middle-dose group, and the combined decoction was superior to the individual decoction. SBG-CCF gavage can reduce the activity of AST, ALT, TC, TG, LDH, and MDA in the serum and liver of ALI rats, while increasing the levels of SOD and GSH. Network pharmacological analysis identified 39 active components, mainly flavonoids and alkaloids. Enrichment analysis suggested that SBG-CCF may treat ALI through the regulation of tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), interleukin-17 (IL-17), apoptosis, and the Toll-like receptor signaling pathways. The key targets in the Disease-Signaling Pathway-Target Network were MAPK8, IKBKB, MAPK10, MAPK3, MAPK1, and AKT1. qRT-PCR results indicated that targets regulating inflammation and lipid metabolism are MAPK8, MAPK10, MAPK3, and AKT1.

SBG-CCF separately extracts and combines decoction can alleviate acute alcoholic liver injury, and the effect of combined decoction is more significant than separate decoction, implying that the precipitate produced by the combination of the two is also an active substance. The resistance mechanism of SBG-CCF ALI may be related to the modulation of lipid metabolism, inhibition of lipid peroxidation, and oxidative stress. SBG-CCF has the characteristics of multi-component, multi-pathway, and multi-target resistance to ALI.

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

Arsenic, a ubiquitous environmental toxicant with various forms and complex food matrix interactions, can reportedly exert differential effects on the liver compared to drinking water exposure. To examine its specific liver-related harms, we targeted the liver in C57BL/6 J mice (n=48, 8-week-old) fed with arsenic-contaminated food (30 mg/kg) for 60 days, mimicking the rice arsenic composition observed in real-world scenarios (iAsV: 7.3%, iAsIII: 72.7%, MMA: 1.0%, DMA: 19.0%). We then comprehensively evaluated liver histopathology, metabolic changes, and the potential role of the gut-liver axis using human hepatocellular carcinoma cells (HepG2) and microbiota/metabolite analyses. Rice arsenic exposure significantly altered hepatic lipid (fatty acids, glycerol lipids, phospholipids, sphingolipids) and metabolite (glutathione, thioneine, spermidine, inosine, indole-derivatives, etc.) profiles, disrupting 33 metabolic pathways (bile secretion, unsaturated fatty acid biosynthesis, glutathione metabolism, ferroptosis, etc.). Pathological examination revealed liver cell necrosis/apoptosis, further confirmed by ferroptosis induction in HepG2 cells. Gut microbiome analysis showed enrichment of pathogenic bacteria linked to liver diseases and depletion of beneficial strains. Fecal primary and secondary bile acids, short-chain fatty acids, and branched-chain amino acids were also elevated. Importantly, mediation analysis revealed significant correlations between gut microbiota, fecal metabolites, and liver metabolic alterations, suggesting fecal metabolites may mediate the impact of gut microbiota and liver metabolic disorders. Gut microbiota and its metabolites may play significant roles in arsenic-induced gut-liver injuries. Overall, our findings demonstrate that rice arsenic exposure triggers oxidative stress, disrupts liver metabolism, and induces ferroptosis.

There is an accelerated progression of liver necroinflammation and fibrosis in the liver during the immune clearance (IC) phase of Chronic hepatitis B virus (HBV) infection, which are critical indicators of antiviral treatment for chronic hepatitis B (CHB) infection. This study applied serum metabolomics to identify the potential metabolite biomarkers for differential diagnosis between the CHB immune tolerance (IT) and Immune clearance (IC) phases. A liquid chromatography-mass spectrometry (LC-MS)-based approach was applied to evaluate and compared the serum metabolic profiles of 28 patients in IT phase and 33 patients in IC phase and appropriate statistical methods with MetaboAnalystR 2.0 R package to analyze those metabolites. The differential metabolites between IT and TC groups were classified and the top altered classification were lipids and lipid-like molecules and fatty acyls, clearly indicating that there were differences in the lipid metabolomic profile of HBV-infected patients with IT vs. IR phase. We identified the top 10 potential metabolite biomarkers for differential diagnosis between IT and IR. There were four lipid metabolites among them and the AUC of two of them, octadecadienoyl-sn-glycero-3-phosphocholine and 3-Cycloheptene-l-acetic acid, were 0.983 and 0.933. octadecadienoyl-sn-glycero-3-phosphocholine is Diacylglycerol (18:2n6/18:0) and 3-Cycloheptene-l-acetic acid is hydroxy fatty acids, both of which were associated with lipid metabolism. This study not only provides the potential metabolic biomarkers but also insight into the mechanism of CHB progression during IT clearance phase.

Nanoclays are found in the air, water, and soil, and modified nanoclays are being developed and used in several consumer products. For example, modified nanoclays are used to remove pollutants from wastewater. Ironically, however, nanoclays are now considered emerging contaminants. Indeed, release of modified nanoclays in aquatic systems, even as remediating agents, could adversely affect associated wildlife. However, aquatic organisms have interacted with natural nanoclays for millennia, and it is unclear if modified nanoclays induce stronger effects than the nanoclays that occur naturally. The concentrations over which nanoclays occur and illicit negative effects are not well studied. This study investigated the dose response of a natural nanoclay (Na+montmorillonite) relative to two modified nanoclays (Cloisite®30B and Novaclay™) on survival, body condition, and liver pathomorphology of Gambusia holbrooki after 14 days of exposure. Although none of the nanoclays affected survival and body condition of G. holbrooki over 14 days, each nanoclay induced histopathological changes in liver tissues at very low concentrations (LOAEL: 0.01 mgL-1). The effects of nanoclays on hepatic cell circulatory (blood cell aggregation with increased number of Kupffer cells and hemosiderin deposits), regressive (hepatocyte vacuolization), and degenerative (cell death) changes of mosquito fish varied among nanoclay types. Novaclay™ at low concentrations caused circulatory changes on hepatic tissues of G. holbrooki, whereas both natural nanoclays and Cloisite®30B showed little effect on circulatory endpoints. In contrast, all of the nanoclays induced regressive and degenerative changes on liver tissues of mosquito fish across all concentrations tested. This study clearly reveals that natural and modified nanoclays have important health implications for fish and other aquatic organisms. Consequently, the widespread use of modified nanoclays in several applications and increased release of natural nanoclays through erosion or other processes needs to be evaluated in more detail especially in the context of their safety for aquatic systems.

Growth Differentiation Factor 15 (GDF15) has emerged as a pivotal signaling molecule implicated in diverse physiological processes, spanning metabolic regulation, inflammation, and cardiovascular health. This study provides a comprehensive exploration of GDF15's multifaceted role, primarily focusing on its association with obesity-related complications and therapeutic potential. GDF15's involvement in energy homeostasis, specifically its regulation of body weight and appetite through hindbrain neuron activation and the GFRAL-RET signaling pathway, underscores its significance as an appetite-regulating hormone. GDF15's intricate modulation within adipose tissue dynamics in response to dietary changes and obesity, coupled with its influence on insulin sensitivity, highlights its critical role in metabolic health. The manuscript delves into the intricate crosstalk between GDF15 and pathways related to insulin sensitivity, macrophage polarization, and adipose tissue function, elucidating its potential as a therapeutic target for metabolic disorders associated with obesity. GDF15's association with chronic low-grade inflammation and its impact on cardiovascular health, particularly during hyperlipidemia and ischemic events, are explored. The intricate relationship between GDF15 and cardiovascular diseases, including its effects on endothelial function, cardiac hypertrophy, and heart failure, emphasizes its multifaceted nature in maintaining overall cardiovascular well-being. Challenges regarding the therapeutic application of GDF15, such as long-term safety concerns and ongoing clinical investigations, are discussed. Lastly, future research directions exploring GDF15's potential in addressing obesity-related complications and cardiovascular risks are proposed, highlighting its promising role as a therapeutic target in reshaping treatment strategies for obesity and associated health conditions.

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.

This study aimed to investigate, for the first time, the chemical composition and antioxidant activity of fluid extracts obtained from three Romanian cultivars of haskap berries (Lonicera caerulea L.) var. Loni, bitter cherries (Prunus avium var. sylvestris Ser.) var. Silva, and pomace from red grapes (Vitis vinifera L.) var. Mamaia, and their capacity to modulate in vitro steatosis, in view of developing novel anti-obesity products. Total phenolic, flavonoid, anthocyanin, and ascorbic acid content of fluid extracts was spectrophotometrically assessed and their free radical scavenging capacity was evaluated using Trolox Equivalent Antioxidant Capacity (TEAC) and free 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical inhibition assays. The Pearson coefficients showed a moderate correlation between the antioxidant activity of fluid extracts and their phenolic content, but a strong correlation between anthocyanin and ascorbic acid content. HPLC analysis identified and quantified the main phenolic compounds of chlorogenic and syringic acid, catechin, and glycosylated kaempferol, apigenin, and quercetin, in variable proportions. An in vitro experimental model of steatosis was developed in HepG2 hepatocytes treated with a mixture of free fatty acids. Cell culture analyses showed that cytocompatible concentrations of fluid extracts could significantly reduce the lipid accumulation and inhibit the reactive oxygen species, malondialdehyde, and nitric oxide secretion in stressed hepatocytes. In conclusion, these results put an emphasis on the chemical compounds' high antioxidant and liver protection capacity of unstudied fluid extracts obtained from Romanian cultivars of bitter cherries var. Silva and pomace of red grapes var. Mamaia, similar to the fluid extract of haskap berries var. Loni, in particular, the positive modulation of fat deposition next to oxidative stress and the lipid peroxidation process triggered by fatty acids in HepG2 hepatocytes. Consequently, this study indicated that these fluid extracts could be further exploited as hepatoprotective agents in liver steatosis, which provides a basis for the further development of novel extract mixtures with synergistic activity as anti-obesity products.

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes.