Search Results (101)

The aim of this study was to determine whether a low dose of zearalenone (ZEN) affects the mRNA expression of the CYP1A1 (P450 cytochrome) and GSTπ1 (glutathione S-transferase) genes in the large intestine of pre-pubertal gilts. Materials: Control (C) group gilts (n = 18) received a placebo. Experimental (E) group gilts (n = 18) were orally administered 40 μg ZEN/kg body weight (BW) each day before morning feeding for 42 days. Three animals from each group were sacrificed each week of the study. Tissue samples were collected from the medial parts of the ascending colon and the descending colon on six dates. Results: Zearalenone concentrations were multiple times higher in the last three weeks of exposure, and ZEN metabolites were not detected. In phase I, CYP1A1 mRNA expression in the ascending colon was suppressed in the final three weeks of exposure, which substantially increased the ZEN concentration in the descending colon. In phase II, ZEN levels were high in the descending colon due to CYP1A1 suppression in the ascending colon. Consequently, the phase II detoxification processes could not take place due to the absence of a substrate. Conclusion: This study demonstrated that low-dose ZEN mycotoxicosis disrupts the expression of the CYP1A1 and GSTπ1 genes, which co-participate in the enzymatic biotransformation of ZEN in both examined sections of the large intestine. The above could have contributed to increased ZEN accumulation in the mucosa of the descending colon in the last three weeks of exposure. Full article

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

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. Full article

To investigate the effects and underlying mechanisms of the Chinese herbal medicine berberine hydrochloride (BBH) on the pharmacokinetics of the antibiotic ciprofloxacin hydrochloride (CIP) in yellow catfish (Pelteobagrus fulvidraco), this study established two experimental groups: CIP alone and CIP combined with BBH. After administering the two treatment groups, we analyzed the pharmacokinetic characteristics and tissue distribution of CIP in yellow catfish, as well as the differences in the expression levels of two key genes involved in drug disposition—ABCB4 (ATP-binding cassette subfamily B member 4, related to drug transport) and CYP3A40 (cytochrome P450 3A40, related to drug metabolism)—in the intestinal tract. The results demonstrated that co-administration of CIP and BBH increased the maximum concentration (C_max) and area under the concentration–time curve (AUC) of CIP while reducing its total body clearance (CL/F). Regarding gene expression, the combined treatment significantly downregulated ABCB4 expression in the intestine at certain time points compared to CIP alone, whereas CYP3A40 expression showed a non-significant decreasing trend. These findings suggest that BBH may enhance the absorption of CIP in yellow catfish by suppressing ABCB4 expression, thereby improving therapeutic efficacy at the same dosage. Full article

Fumonisin B₁ (FB₁) is considered the most toxic fumonisin produced by fungi and is commonly found in contaminated feed and crops. Fumonisin and its metabolites extensively exist in feed and crops, where FB₁-polluted crop ingestion can do harm to livestock and poultry, causing poultry intestinal toxicity in the latter. For investigating FB₁-mediated intestinal toxicity, we assessed the function of FB₁ exposure in quail intestines and explored its possible molecular mechanisms. In total, 120 quail pups were classified into two groups, where those in the control group were given a typical control diet, and those in the experimental group were given a typical diet that contained 30 mg/kg FB₁. We evaluated the histopathological and ultrastructural changes in quails’ intestines on days 14, 28, and 42, and studied the molecular mechanisms by assessing oxidative stress, inflammation, and nuclear xenobiotic receptors (NXRs). Our results suggest that FB₁ exposure causes intestinal inflammation by triggering oxidative stress pathways and modulating NXRs to induce Cytochrome P450 proteins (CYP) isoforms, leading to intestinal histopathological damage. The results of this study shed novel light on the molecular mechanism underlying FB₁-induced intestinal injury in juvenile quails. Full article

Plant extracts contain many small molecules that are less investigated. The present paper aims to study in silico physical-chemical, pharmacokinetic, medicinal chemistry and lead/drug-likeness properties and the ability to interfere with the activity of P-glycoprotein (P-gp) transporter and cytochrome P450 (CYP) oxidase system in humans of phloridzin, phloretin, 4-methylchalcone metabolic series alongside the top three compounds found in the ethanolic extract from strawberries (S), namely 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 2-pyrrolidinone 5-(cyclohexylmethyl) and hexadecanoic acid. The phloridzin derivatives also were studied for their inhibitory potential upon Bcl-2, TNKS1 and COX-2 molecular targets. In vitro, Caco-2 studies analyzed the cytoprotective and anti-proliferative activity of S and the three phloridzin derivatives (pure compounds) in comparison with their combination 1:1 (GAE/pure compound, w/w), in the range 1 to 50 µg active compounds per test sample. Altogether, it was concluded that phloretin (Phl) can be used alone or in combination with S to support intestinal cell health in humans. Phloridzin (Phd) and phloridzin combined with S were proven ineffective. 4-methylchalcone (4-MeCh) combined with S indicated no advantages, while the pure compound exhibited augmented inhibitory effects, becoming a candidate for combinations with anticancer drugs. Overall, in silico studies revealed possible limitations in the practical use of phloridzin derivatives due to their potential to interfere with the activity of several major CYP enzymes. Full article

Background: Berberine has extremely low oral bioavailability, but shows a potent lipid-lowering effect, indicating its potential role in regulating intestinal microbiota, which has not been investigated. Methods: In the present study, five experimental diets, a control diet (Con), a high-lipid diet (HL), and high-lipid·diets·supplemented with an antibiotic cocktail (HLA), berberine (HLB), or both (HLAB) were fed to zebrafish (Danio rerio) for 30 days. Results: The HLB group showed significantly greater weight gain and feed intake than the HLA and other groups, respectively (p < 0.05). Hepatic triglyceride (TG) and total cholesterol (TC) levels, lipogenesis, and proinflammatory cytokine gene expression were significantly upregulated by the high-lipid diet, but significantly downregulated by berberine supplementation. Conversely, the expression levels of intestinal and/or hepatic farnesoid X receptor (fxr), Takeda G protein-coupled receptor 5 (tgr5), lipolysis genes, and zonula occludens 1 (zo1) exhibited the opposite trend. Compared with the HLB group, the HLAB group displayed significantly greater hepatic TG content and proinflammatory cytokine expression, but significantly lower intestinal bile salt hydrolase (BSH) activity and intestinal and/or hepatic fxr and tgr5 expression levels. The HL treatment decreased the abundance of certain probiotic bacteria (e.g., Microbacterium, Cetobacterium, and Gemmobacter) and significantly increased the pathways involved in cytochrome P450, p53 signaling, and ATP-binding cassette (ABC) transporters. The HLB group increased some probiotic bacteria abundance, particularly BSH-producing bacteria (e.g., Escherichia Shigella). Compared with the HLB group, the abundance of BSH-producing bacteria (e.g., Bifidobacterium and Enterococcus) and pathways related to Notch signaling and Wnt signaling were reduced in the HLAB group. Conclusions: This study revealed that berberine’s lipid-lowering and intestine-protective effects are closely related to the intestinal microbiota, especially BSH-producing bacteria. Full article

Reduced glutathione (GSH) is a main nonenzymatic antioxidant, but its effects and underlying mechanisms on growth and intestinal health in weaned piglets still require further assessment. A total of 180 weaned piglets were randomly allotted to 5 groups: a basal diet (CON), and a basal diet supplemented with antibiotic chlortetracycline (ABX), 50 (GSH1), 65 (GSH2), or 100 mg/kg GSH (GSH3). Results revealed that dietary GSH1, GSH2, and ABX improved body weight and the average daily gain of weaned piglets, and ABX decreased albumin content but increased aspartate aminotransferase (AST) activity and the ratio of AST to alanine transaminase levels in plasma. GSH2 significantly decreased glucose content but increased the content of triglyceride and cholesterol in the plasma. Both GSH1 and GSH2 improved the jejunal mucosa architecture (villus height, crypt depth, and the ratio of villus height to crypt depth), tight junction protein (ZO-1 and Occludin), and antioxidant capacity (CAT and MDA), and the effects were superior to ABX. Dietary GSH improved the jejunal barrier by probably inhibiting the myosin light chain kinas pathway to up-regulate the transcript expression of tight junction protein (ZO-1 and Occludin) and Mucins. Through the proteomics analysis of the jejunal mucosa using 4D-DIA, the KEGG pathway enrichment analysis showed that differentiated proteins were significantly enriched in redox homeostasis-related pathways such as glutathione metabolism, cytochrome P450, the reactive oxygen species metabolic pathway, the oxidative phosphorylation pathway, and the phosphatidylinositol 3-kinase-serine/threonine kinase pathway in GSH2 vs. CON and in GSH2 vs. ABX. The results of proteomics and qRT-PCR showed that GSH supplementation might dose-dependently promote growth performance and that it alleviated the weaning stress-induced oxidative injury of the jejunal mucosa in piglets by activating SIRTI and Akt pathways to regulate GPX4, HSP70, FoxO1. Therefore, diets supplemented with 50–65 mg/kg GSH can promote the growth of and relieve intestinal oxidative injury in weaned piglets. Full article

Cadmium (Cd) pollution poses an important problem, but limited information is available about the toxicology effects of Cd on freshwater invertebrates. We investigated the accumulation, oxidative stress, microbial community changes, and transcriptomic alterations in apple snails (Pomacea canaliculata) under Cd stress. The snails were exposed to the 10 μg/L Cd solution for 16 days, followed by a 16-day elimination period. Our results showed that the liver accumulated the highest Cd concentration (17.41 μg/g), followed by the kidneys (8.00 μg/g) and intestine-stomach (6.68 μg/g), highlighting these tissues as primary targets for Cd accumulation. During the elimination period, Cd concentrations decreased in all tissues, with the head-foot and shell exhibiting over 30% elimination rates. Cd stress also resulted in reduced activities of superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST) compared to the control group. Notably, even after 16 days of depuration, the enzyme activities did not return to normal levels, indicating persistent toxicological effects. Cd exposure significantly reduced the diversity of gut microbiota in P. canaliculata. Moreover, transcriptome analysis identified differentially expressed genes (DEGs) primarily associated with lysosome function, motor proteins, protein processing in the endoplasmic reticulum, drug metabolism via cytochrome P450 (CYP450), arachidonic acid metabolism, and ECM–receptor interactions. These findings suggest that Cd stress predominantly disrupts cellular transport and metabolic processes. Overall, our study provides comprehensive insights into the toxicological impact of Cd on P. canaliculata and emphasizes the importance of understanding the mechanisms underlying Cd toxicity in aquatic organisms. Full article

Fusarium mycotoxins often co-occur in broiler feed, and their presence negatively impacts health even at subclinical concentrations, so there is a need to identify the concentrations of these toxins that do not adversely affect chickens health and performance. The study was conducted to evaluate the least toxic effects of combined mycotoxins fumonisins (FUM), deoxynivalenol (DON), and zearalenone (ZEA) on the production performance, immune response, intestinal morphology, and nutrient digestibility of broiler chickens. A total of 960 one-day-old broilers were distributed into eight dietary treatments: T1 (Control); T2: 33.0 FUM + 3.0 DON + 0.8 ZEA; T3: 14.0 FUM + 3.5 DON + 0.7 ZEA; T4: 26.0 FUM + 1.0 DON + 0.2 ZEA; T5: 7.7 FUM + 0.4 DON + 0.1 ZEA; T6: 3.6 FUM + 2.5 DON + 0.9 ZEA; T7: 0.8 FUM + 1.0 DON + 0.3 ZEA; T8: 1.0 FUM + 0.5 DON + 0.1 ZEA, all in mg/kg diet. The results showed that exposure to higher mycotoxin concentrations, T2 and T3, had significantly reduced body weight gain (BWG) by 17% on d35 (p < 0.05). The T2, T3, and T4 groups had a significant decrease in villi length in the jejunum and ileum (p < 0.05) and disruption of tight junction proteins, occludin, and claudin-4 (p < 0.05). Higher mycotoxin groups T2 to T6 had a reduction in the digestibility of amino acids methionine (p < 0.05), aspartate (p < 0.05), and serine (p < 0.05); a reduction in CD4+, CD8+ T-cell populations (p < 0.05) and an increase in T regulatory cell percentages in the spleen (p < 0.05); a decrease in splenic macrophage nitric oxide production and total IgA production (p < 0.05); and upregulated cytochrome P450-1A1 and 1A4 gene expression (p < 0.05). Birds fed the lower mycotoxin concentration groups, T7 and T8, did not have a significant effect on performance, intestinal health, and immune responses, suggesting that these concentrations pose the least negative effects in broiler chickens. These findings are essential for developing acceptable thresholds for combined mycotoxin exposure and efficient feed management strategies to improve broiler performance. Full article

Diets containing higher-amylose-content starches were proved to have some beneficial effects on monogastric animals, such as promoting the proliferation of intestinal probiotics. However, current research on the effects of diets with different starch sources on animals at the extraintestinal level is still very limited. We hypothesized that diets with different starch sources may affect lipid-related gene expression and metabolism in the liver of pigs. This study aimed to use adult pig models to evaluate the effects of diets with different starch sources (tapioca starch, TS; pea starch, PS) on the liver gene expressions and metabolism. In total, 48 growing pigs were randomly assigned to the TS and PS diets with 8 replicate pens/group and 3 pigs per pen. On day 44 of the experiment, liver samples were collected for metabolome and transcriptome analysis. Metabolome data suggested that different starch sources affected (p < 0.05) the metabolic patterns of liver. Compared with the TS diet, the PS diet increased (p < 0.05) some unsaturated fatty acids and several amino acids or peptide levels in the liver of pigs. Moreover, transcriptome data indicated the PS diets elevated (p < 0.05) fatty acid β-oxidation-related gene expression in the liver of pigs, and reduced (p < 0.05) unsaturated fatty acid metabolism-related gene expression. The results of quantitative real-time PCR confirmed that the PS diet upregulated (p < 0.05) the expression of acyl-CoA dehydrogenase very long chain (ACADVL), carnitine palmitoyl transferase (CPT) 1A, and malonyl-CoA decarboxylase (MLYCD), and downregulated (p < 0.05) the expression level of cytochrome P450 2U1 (CYP2U1) and aldehyde dehydrogenase 1B1 (ALDH1B1) in the liver. In addition, the results of a Mantel test indicated the muscle fatty acids were significantly closely correlated (p < 0.05) with liver gene expressions and metabolites. In summary, these findings suggest that diets containing higher amylose starches improved the lipid degradation and the unsaturated fatty acid levels in pig livers, and thus can generate some potential beneficial effects (such as anti-inflammatory and antioxidant) on pig health. Full article

Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α₁-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4. Full article

Producing translucent eggs has been found to reduce the quality and safety of the eggs, as well as the demand from consumers. However, the intestinal function and the molecular mechanism for the production of translucent eggs remain uncertain. A total of 120 eggs from 276-day-old Jining Bairi were divided into two groups based on eggshell translucence: the translucent egg group (group T) and the normal group (group C). Group T exhibited thicker eggshells and a lower egg yolk color. Subsequently, we divided the chickens into translucent and normal groups based on their egg quality. We then assessed the plasma biochemical index, intestinal morphology and structure, enzyme activity, and antioxidant capacity of the hens producing translucent eggs compared to those producing normal eggs. The results showed that the ratio of duodenal villus length to crypt depth, succinate dehydrogenase (SDH) activity, chymotrypsin, total ATPase (T-ATPase), alkaline phosphatase (AKP), and glutathione peroxidase (GSH-Px) activities were decreased in the hens produced translucent eggs (p < 0.05), but malondialdehyde (MDA) content was increased (p < 0.05); jejunal lipase activity, Na⁺K⁺-ATPase activity, total antioxidant capacity (T-AOC), and GSH-Px activities were decreased (p < 0.05) in group T; ileal amylase and Ca²⁺Mg²⁺-ATPase activities were also decreased (p < 0.05) in group T. In addition, we identified a total of 471 differentially expressed genes (DEGs) in duodenal tissue, with 327 up-regulated genes and 144 down-regulated genes (|log₂FC| ≥ 1 and p < 0.05). Enrichment analysis showed that the up-regulated genes, such as GSTT1, GSTO2, and GSTA3, were mostly enriched in metabolism of xenobiotics by cytochrome P450, drug metabolism-cytochrome P450, and oxidative phosphorylation pathways. The results of our study indicate that plasma lipid metabolism disorder, decreased intestinal antioxidant capacity, and altered intestinal metabolism capabilities may influence the formation of translucent eggs. Full article

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver–gallbladder–compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition. Full article

Phycocyanin (PC) is a naturally occurring green pigment in Spirulina. It was extracted by ultrasonic extraction using green technology, and its structure was studied using IR- and NMR-spectroscopy. Spectral data confirmed the PC structure. This study also involves an in silico assessment of the diverse applications of green pigment PC. Utilizing QSAR, PreADME/T, SwissADME, and Pro-Tox, this study explores the safety profile, pharmacokinetics, and potential targets of PC. QSAR analysis reveals a favorable safety profile, with the parent structure and most metabolites showing no binding to DNA or proteins. PreADME/T indicates low skin permeability, excellent intestinal absorption, and medium permeability, supporting oral administration. Distribution analysis suggests moderate plasma protein binding and cautious blood–brain barrier permeability, guiding formulation strategies. Metabolism assessments highlight interactions with key cytochrome P450 enzymes, influencing drug interactions. Target prediction analysis unveils potential targets, suggesting diverse therapeutic effects, including cardiovascular benefits, anti-inflammatory activities, neuroprotection, and immune modulation. Based on the in silico analysis, PC holds promise for various applications due to its safety, bioavailability, and potential therapeutic benefits. Experimental validation is crucial to elucidate precise molecular mechanisms, ensuring safe and effective utilization in therapeutic and dietary contexts. DFT calculations, including geometry optimization, MEP analysis, HOMO-LUMO energy surface, and quantum reactivity parameters of the PC compound, were obtained using the B3LYP/6–311G(d,p) level. This integrated approach contributes to a comprehensive understanding of PC’s pharmacological profile and informs future research directions. Full article