Search Results (630)

Background: Interindividual differences in statin efficacy and tolerability are partly determined by genetic and metabolic factors. The SLCO1B1 c.521T>C polymorphism affects hepatic statin transport, while vitamin D deficiency may influence lipid metabolism and muscular tolerance. This study aimed to assess the impact of SLCO1B1 genotype and vitamin D status on lipid-lowering response and adverse events in postmenopausal women treated with atorvastatin or rosuvastatin. Methods: A total of 145 Croatian postmenopausal women were prospectively followed for 16 weeks. Participants received atorvastatin or rosuvastatin with dose titration to achieve low-density lipoprotein cholesterol (LDL-C) targets. Serum lipids, liver enzymes, and creatine kinase were monitored monthly. Serum levels of 25-hydroxyvitamin D were quantified by LC–MS/MS, while SLCO1B1 c.521T>C genotyping was performed using real-time PCR. Results: Rosuvastatin achieved a higher LDL-C target attainment rate compared with atorvastatin (81.1% vs. 67.6%, p = 0.02). The SLCO1B1 genotype was not associated with lipid response but was significantly associated with adverse effects. In multivariable regression analysis, patients with the T/C genotype had a significantly higher risk of developing adverse effects compared with those with the T/T genotype (OR 7.4, 95% Cl 2.1–26.7, p = 0.002). Vitamin D status showed no significant association with lipid outcomes or adverse events, although participants with severe deficiency exhibited a weaker LDL-C response. Conclusions: Rosuvastatin demonstrated superior lipid-lowering efficacy and tolerability compared with atorvastatin in postmenopausal women. The SLCO1B1 c.521T>C variant primarily affected safety rather than efficacy, while severe vitamin D deficiency might contribute to diminished statin response. Integrating pharmacogenetic and endocrine profiling could enhance individualized statin therapy and cardiovascular prevention in women. Full article

This study aims to investigate the effects of dietary vitamin C supplementation on vitamin C synthesis, transport, and egg deposition in breeding geese. A total of 450 female and 90 male 221-day-old Yangzhou geese were randomly assigned to five treatment groups with six replicates each (15 females and 3 males per replicate). The control group received a basal diet, while the other four groups were fed diets supplemented with 100, 200, 300, and 400 mg/kg vitamin C over a 16-week feeding trial. The results showed that dietary vitamin C supplementation increased the vitamin C content in both serum and egg yolks and modulated the expression of key vitamin C-related genes. Specifically, the intestinal and ovarian sodium-dependent vitamin C transporters 1 and 2 (SVCT1/SVCT2) were upregulated, whereas hepatic and renal L-Gulonolactone oxidase (GLO) and SVCT1 were suppressed. These findings indicate that exogenous vitamin C enhances intestinal absorption, inhibits hepatic synthesis, and promotes yolk deposition, with 300 mg/kg emerging as an effective and practical supplementation level that provides a physiological basis for its application in poultry nutrition. Full article

Type 2 diabetes mellitus (T2D) affects hundreds of millions worldwide, with recent estimates indicating approximately 589 million adults living with diabetes, most with type 2 disease. Beyond classical insulin signaling pathways, increasing evidence implicates altered protein glycosylation in metabolic dysfunction. The solute carrier 35 (SLC35) family of nucleotide sugar transporters mediates the import of activated sugars into the endoplasmic reticulum and Golgi lumen, thereby influencing global glycosylation patterns. Dysregulation of these transporters can perturb glucose homeostasis, insulin responsiveness, and nutrient-sensing pathways through changes in glycosylation flux. In this review, we dissect the molecular mechanisms by which these transporters modulate glucose homeostasis, insulin signaling pathways, protein O-GlcN acylation, and broader glycosylation processes. We integrate findings from human genetic studies, rodent models, and in vitro functional analyses to characterize how altered SLC35 activity is associated with T2D and metabolic syndrome. Four members demonstrate particularly compelling evidence: SLC35B4 modulates hepatic glucose metabolism, SLC35D3 mutations impair dopaminergic signaling and energy balance, and SLC35F3 variants interact with high-carbohydrate intake to increase metabolic-syndrome risk. SLC35A3, though less studied, may influence glycosylation-dependent insulin signaling through its role in N-glycan biosynthesis. Beyond these characterized transporters, this review identifies potential metabolic roles for understudied family members, suggesting broader implications across the entire SLC35 family. We also discuss how such alterations can lead to disrupted hexosamine flux, impaired glycoprotein processing, aberrant cellular signaling, and micronutrient imbalances. Finally, we evaluate the therapeutic potential of targeting SLC35 transporters, outlining both opportunities and challenges in translating these insights into novel T2D treatments. Full article

Probiotics hold great potential in aquaculture, as they can effectively modulate gut microbiota and improve fish health, thereby enhancing farming efficiency. Translating this potential into practical application critically relies on screening high-efficacy probiotic strains. This study evaluated the growth-promoting and health-enhancing effects of probiotic candidates Lactobacillus rhamnosus GG (LGG), Lactobacillus plantarum FZU310 (LP-FZU310) and Bacillus subtilis FZU103 (BS-FZU103) in largemouth bass (Micropterus salmoides). After feeding different probiotics for 30 days, the growth, antioxidant, and intestinal enzyme indicators of M. salmoides were detected. BS-FZU103 demonstrated superior efficacy among the tested strains, showing significant differences in both specific growth rate (SGR) (p < 0.05) and condition factor (CF) (p < 0.05). It also markedly enhanced hepatic antioxidant status, elevating superoxide dismutase and glutathione peroxidase activities while reducing malondialdehyde levels by 80%. Improved liver integrity was indicated by significant decreases in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Digestively, BS-FZU103 specifically increased intestinal amylase activity by 14.7%, without affecting protease or lipase, suggesting enhanced carbohydrate digestion. 16S rRNA sequencing revealed BS-FZU103 remodeled gut microbiota, increasing Proteobacteria abundance at the phylum level and enriching Bacillus while reducing Clostridium sensu stricto 1 at the genus level. Functional prediction based on PICRUSt2 indicated an enhanced metabolic potential of the gut microbiota, with inferred upregulation of pathways related to carbohydrate transport and metabolism (e.g., ABC transporters) and intestinal enzymatic activities. Collectively, BS-FZU103 is associated with metabolic modulation, promoting M. salmoides growth through gut microbiota remodeling, hepatic antioxidant fortification, and targeted augmentation of carbohydrate utilization efficiency. Full article

Background and Aims: Diabetes mellitus and chronic hepatitis B/C infection are risk factors for liver cirrhosis and hepatocellular carcinoma (HCC). This study aimed to evaluate whether sodium-glucose cotransporter-2 inhibitors (SGLT2i) improved liver-related outcomes in patients with chronic viral hepatitis and co-existing diabetes. Methods: Using data from the Korean nationwide cohort, this study included 37,629 patients with concurrent diabetes and chronic hepatitis B/C infection, without prior HCC, who were treated with oral hypoglycemic agents. Patients who were treated with SGLT2is for over 90 days were allocated to the SGLT2i group, whereas those who never received SGLT2is comprised the non-SGLT2i group. The primary outcome was the occurrence of liver-related events, including HCC. Results: After 1:2 propensity score matching, the SGLT2i group comprised 12,543 patients (chronic hepatitis B, CHB: n = 9392; chronic hepatitis C, CHC: n = 4300, CHB & CHC: n = 1149), while the non-SGLT2i group included 25,086 patients (CHB: n = 18,806; CHC: n = 8553, CHB & CHC: 2273). The incidence rate of composite liver-related complications was lower in the SGLT2i group than that in the non-SGLT2i group (6.67 per 1000 vs. 8.99 per 1000). Moreover, SGLT2i therapy was associated with a reduced risk of HCC development (subdistribution hazard ratio [sHR] = 0.77, 95% confidence interval [CI] = 0.66–0.91; p = 0.002) and developing cirrhosis (sHR = 0.67, 95% CI = 0.54–0.83; p < 0.001). Conclusions: SGLT2is should be considered a therapeutic option for controlling diabetes, reducing the metabolic burden, and improving liver outcomes in patients with concurrent diabetes and chronic viral hepatitis. Full article

Kratom alkaloids are classified as aromatic pentacyclic indole and substituted carbonyl oxindole alkaloids. This study investigates the metabolism and interactions of indole alkaloids using in silico tools, including ADMET Predictor 13.0™, to assess pharmacokinetic and metabolic profiles. The analysis examined absorption, distribution, metabolism, and excretion (ADME), focusing on cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzyme interactions, drug transporters, and clearance. Most indole alkaloids showed strong substrate interaction and inhibition of CYP3A4 (79–99% confidence) and induction of CYP1A2 (up to 94% confidence). Among UGT enzymes, UGT1A1 demonstrated the highest substrate affinity (97%), while none interacted with UGT2B15. All alkaloids showed strong P-glycoprotein (Pgp) interaction but minimal inhibition of BCRP. Mitralactonine exhibited the highest skin permeability, and Mitralactonal showed maximal jejunal permeability. Most indole alkaloids demonstrated significant blood–brain barrier penetration (up to 99% confidence) and compliance with Lipinski’s rule of five. Predictive modeling indicated notable effects on hepatic microsomal clearance parameters. This investigation offers the first comprehensive in silico ADMET profiling of kratom indole alkaloids, uncovering their CYP3A4 inhibition potential and metabolic liabilities to prioritize candidates for safer therapeutic development, though limited by model biases, applicability domain restrictions, and inability to fully capture biological complexity, stereochemistry, or interindividual variability necessitating experimental in vitro and in vivo validation. Full article

Organic anion-transporting polypeptides (OATPs) are key transporters of hepatic uptake for endogenous compounds and xenobiotics. Human OATP1B1 and OATP1B3 are well-studied due to their role in drug–drug interactions. In contrast, data on murine OATP1B2, the rodent orthologue of these transporters, are limited, despite its importance in early drug development. Here, we systematically compared the transport characteristics of mouse and rat OATP1B2 under identical experimental conditions. The K_m values for estrone-3-sulfate (E₁S) and taurocholate (TCA) were 242 and 73 µM for mOATP1B2 and 90 and 16 µM for rOATP1B2. Nine clinically relevant drugs were evaluated for inhibitory effects, showing strong correlation between species. Cyclosporine A, ritonavir, odevixibat, rosuvastatin, and rifampicin markedly inhibited uptake. Rifampicin demonstrated species-specific differences, with higher IC₅₀ values for mOATP1B2 (E₁S: 9.6 µM; TCA: 7.7 µM) than rOATP1B2 (E₁S: 1.1 µM; TCA: 2.4 µM). A comparison of the rodent data with the human orthologues revealed similar inhibition patterns but distinct substrate selectivity: hOATP1B1 showed high affinity for E₁S but negligible TCA uptake, while hOATP1B3 transported TCA weakly but not E₁S. This study provides insights into species-specific differences in OATP-mediated hepatic uptake and is therefore valuable for the interpretation of preclinical studies and their transfer to human pharmacology. Full article

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31′s biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses. Full article

Anemia, characterized by reduced hemoglobin (Hb), remains a major health concern. Although iron and erythropoietin (EPO) therapies are effective, limitations in safety and accessibility have prompted interest in nutritional alternatives. Hydrolyzed milk-derived peptides (H-MDPs) contain bioactive sequences with diverse physiological effects, yet their role in erythropoiesis remains poorly defined. This study investigated the hematopoietic actions of H-MDP using zebrafish and mouse models. Adult zebrafish underwent phlebotomy-induced anemia and received oral H-MDP for 3 weeks. Hb levels, erythrocyte morphology, and expression of erythropoiesis- and iron-metabolism genes were assessed. In healthy mice, renal Epo expression, circulating EPO, and serum cytokines were measured after 2 weeks of H-MDP administration. H-MDP significantly accelerated Hb recovery in anemic zebrafish (4.6 ± 0.64 g/dL vs. 3.4 ± 0.66 g/dL in untreated fish at week 1) and markedly improved erythrocyte maturation. These effects coincided with strong induction of epo, hif1aa/b, igf1, csf1a, and csf3b in the heart and liver, as well as normalization of anemia-induced hepatic iron-transport genes (tfa, fpn1, tfr2) and reactivation of hamp. In mice, H-MDP elevated renal Epo mRNA and circulating EPO (approximately 2.3-fold) without altering steady-state Hb, and cytokine profiling with IPA-predicted activation of the erythropoietin signaling pathway. Collectively, these findings indicate that H-MDPs modulate erythropoiesis by coordinating the activation of EPO-related and iron-regulatory networks, supporting their potential as functional food ingredients for hematologic recovery and anemia management. Full article

Ochratoxin A (OTA), Zearalenone (ZEA), and Fumonisins (FB) are common contaminants of poultry feed associated with oxidative damage and potentially dangerous residues in products from exposed animals. We investigated the molecular effects in broilers of a short-term (10 days) dietary exposure to OTA (0.26 mg/kg), ZEA (2.9 mg/kg), or FB (60 mg/kg) on cytochrome P450 enzymes (CYP), drug transporters (DT) and the antioxidant defence system. OTA markedly decreased serum antioxidant capacity, while all mycotoxins depressed reduced glutathione content and increased lipid peroxidation in the liver, indicating a hepatic pro-oxidant effect. All the tested mycotoxins also reduced both the activities and the gene expression of selected antioxidant enzymes in the liver and duodenum as a result of the modulation of the Nrf2/Keap1 pathway. Moreover, mycotoxins differentially altered the hepatic and intestinal gene expression of CYP enzymes (i.e., CYP2A6, CYP2C45, CYP3A4, and CYP1A isoforms). Finally, the transcription of selected DT (i.e., ABCB1, ABCC2 and ABCG2) was generally enhanced in both the liver and duodenum. In conclusion, short-term exposure to OTA, ZEA, or FB at dietary concentrations higher than those recommended in the EU, but occurring in third countries, not only disrupt the antioxidant defence but also affect the expression of CYP and DT, which might potentially alter the kinetics of drugs and toxicants. Our results provide new insights into mycotoxin adverse effects in the light to assess the effectiveness of new mitigation strategies that contribute to food and feed safety. Full article

(1) Background: Swine hepatitis E (SHE) is a novel zoonotic disease caused by the swine hepatitis E virus. Open Reading Frame 3 (ORF3) is an important virulence protein of swine hepatitis E virus, which promotes the survival and replication of the virus within host cells by regulating the ERK pathway, modulating the transport of growth factors that affect apoptosis, and facilitating the transmission of death signals during HEV infection. (2) Methods: In our previous study, we used adenovirus-mediated overexpression of HEV-4 in swine ORF3 in HepG2 cells, extracted total RNA, and performed high-throughput lncRNA, circRNA, and transcriptome sequencing. Based on the role of ORF3 in regulating the innate immunity of host cells, maintaining ERK activity, inhibiting the transport of growth factors, and suppressing the immune response, the pathways and differentially expressed genes were screened. A clustering analysis was conducted on circRNAs and lncRNAs, which were significantly differentially expressed across the four pathways, and a regulatory network of circRNA-miRNA and lncRNA-mRNA was constructed. (3) Results: In this study, a total of 24 circRNAs and 4 lncRNAs were screened in HepG2 cells expressing ORF3 of HEV-4 in swine, including 8 circRNAs that regulate host cell innate immunity and 18 circRNAs that maintain ERK activity. Four circRNAs inhibited growth factor transport, and three circRNAs inhibited immune responses, predicting the regulatory networks of circRNA-miRNA and lncRNA-mRNA, respectively. (4) Conclusions: In this study, differential genes involved in regulating host cell innate immunity, maintaining ERK activity, inhibiting growth factor transport, and inhibiting immune response processes were successfully screened in HepG2 cells expressing ORF3 in HEV-4 in swine, and the regulatory networks of circRNA-miRNA and lncRNA-mRNA were predicted, respectively, which laid a foundation for further elucidating the function of swine hepatitis E virus ORF3 and elucidating the infection mechanism of swine hepatitis E virus. Full article

Introduction/Objectives: Ginsenoside F1, a pharmacologically active saponin derived from Panax ginseng, exhibits diverse bioactivities, but its use is limited because it is difficult to purify and has high production costs. To overcome these challenges, a ginsenoside F1-enriched extract named SGB121 was developed. This study aimed to evaluate the therapeutic efficacy of SGB121 in a high-fat, high-carbohydrate (HFHC) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mouse model and to elucidate its mechanism of action using F1-based cellular assays. Methods: Male C57BL/6 mice (6 weeks old) were fed an HFHC diet to induce MAFLD and were treated with SGB121. Hepatic lipid accumulation, oxidative stress markers, and metabolic parameters were analyzed. In parallel, human hepatocellular carcinoma (HepG2) cells exposed to free fatty acids (FFAs) were used to assess oxidative stress and lipid accumulation. Mechanistic studies were conducted using purified F1 to examine adenosine monophosphate-activated protein kinase (AMPK) activation and related pathways. Results: SGB121 reduced hepatic lipid accumulation, malondialdehyde (MDA) levels, and fasting insulin while restoring glutathione (GSH) content and improving the homeostasis model assessment of insulin resistance (HOMA-IR) in MAFLD mice. In FFA-treated HepG2 cells, both SGB121 and F1 decreased reactive oxygen species (ROS), suppressed sterol regulatory element-binding protein 1 (SREBP1), enhanced peroxisome proliferator-activated receptor-α (PPARα) and β-oxidation, and restored insulin receptor substrate (IRS)/protein kinase B (Akt)/glucose transporter 2 (GLUT2) signaling. Conclusions: SGB121 ameliorates MAFLD and related metabolic dysfunction through antioxidant, lipid-regulating, and insulin-sensitizing actions, highlighting its potential as a safe multifunctional nutraceutical for MAFLD management. Full article

There is increasing interest in foods that support both physical and psychological health. Red and black fruits are notable for their high phenolic content and associated biological activities. However, their natural sugar content may raise concerns regarding glycemic impact. Recent breeding programs have developed new seedless table grape varieties with black skin and red pulp, aiming to enhance phenolic content and reduce glycemic response. This study evaluates these novel grape varieties using in vitro models of intestinal absorption and hepatic insulin resistance. Specifically, we assessed phenolic content, antioxidant capacity, glucose transport across intestinal cells, and the modulation of biomarkers related to insulin resistance. The results showed that the new grape varieties (hybrids) showed total phenolic contents of 52.4–187.3 mg GAE/100 g FW and antioxidant capacities ranging between 195.3 and 762.7 mg Trolox equivalents/100 g FW, both higher than those of commercial table grapes. These new varieties also showed a lower percentage of intestinal glucose transport than commercial grapes and pineapple in caco-2 cells, suggesting an improved regulation of glucose uptake. Theoretical transport values confirmed a reduced glycemic impact for most hybrids, while absorbed fractions of RF03, RF05, and RF06 also restored hepatic glycogen levels under insulin-resistant conditions, indicating enhanced glucose metabolism. Overall, our in vitro findings suggest that these new grape varieties may help modulate postprandial glucose levels, supporting their potential as a healthier fruit option. Full article

Bilirubin, a metabolite derived from heme degradation, has traditionally been regarded as a waste product and a marker of liver injury. However, increasing evidence suggests that bilirubin also functions as a hormone, and reduced levels are associated with metabolic dysfunction. Studies have shown a strong association between low circulating bilirubin levels and an increased risk of metabolic disorders and cardiovascular disease. To advance bilirubin-based treatment strategies, it is essential to elucidate the mechanisms underlying bilirubin transport and metabolism. Therefore, we provide an in-depth discussion of bilirubin production and its subsequent fates, with a particular focus on the transport between the liver and the intestine. We describe the molecular players involved in heme degradation and biliverdin formation, leading to bilirubin production, followed by its transport from the bloodstream to hepatocytes and from the liver to the intestine. We discuss intestinal bilirubin catabolism, including the microbiome generation of urobilinogen, urobilin, and other metabolites. Finally, we discuss how bilirubin clearance and catabolism intersect with its metabolic effects, highlighting potential therapeutic targets. By integrating these aspects, this review provides a comprehensive understanding of bilirubin’s physiological importance, intestinal transport, and breakdown, as well as insights into novel strategies for treating hypobilirubinemia-associated disorders. Full article

A hypercaloric diet is associated with oxidative stress and the dysfunction of ATP-Binding Cassette transporter A1 (ABCA1), a key element in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. Nicotinamide (NAM) presents antioxidant properties, which may contribute to maintaining lipid metabolism. Therefore, we aimed to evaluate the effect of NAM on HDL-cholesterol (HDL-C) level, oxidative stress markers, and the gene expression and protein levels of ABCA1 in Sprague-Dawley rats fed a hypercaloric diet. Forty male rats were divided into five groups: one group received a standard diet, and the remaining groups received a single high-fat, high-fructose diet (HFDF). Three of the HFDF groups received NAM treatment (5, 10, and 15 mM) in drinking water for 16 weeks (5 h/day). While HDL-C and oxidative stress were measured in serum samples, oxidative stress markers, and the gene expression and protein levels of ABCA1 were quantified in liver samples. The HDL-C level altered by the HFDF was improved by treatment with NAM. Furthermore, NAM reduces systemic lipid peroxidation levels and enhances the hepatic antioxidant response affected by the HFDF. In addition, NAM modulates the hepatic ABCA1 gene expression and protein level, altered by the HFDF. Our results suggest that NAM may modify the serum HDL-C level by an improvement of antioxidant response, and a possible modulation of the hepatic ABCA1 gene and protein expression. Further metabolic and molecular studies are needed to support the potential therapeutic role of NAM to prevent or treat lipid alterations promoted by a hypercaloric diet. Full article