Search Results (280)

Caffeine is a widely consumed psychoactive compound known to influence drug metabolism and efficacy through interactions with key enzymes such as cytochrome P450 3A4 (CYP3A4). This study investigates the molecular impact of caffeine on the binding behavior of imatinib, a first-line BCR-ABL tyrosine kinase inhibitor, using molecular docking simulations. Structural optimization and lipophilicity analyses were conducted using HyperChem, while docking was performed with HEX software (Version 8.0.0) against the CYP3A4 receptor (PDB ID: 1W0E). Two administration scenarios were evaluated: concurrent caffeine–imatinib complex formation and sequential administration with caffeine pre-bound to CYP3A4. The caffeine–imatinib complex exhibited a predicted increase in lipophilicity (logP = 3.09) compared to imatinib alone (logP = −1.29), which may indicate the potential for enhanced membrane permeability and tissue distribution. Docking simulations revealed stronger binding affinity of the complex to CYP3A4 (−350.53 kcal/mol) compared to individual compounds, and improved imatinib binding when CYP3A4 was pre-complexed with caffeine (−294.14 kcal/mol vs. −288.19 kcal/mol). Frontier molecular orbital analysis indicated increased reactivity of the complex (ΔE = 7.74 eV), supporting the hypothesis of altered pharmacodynamic behavior. These findings suggest that caffeine may modulate imatinib’s metabolic profile and therapeutic efficacy by enhancing receptor binding and altering drug distribution. The study underscores the importance of evaluating dietary components during drug development and therapeutic planning, particularly for agents metabolized by CYP3A4. Full article

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

Bombyx mori, a key lepidopteran model with economic importance, is highly susceptible to environmental heavy metal pollution. This study investigated the mechanisms of Pb toxicity and the associated detoxification and metabolic defense responses in silkworms, employing transcriptome sequencing, enzyme activity assays, and histopathological analysis. Pb exposure caused significant histopathological changes and apoptosis in the fat body, marked by structural disorganization, swollen adipocytes, and degraded extracellular matrix. Molecular analysis showed activation of antioxidant defenses, with superoxide dismutase (SOD) and catalase (CAT) activities significantly elevated (p < 0.05), while peroxidase (POD) activity declined (p < 0.05). Levels of malondialdehyde (MDA) and glutathione (GSH) also decreased. In detoxification responses, carboxylesterase (CarE) activity was reduced, whereas cytochrome P450 (P450) and glutathione S-transferase (GST) activities increased (p < 0.05). Transcriptome sequencing revealed 1,418 differentially expressed genes (DEGs), with notable upregulation of key detoxification genes (p < 0.05), including six cytochrome P450s (CYPs), five uridine diphosphate-glycosyltransferases (UGTs), three glutathione S-transferases (GSTs), and six ATP-binding cassette transporters (ABCs). KEGG enrichment analysis highlighted the involvement of these DEGs in drug metabolism, glutathione metabolism, and ABC transporter pathways (p < 0.05). Functional validation showed that knocking down Cap ‘n’ Collar C (CncC) significantly suppressed key detoxification genes (CYP18A1, CYP332A1, GSTd3, GSTt1, UGT33D8; p < 0.05). qRT-PCR and Western blot analyses confirmed that the Caspase-3 pathway mediates Pb-induced apoptosis, with increased cleaved Caspase-3 and Caspase-4 levels following CncC silencing. Overall, our findings elucidate the mechanisms of Pb toxicity in silkworms and identify CncC as a critical regulator of detoxification and defense against heavy metal stress in lepidopteran insects. Full article

The incidence of Hashimoto’s disease (HD) increases with age and in people who have other autoimmune diseases. It is characterized by lymphocytic infiltration, fibrosis, and atrophy of the thyroid parenchyma with the simultaneous presence of thyroid peroxidase antibodies (ATPO) and/or thyroglobulin antibodies (ATG). Eicosanoids are formed via the cyclooxygenase (COX), lipoxygenase (LOX), and monooxygenase (CYP450) pathways with arachidonic acid (ARA), resulting in the production of epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs). These eicosanoids can act in an autocrine or paracrine manner on target cells. This study aimed to examine whether a gluten-free diet (GFD) can modulate the enzymatic pathways of the pro-inflammatory ARA cascade. The study material consisted of serum samples from Caucasian female patients with HD aged 18–55 years. Participants were enrolled in the study based on the presence of an ultrasound characteristic of HD, and elevated serum levels of anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies. Patients with confirmed celiac disease did not participate in the study. A total of 78 samples were analyzed, with 39 collected after 3 months of following a GFD. Eicosanoids (thromboxane B2, prostaglandin E2, leukotriene B4, and 16R-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (16-RS HETE)) were extracted using high-performance liquid chromatography. The contribution of leukotriene (LTB) was analyzed in the LOX pathway, prostaglandins (PGE2) and thromboxane (TXB2) were selected for the involvement of the COX pathway, and 16RS HETE was used for the CYP450 pathway. All parameters were analyzed before and after a 3-month dietary intervention that included a gluten-free diet. In the obtained results, only one mediator, leukotriene B4, was significant (p < 0.05). The mean level on the initial visit was 0.202 ± 0.11 (SD), while it was 0.421 ± 0.27 (SD) on the subsequent visit, indicating a significant increase in its level after implementing a GFD. Although there was a trend in the CYP 450 pathway of decreased 16-RS HETE, the presented correlations show that thromboxane B4 and 16RS-HETE were positively correlated with the body mass and body fat mass of the examined patients. There was a trend in the CYP 450 pathway of decreased 16-RS HETE after GFD. Thromboxane B4 and 16RS-HETE levels before GFD were positively correlated with the body mass and body fat mass of the examined patients. A gluten-free diet in HD does not suppress the synthetic pathways of LOX, COX, or cytochrome P450 (CYP450). The level of adipose tissue has a greater impact on the inflammatory processes in HD than a gluten-free diet. This study does not confirm the suppressive effect of a gluten-free diet on the pro-inflammatory arachidonic acid cascade in any of the three analyzed mediator synthesis LOX, COX, CYP450 pathways. 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

Aroma composition serves as a pivotal quality determinant in table grapes (Vitis vinifera). While the cytochrome P450 enzyme CYP76F14 is implicated in aroma biosynthesis, its functional role in grape berries remains uncharacterized. A comparative analysis of three aroma-distinct cultivars—Muscat type ‘Irsai Oliver’, Neutral type ‘Yanhong’, and Berry-like type ‘Venus Seedless’—revealed cultivar-specific linalool accumulation patterns. ‘Irsai Oliver’ exhibited sustained linalool biosynthesis from the fruit set through to maturity (from Stage 1 to Stage 5), with concentrations peaking at Stage 3 (veraison phase) and remaining elevated until harvest, surpassing the other two cultivars. Transcriptional profiling demonstrated that the CYP76F14 expression exhibited a similar trend with the accumulation of linalool levels, showing a higher expression in ‘Irsai Oliver’ across the developmental stages. A structural analysis identified 12 divergent residues in the ‘Irsai Oliver’ CYP76F14 variant, including E378 and T380 within the conserved substrate recognition site. The site-directed mutagenesis of these residues (CYP76F14-E378G/T380A) reduced the catalytic efficiency by 68–72% compared to the wild-type (in vitro LC-MS/MS assays), confirming their functional significance. This work reveals that cytochrome P450 CYP76F14 mediates the conversion of its substrate linalool in table grape berries, especially of Muscat type grapes, and proposes the CYP76F14 polymorphic variants as molecular markers for aroma-type breeding. The identified catalytic residues (E378/T380) provide targets for enzymatic engineering to modulate the terpenoid profiles in Vitis species. Full article

Food components and herbal substances can inhibit or enhance the therapeutic effects of drugs, thus influencing their efficacy and safety. As relatively little in known of these interactions, the aim of this review is to shed further light on the potentially dangerous influences that food and herbs may have on cytochrome P450 enzyme (CYP) and monoamine oxidase (MAO) activity in the first stage of drug biotransformation. The review includes documented cases in which such interactions have led to health complications in patients. For example, fruit juices, such as grapefruit juice, cranberry juice, and pomegranate juice, have been found to interact with drugs, and to particularly inhibit CYP450 activity, and commonly used herbs are known to inhibit (e.g., Astragalus membranous) or induce (e.g., Hypericum perforatum) CYP enzymes involved in drug metabolism. CYP is also induced by polycyclic aromatic hydrocarbons (PAHs), found in grilled meat and tobacco smoke. The paper also discusses the toxic effects of tyramine, present in inter alia blue cheese, resulting from interactions with MAO-metabolised drugs. Most importantly, while the quantity of food and herbs consumed plays a significant role in the described drug interactions, it is possible for toxic effects to be observed even after the consumption of relatively small amounts. Patients are encouraged to consult a healthcare provider about any potential drug interactions that may occur when starting a new medication. Full article

Increases in flow elicit dilations in the basilar artery (BA) supplied by the posterior cerebral circulation (PCC), and ensuring efficient blood supply to the circle of Willis in which blood flow and pressure can distribute and equalize, and thus provide the appropriate supply for the daughter branches to reach certain brain areas. In contrast, increases in flow elicit constrictions in the middle cerebral artery (MCA), supplied by the anterior cerebral circulation (ACC) and regulating the blood pressure and flow in distal cerebral circulation. Mediators of flow-dependent responses include arachidonic acid (AA) metabolites and nitric oxide (NO). We hypothesized that mediators of flow-dependent responses are differentially expressed in cerebral arteries of the PCC (CA_PCC) and ACC (CA_ACC). The expressions of key enzymes of the AA pathway—cyclooxygenases (COX1/COX2), cytochrome P450 hydroxylases (Cyp450), thromboxane synthase (TXAS), thromboxane A2 (TP) receptor, prostacyclin synthase (PGIS), prostacyclin (IP) receptor (IP); neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS)—in the BA and MCA from rats (n = 20) were determined by western blotting. Transcriptome analysis in CA_PCC and CA_ACC from rats (n = 25) was assessed by RNA sequencing. In BA compared to MCA, COX1/2 and Cyp450 protein expressions were lower, PGIS was higher, TXAS and nNOS/eNOS were similar, TP receptors were lower, and IP receptors were higher. Gene expressions of vasodilator canonical pathways were higher in CA_PCC; vasoconstriction canonical pathways were higher in CA_ACC. Mediators of flow-dependent vasomotor signaling are differentially expressed in cerebral arteries of the posterior and anterior circulation, corresponding to their vasomotor function. Full article

The overdose of acetaminophen (APAP) has become the leading cause of acute liver failure in the United States and some Western countries. As a principal member of the cytochrome P450 enzymes (CYPs), CYP2E1 is a vital enzyme in regard to the production of toxic APAP metabolites and in the development of APAP-induced liver injury (AILI). In this study, we investigated the therapeutic effects and mechanisms of lipid nanoparticle (LNP)-based delivery of small interfering RNA targeting Cyp2e1 (si-Cyp2e1 LNPs) on AILI in mice. C57BL/6J male mice were injected with 300 mg/kg APAP to establish an AILI model, and si-Cyp2e1 LNPs were administered via the tail vein. The results showed that the levels of serum alanine aminotransferase and aspartate aminotransferase were lower than those in APAP mice after treatment with si-Cyp2e1 LNPs immediately. Moreover, si-Cyp2e1 LNPs significantly inhibited liver necrosis and oxidative stress in APAP mice. RNA sequencing revealed that si-Cyp2e1 LNPs exerted regulatory effects on pathways and genes related to peroxisome proliferator-activated receptor (PPAR). Consistent with this finding, we also proved that si-Cyp2e1 LNPs markedly regulated the expressions of genes involved in the PPAR signaling pathway (CYP4A, PPARα, FABP 1, and CD36) in APAP mice, as well as inflammatory factors (Il-6, Il-1β, and Tnf-α). These findings suggested that si-Cyp2e1 LNPs may alleviate APAP-induced oxidative stress and inflammation by regulating lipid metabolism via PPAR-related pathways. Full article

Enzymes of the cytochrome P450 monooxygenase family 4 (CYP4) in mammals are generally involved either in endobiotic metabolism (e.g., acting on fatty acids or eicosanoids), or the modification of xenobiotics including therapeutic drugs. CYP4B1 is special, as it is an enigmatic enzyme acting at the interface between xenobiotic and endobiotic metabolism. However, a systematic analysis of CYP4B1’s substrate scope has not yet been reported. Herein, a three-step approach to identify novel substrates for three CYP4B1 orthologs (namely from rabbits, green monkeys, and mouse lemurs) is described. First, screening of a library containing 502 natural products revealed potential novel substrate groups for CYP4B1. Second, based on these results, a systematic library was defined consisting of 63 compounds representing 10 compound groups. Third, in vitro conversion of these compounds by CYP4B1 and identification of conversion products were conducted, supported by in silico docking, allowing the prediction of binding probabilities and potential oxidation sites. We report five new substrate groups (acyclic, monocyclic and bicyclic terpenoids, stilbenoids, and vanilloids), twenty-eight new substrates (inter alia capsaicin, gingerol, genistein, stilbene, myristicin, thioanisole), and two new reaction types for CYP4B1 (S-oxidation, O-demethylation). Consequently, CYP4B1 is a far more promiscuous enzyme than previously thought. Full article

Chinese native pig breeds exhibit unique advantages over Western pig breeds, but the specific lipid metabolism mechanisms remain unclear. The phenotypic characteristics of Mashen (MS) pigs and Duroc × (Landrace × Yorkshire) (DLY) pigs are studied. The results show that MS pigs exhibit higher intramuscular fat (IMF) content. The area of adipocytes of MS pigs is significantly greater than that in DLY pigs (p < 0.01). Lipidomics analysis reveals distinct profiles in the upper layer of backfat (ULB), leaf lard (LL), greater omentum (GOM), and IMF, with MS pigs showing higher polyunsaturated fatty acids (PUFAs) in ULB, LL, and GOM. Key differential lipids identified in the two pig breeds include the following triglycerides (TGs) and phosphatidylcholines (PC): TG(16:1_18:1_18:3), TG(18:1_18:2_18:3), TG(18:3_18:2_18:2), PC(18:0_18:1), and PC(18:0_18:2). Weighted gene co-expression network analysis (WGCNA) reveals lipid molecules associated with serum biochemical indices. Transcriptomics analysis highlights 1944 differentially expressed genes between the MS-ULB and DLY-ULB. Notably, multiple genes from the cytochrome P450 family (CYP2E1, CYP4A24, CYP2J2), along with PLA2G2D, PLA2G4A, and multiple PCs, are associated with the metabolism of arachidonic acids and linoleic acids. PLA2G2D and PLA2G4A are also involved in the metabolism of α-linolenic acids. This comprehensive analysis provides essential information for breeding strategies and meat quality improvement. Full article

Fungal diseases of agricultural crops cause severe economic losses to the growers. For the control of these diseases, azoxystrobin is one of the recommended fungicides. This fungicide is systemic in action and is expected to reach the floral part of the treated crop and its residue in the pollen and nectar, the natural food sources of honey bees, which could be collected and fed on by honey bees, thus affecting their health. The purpose of this study was to determine the physiological and chemical changes caused by this fungicide in honey bee workers (Apis mellifera L). Workers of this honey bee at 1, 8, and 21 days old were treated with 125, 167, and 250 mg/L concentrations of azoxystrobin for seven days; their survival rates, activities of carboxylesterase (CarE), glutathione S-transferases (GSTs), cytochrome P450 enzyme (CYP450), catalase (CAT), and superoxide dismutase (SOD) enzymes, and the expression levels of immune (Aba, Api, Def1, and Hym) and nutrition genes (Ilp1, Ilp2, and Vg) were detected. Our findings revealed that azoxystrobin affected the survival of workers, particularly 1- and 21-day-old workers, who responded to azoxystrobin stress with increased activities of detoxification and protective enzymes, which might have physiological costs. Additionally, azoxystrobin affected the expression of immune and nutrition genes, with a decreased expression trend in 21-day-old workers compared to the 1- and 8-day-old workers, leading to reduced resistance to external stressors and increased mortality rates. These findings provide important insights into the adverse effects of azoxystrobin on workers of different ages and emphasize the potential risks of this chemical to colony stability and individual health. This study recommends an urgent ban on such a harmful fungicide being used for fungi control in agriculture, especially during plant flowering. Full article

This study aimed to explore the physiological and biochemical mechanisms of the interaction between N. grossedentata and A. nigripes. First, specimens were categorized into low- (6.16% ± 0.66%), medium- (9.23% ± 1.19%), and high-content groups (21.23% ± 1.23%) based on the initial dihydromyricetin concentration in N. grossedentata. Subsequently, we assessed the variations in total flavonoids, dihydromyricetin, myricitrin, and myricetin in plants 24, 48, and 72 h post-feeding. Concurrently, we analyzed the impact of plant leaf consumption on the detoxifying [glutathione S-transferase (GST), carboxylesterase (CarE), acetylcholinesterase (AchE), and cytochrome P450 (CYP450)] and protective enzyme [superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT)] activities in A. nigripes, along with its metabolic processes. The results demonstrated that N. grossedentata enhanced its secondary metabolites, particularly dihydromyricetin, as a defensive response to insect-induced stress. A. nigripes utilized its detoxification and protective enzyme systems to mitigate the effects of high flavonoid levels in the host plant, with particular emphasis on the roles of detoxification enzymes (GST, AchE, CYP450, and CarE) in detoxification metabolism, which showed significant correlation (p < 0.01) with dihydromyricetin, exhibiting correlation coefficients of 0.689, 0.633, 0.579, and 0.561, respectively. Additionally, key flavonoids in N. grossedentata were observed to accumulate with different degrees during digestion and metabolism in insects. These findings lay a theoretical foundation for the further exploration of the molecular mechanisms of A. nigripes adaptation to a flavonoid-rich plant N. grossedentata and inform the development of novel pest control strategies and the selection of resistant plant varieties. Full article

Herbicide resistance is an emerging phytosanitary threat, causing serious yield and economic losses. Although this phenomenon has been widely studied, only recently has the role of epigenetic factors in its occurrence been considered. In the present study, we analyzed the microRNA-mediated regulation in Echinochloa oryzicola (Vasinger) Vasinger (late-watergrass) of the expression of cytochromes P450, glutathione S-transferase (GST), and eIF4B, all of which are enzymes involved in profoxydim (AURA^®) detoxification. Before and after profoxydim application, the expression profiles of microRNAs (miRNAs) were selected for their ability to target the genes considered, and their targets were assessed by means of RT-qPCR. Susceptible and resistant biotypes showed different responses to this herbicide. After profoxydim application, in resistant biotypes, osa-miR2099-5p, ath-miR396b, osa-miR395f, osa-miR396a-5p, osa-miR166a-5p, osa-miR166d-5p, gra-miR8759, and gma-miR396f were not triggered, allowing the expression of CYP81A, GSTF1, and eIF4B genes and the herbicide’s detoxification. Meanwhile, the transcription of ata-miR166c-5p, ath-miR847, osa-miR5538, and gra-miR7487c was triggered, down-regulating CYP71AK2, CYP72A254, CYP72A122, and EcGST expression. In susceptible biotypes, the herbicide stimulated ata-miR166c-5p, ath-miR847, osa-miR5538, gra-miR7487c, osa-miR166a-5p, and gra-miR8759, down-regulating their respective target genes (CYP72A122, CYP71AK2, EcGST, CYP72A254, CYP81A12, and eIF4B). A better understanding of the role of miRNA-mediated epigenetic regulation in herbicide resistance will be useful in planning more targeted and sustainable methods for controlling this phytosanitary threat. Full article

Gleditsia sinensis Lam. (G. sinensis) is a widely known medicinal plant, and its primary bioactive compound is gleditsioside. So far, the significant economic and medicinal value of gleditsioside has been widely recognized. However, the transcriptional regulation governing the biosynthesis of gleditsioside during G. sinensis pod development remains unclear. In this investigation, we observed that gleditsioside levels increased in the pods of G. sinensis from June to November, and we performed a transcriptome analysis to explore the phenomenon. A total of 703 and 162 differentially expressed unigenes (DEGs) were identified in the terpenoid backbone and triterpenoid biosynthesis pathways, respectively. In total, 99 unigenes encoding 17 enzymes, such as ENIN, cytochrome P450 (CYP93E1), and UDP-glucosyltransferase, were identified in the gleditsioside biosynthesis pathway. Moreover, DEGs encoding crucial enzymes, such as HMGCR and AGBH, might determine gleditsioside synthesis during G. sinensis pod development. Interestingly, the gleditsioside synthesis pathway extended to ten metabolic pathways, including the sterol biosynthesis pathway and the brassinolide biosynthesis pathway, among other pathways involved in various hormonal regulations. These pathways shared the same precursor substances (IPP and DMAPP). In addition, weighted gene correlation network analysis (WGCNA) revealed that CL5845.Contig1 (HMGCR) and CL8823.Contig2 (LUP4) might be involved in the gleditsioside biosynthesis. Furthermore, transient transformation validation experiments demonstrated overexpression of CL5845.Contig1 (HMGCR), CL8823.Contig2 (LUP4), and CL11248.Contig4 (CYP93E1) significantly enhanced gleditsioside biosynthesis. Overall, our findings provide important genetic resources for future functional research and new insights into the basic mechanism of saponin biosynthesis. Full article