Search Results (1,270)

Aspartame, a widely used artificial sweetener, has been linked to various cancers, including kidney renal papillary cell carcinoma (KIRP). However, the molecular mechanisms underlying this association remain unclear. This study employed network toxicology and molecular docking to investigate potential mechanisms of aspartame-induced KIRP. Differentially expressed genes from TCGA were intersected with aspartame targets and KIRP-related genes, yielding 61 common targets. GO and KEGG analyses revealed enrichment in extracellular matrix degradation, signaling pathways, and immune microenvironment regulation. Univariate Cox regression identified 23 prognostically significant genes, from which multifactorial Cox regression with stepwise selection determined 8 core genes (APLNR, CYP2C19, EDNRA, KLK5, F2R, RAD51, AURKA, and TLR2). A risk model was constructed and validated through VIF analysis, Schoenfeld residual testing, and internal validation using a training–validation split. SHAP analysis identified EDNRA as the primary driver gene. Survival analysis demonstrated that the model effectively stratified KIRP patients, with risk score and tumor stage serving as independent prognostic factors. Molecular docking confirmed stable binding between aspartame and core target proteins. These findings provide mechanistic insights into aspartame-induced KIRP pathogenesis and establish a foundation for future experimental validation. Full article

Origanum vulgare L., a medicinal herb rich in bioactive phenols and terpenes, is recognized for its anti-inflammatory and antimicrobial properties. Heavy-ion beam mutagenesis, a sophisticated breeding technique, can induce significant variations in plants, thereby affecting their secondary metabolite production. This study utilized metabolomic and transcriptomic approaches to investigate the effects of ¹²C⁶⁺ heavy-ion irradiation on oregano. Our results indicated substantial changes in mutant lines, including marked alterations in plant height, leaf morphology, and biomass accumulation. Metabolomic analysis indicated that the differentially accumulated volatile compounds were primarily terpenoids. Furthermore, transcriptomic analysis indicated a predominant enrichment of differentially expressed genes in terpenoid biosynthesis. Integrated analyses identified key transcriptional changes in genes encoding terpenoid backbone enzymes, such as GPPS, GGPPS, DXS, and HMGR, and pinpointed candidate genes, including TPS3, TPS6A, TPS6C, CYP71D178, CYP71D181, and CYP71D10B, whose expression patterns were closely associated with the differential accumulation of carvacrol and thymol. This comprehensive study elucidates the molecular mechanisms underlying metabolic reprogramming induced by heavy-ion irradiation in oregano and offers valuable genetic resources for future metabolic engineering and precision breeding initiatives aimed at enhancing the production of valuable bioactive compounds. Full article

Background: Recent studies have associated the presence of the CYP2C:TG haplotype with increased metabolism of CYP2C19 substrates such as escitalopram and sertraline, suggesting a potential regulatory interaction between CYP2C18 and CYP2C19. However, this association has not been demonstrated for other CYP2C19 substrates. Objective: This study aims to elucidate the role of the CYP2C:TG haplotype in modulating CYP2C19 activity using the omeprazole metabolic ratio (MR) within a cocktail drug approach, to characterize its distribution and prevalence among Native Mexican populations, and to evaluate its potential impact on CYP2C19 metabolic phenotypes. Materials and Methods: A total of 256 volunteers from various ethnic native groups from Mexico were genotyped for CYP2C19 (*2, *3, *4, *5, *17) and the CYP2C haplotype (rs2860840 and rs11188059). The MR of omeprazole to 5-hydroxyomeprazole was analyzed to determine individual CYP2C19 metabolic phenotypes and assess metabolic capacity. Results: The CYP2C:TG haplotype was the most prevalent (42.77%), followed by CYP2C:CG (35.74%) and CYP2C:TA (21.48%). The CYP2C:TG haplotype was consistently associated with the CYP2C19*1 allele. Significant differences in logMR values were observed between individuals with and without the TG haplotype (p = 0.02). A trend toward increased metabolic activity associated with CYP2C:TG was observed across most CYP2C19 metabolizer groups, except for rapid metabolizers. No significant association was found between molecular ancestry and the presence or functionality of the haplotype. Conclusions: The CYP2C:TG haplotype appears to be associated with increased CYP2C19 activity, warranting further functional validation before clinical implementation. Full article

Aquatic ecosystems are currently facing anthropogenic pollution, mainly derived from agricultural, industrial, and urban runoff, including heavy metals, polycyclic aromatic hydrocarbons (PHAs), pesticides, fertilizers, and untreated wastewater discharges. To understand the impact of environmental contamination on fish, this research compared cytochrome P450 1A (CYP1A) gene expression in armored catfish across three locations in the lower Grijalva–Usumacinta River basin known for varying levels of pollution. Samples from the Ribera Alta, the Bitzales River, and the Chaschoc lagoon were collected during the dry and rainy seasons. We isolated RNA from liver samples, which were subsequently converted to cDNA. We used quantitative PCR to analyze CYP1A gene expression. Results showed that, of the three locations, Ribera Alta demonstrated the highest expression during the rainy season. Only in Chaschoc Lagoon did we observe significant differences between seasons (p = 0.03). This indicates that seasonal factors and the presence of pollutants in the water bodies and sediments likely play a role in regulating CYP1A gene expression in this fish species. Full article

Of the Cytochrome P450 enzymes, the CYP2C9 variant is very important in the metabolism of several human drugs, acting as a natural bioscavenger. Previously, CYP2C9 was shown to convert the thion (P=S) to the oxon (P=O) form for some organophosphorus (OP) pesticides, such as dimethoate, diazinon, and parathion. In this study, we tested the ability of CYP2C9 to degrade other OP compounds. We investigated the metabolism of OP compounds by CYP2C9 using LC-MS/MS as well as time-dependent inhibition using the previously developed pFluor50 fluorogenic assay. We found that CYP2C9 metabolizes thions preferentially over oxons, and that many OP compounds inhibit CYP2C9 activity in a time-dependent manner. Additionally, we performed molecular docking based on the crystal structure (1OG5) of the CYP2C9 receptor. We observed a positive, though moderate, correlation between the calculated binding energy and the CYP2C9 metabolism of various OP compounds (R = 0.59). These in vitro data, combined with further analysis and additional OP derivatives, could potentially be used to develop artificial intelligence (AI)/machine learning (ML) models to predict the metabolism of specific OP compounds by CYP2C9. This type of approach could be particularly relevant for the prediction of the metabolism of current and emerging chemical warfare agents. Full article

Background/Objectives: In recent years, it has been suggested that sedatives may cause brain damage. One possible mechanism is interference with oxidative phosphorylation of brain mitochondria, but much remains unknown. In this study, we focused on dexmedetomidine, midazolam, and propofol, essential sedatives in anesthesia and intensive care, and aimed to understand the effects of these drugs on mouse brain mitochondria. Methods: We measured changes in mitochondrial respiratory capacity and swelling rate upon exposure to these sedatives in a wide concentration range. For the sedative that demonstrated impaired mitochondrial function we explored the possible involvement of mitochondrial permeability transition pore opening using brain mitochondria from cyclophilin D knockout (CypD KO) mice and detected cytochrome c (cyt c) release by Western blot. Results: Of the three sedatives, only high concentrations of propofol exhibited reduced respiratory capacity and mitochondrial swelling, toxicity which was not prevented by CypD KO. Furthermore, propofol did not induce cyt c release. Conclusions: These results suggest that propofol-induced brain mitochondrial dysfunction is a mechanism independent of mPTP opening. Full article

Cold resistance is an important characteristic of sustainable development in the grape industry. The intraspecific recurrent selection in the Vitis vinifera (V. vinifera) method uses high-quality varieties as breeding materials and the substitution and accumulation of minor resistance genes, breeding high-quality grapes with cold resistance. This study was conducted to identify and genetically analyse the cold resistance of a V. vinifera hybrid population (Ecolly × Dunkelfelder), screen for highly resistant and sensitive plant samples, and use high-throughput sequencing to perform transcriptome sequencing and related differential gene expression analysis on each sample. The results revealed that the cold resistance of the hybrid offspring population was characterised by continuous quantitative trait inheritance, with 38 differentially expressed genes (7 upregulated genes and 31 downregulated genes) between the high resistance and high-sensitivity types. Analysis of genes related to various pathways, related to cold resistance, revealed that CYP76F10, Dxs, GERD, NMT, GDE1, glgC, and DHQ-SDH, as well as transcription factor MYB, HB, and MADS family genes, are key candidate genes for V. vinifera cold resistance research. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to investigate the expression characteristics of the six genes that were differentially expressed genes, the results of which were essentially consistent with the results of RNA-seq. Specifically, NMT may enhance cold resistance by enhancing membrane lipid stability. The synergistic expression pattern of CYP76F14 and Dxs suggests its key role in terpene synthesis. By exploring potential genes related to micro effects, a theoretical foundation for further exploration of new high-quality cold-resistant grape varieties has been provided. Full article

Rhododendron fortunei Lindl is known for its unique aroma, but the molecular mechanism behind plant hormone-mediated aroma biosynthesis remains unclear. To explore how brassinosteroids (BRs) and methyl jasmonate (MeJA) regulate its aroma, this study analyzed R. fortunei petal samples via physiological assays, volatile metabolome analysis, and transcriptome sequencing. Physiologically, BR/MeJA significantly increased the superoxide dismutase (SOD) and catalase (CAT) activity and decreased the malondialdehyde (MDA) content. Metabolome analysis identified 1268 volatile organic compounds (VOCs), with 265/70 VOCs up-/downregulated in the BR group and 248/181 VOCs up-/downregulated in the MeJA group compared to the controls. Transcriptome sequencing identified 19,333 differentially expressed genes (DEGs), which were enriched in pathways such as terpenoid and polyketide metabolism. Multi-omics screening revealed the candidate gene RfCYP92C6, whose transient overexpression in Nicotiana benthamiana increased the terpenoid content 2.2-fold. These findings clarify the aroma regulation mechanism of BRs/MeJA in R. fortunei and support the improvement of its aroma traits via genetic engineering. Full article

To investigate the effect of epigenetic modifications on sex determination and differentiation in northern pike (Esox lucius), we employed Whole-Genome Bisulfite Sequencing (WGBS) to analyze the DNA methylation patterns in gonadal tissues of females, males, and neomales. First, we obtained high-quality sequencing data, including a total of 410.16 Gb of raw reads and 361.48 Gb of clean reads, with an 86% unique mapping rate, and a bisulfite conversion efficiency of 99.6%. Subsequently, comparative analysis revealed that 66,581 differentially methylated CG regions (i.e., DNA regions with a high frequency of CG dinucleotides), 1215 differentially methylated CHG regions (i.e., DNA regions where CG is followed by another nucleotide), and 3185 differentially methylated CHH regions (i.e., regions where cytosine is methylated in a CHH sequence, with ‘H’ representing A, T, or C) were identified among the three groups. Furthermore, we identified four key differentially methylated candidate genes (Rspo1, hsd11b2, CYP27A1 and smad3) associated with sex determination and differentiation processes in E. lucius. Finally, by integrating GO and KEGG enrichment analyses, we explored the role of epigenetic modification regulatory networks in the sex determination and differentiation of E. lucius and identified multiple metabolic pathways related to sex determination and differentiation processes (Notch signaling pathway, Wnt signaling pathway and Ovarian steroidogenesis). This study thereby lays a foundation for subsequent functional verification. Full article

Personalizing therapy using medical marijuana (MM) is based on understanding the pharmacogenomics (PGx) and drug–drug interactions (DDIs) involved, as well as identifying potential epigenetic risk markers. In this work, the evidence regarding the role of variants in phase I (CYP2C9, CYP2C19, CYP3A4/5) and II (UGT1A9/UGT2B7) genes, transporters (ABCB1), and selected neurobiological factors (AKT1/COMT) in differentiating responses to Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been reviewed. Data indicating enzyme inhibition by CBD and the possibility of phenoconversion were also considered, which highlights the importance of a dynamic interpretation of PGx in the context of current pharmacotherapy. Simultaneously, the results of epigenetic studies (DNA methylation, histone modifications, and ncRNA) in various tissues and developmental windows were summarized, including the reversibility of some signatures in sperm after a period of abstinence and the persistence of imprints in blood. Based on this, practical frameworks for personalization are proposed: the integration of PGx testing, DDI monitoring, and phenotype correction into clinical decision support systems (CDS), supplemented by cautious dose titration and safety monitoring. The culmination is a proposal of tables and diagrams that organize the most important PGx–DDI–epigenetics relationships and facilitate the elimination of content repetition in the text. The paper identifies areas of implementation maturity (e.g., CYP2C9/THC, CBD-CYP2C19/clobazam, AKT1, and acute psychotomimetic effects) and those requiring replication (e.g., multigenic analgesic signals), indicating directions for future research. Full article

Fritillaria pallidiflora Schrenk ex Fisch. & C.A.Mey. (Yi Beimu) is a culturally significant Beimu drug in Northwest China, officially listed in the Chinese Pharmacopoeia and traditionally used to clear heat, moisten the lung, resolve phlegm, and relieve cough and wheeze. This narrative, critical review synthesizes current evidence on ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics/toxicology, and conservation of F. pallidiflora to support sustainable, evidence-based development. Literature was retrieved from major English and Chinese databases and screened for studies that unambiguously involved Yi Beimu or its key constituents. Ethnomedicinal records consistently support antitussive, expectorant, and anti-asthmatic use in Xinjiang and the Ili River Valley. Chemically, F. pallidiflora is rich in cevanine-type steroidal alkaloids (e.g., imperialine, peimine, yibeinones), steroidal saponins (pallidiflosides), polysaccharides, and minor phenolics. Preclinical data show that alkaloids relax airway smooth muscle, suppress inflammatory mediators, and contribute to antitussive and anti-asthmatic effects, while polysaccharides and total alkaloid extracts exhibit antioxidant and cytoprotective activity in cell and animal models of airway injury. Additional studies report cytotoxic saponins and seed-derived antimicrobial peptides. Pharmacokinetic work highlights low to moderate and variable oral bioavailability, shaped by P-glycoprotein efflux and CYP-mediated metabolism, and reveals potential hERG channel inhibition for peimine as a cardiac safety concern. Overharvesting and habitat loss have reduced wild resources, underscoring the need for conservation, cultivation, and marker-guided quality control. Overall, Yi Beimu shows credible ethnopharmacological rationale and promising multi-target pharmacology for respiratory disorders, but translation will require bioactivity-guided isolation coupled with PK–PD-guided in vivo studies, rigorous safety evaluation, and conservation-aware cultivation to move from traditional remedy toward validated therapeutic resource. 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

Background/Objectives: Pharmacogenetic (PGx) testing is gaining importance in optimizing psychiatric pharmacotherapy, yet routine use remains limited due to cost and unclear patient selection criteria. The CYP Pharmacogenetic Risk Score (CYPRI) is a clinical tool designed to identify psychiatric patients most likely to benefit from PGx testing, based on medication profile, adverse drug reactions (ADRs), and therapeutic drug monitoring (TDM) results. This study aimed to evaluate the clinical relevance of the CYPRI by identifying its weaknesses and gaps in a clinical setting, propose targeted modifications to address those limitations, and assess the applicability of the improved version in a routine clinical setting. Methods: In a retrospective analysis, data from 92 patients with depression at Frankfurt University Hospital were evaluated using the CYPRI score. Its association with the clinical impact of PGx testing, measured by the IMPACT score, was analyzed using ordinal regression and Receiver Operating Characteristic (ROC) analysis. Based on the findings, a revised version of CYPRI was developed and applied to the retrospective cohorts of Frankfurt and Prague. Results: The original CYPRI score was significantly associated with increased IMPACT score, suggesting its clinical value in detecting non-normal CYP2D6 and/or CYP2C19 metabolizers. However, the corrected version (hereafter referred to as CYPRI_cor), which emphasized clinically relevant pharmacokinetic factors, showed improved clinical specificity while maintaining similar discriminative performance. In the Frankfurt cohort, the area under the curve (AUC) for CYPRI_cor was 0.68 (95% CI 0.56–0.79), and in the Prague cohort, the AUC for CYPRI_cor was 0.71 (95% CI 0.60–0.81). While the overall discriminative ability in Frankfurt was slightly lower, CYPRI_cor achieved a specificity of 0.69, enabling more precise identification of patients most likely to benefit from PGx testing. A CYPRI Cut-off of ≥4 was determined to indicate clinical impact. Conclusions: The CYPRI_cor score was designed to optimize and to rule out potential limitations of the original score, particularly regarding the attribution of ADRs and the weighting of TDM results. Although the modifications did not improve discriminative performance in the Frankfurt dataset, the proposed changes remain meaningful. Prospective clinical studies need to verify the clinical utility of the CYPRI_cor. Full article

Background/Objectives: Epilepsy is characterized by recurrent, unprovoked, self-limiting seizures of genetic, acquired, or unknown origin. It affects more than 50 million people worldwide. The prevalence in Peru is 11.9–32.1 per 1000 people. Our objective was to describe the association between CYP2C9 and CYP2C19 genetic polymorphisms and adverse reactions induced by antiseizure medications among Peruvian patients with epilepsy. Methods: A descriptive observational study was conducted on Peruvian patients with epilepsy. Non-probability, non-randomized, purposive sampling was carried out through consecutive inclusion. Genomic DNA was obtained from venous blood samples. Genotypes were determined by real-time PCR using specific TaqMan probes to identify the alleles of interest. Results: In total, 89 Peruvian patients with epilepsy were recruited at the Alberto Sabogal Sologuren National Hospital-ESSALUD: 45 were male (23.6 ± 10.0 years) and 44 were female (24.0 ± 12.4 years). The observed frequencies for CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0.034 (T allele), 0.034 (C allele), 0.14 (A allele), 0.00 (A allele), and 0.03 (T allele), respectively. Patients with intermediate and poor metabolic phenotypes of CYP2C9 and CYP2C19 had a significantly higher risk of adverse drug reactions (ADRs) (OR = 3.75; 95%CI: 1.32–10.69; p = 0.013), compared with normal metabolizers. Polytherapy was a predictor increasing the likelihood of ADRs (OR = 4.33; 95% CI: 1.46–12.80; p = 0.008). Conclusions: In this cohort of Peruvian patients with epilepsy, the reduced-function alleles CYP2C9*2, CYP2C9*3, and CYP2C19*2, associated with decreased metabolic activity, were significantly linked to an increased risk of adverse drug reactions induced by antiseizure medications. Polytherapy further heightened this risk. Collectively, these findings highlight the clinical relevance of CYP2C9 and CYP2C19 genotyping to enhance the safety of antiseizure pharmacotherapy in Latin American settings, where pharmacogenomic evidence remains limited. Full article

Background/Objectives: Cirrhosis significantly alters physiological function and drug metabolism, particularly for medications primarily metabolized by CYP2C19 and CYP3A4. This study aims to establish a physiologically based pharmacokinetic (PBPK) modelling framework capable of predicting pharmacokinetic changes across different stages of cirrhosis, and to determine optimal dosing regimens that achieve drug exposure levels comparable to those in healthy individuals. Methods: We constructed a physiologically based pharmacokinetic (PBPK) model that incorporates six drugs, including omeprazole, lansoprazole, midazolam, ondansetron, verapamil, and alfentanil, which are metabolized primarily by CYP2C19 or CYP3A4. The pharmacokinetics of these drugs following oral or injectable administration were simulated in 1000 virtual healthy subjects, and the PBPK model was validated using clinical data. The model was further adapted to account for physiological changes in cirrhotic patients, extending its application to a population of 1000 virtual patients with liver cirrhosis. Results: Most observed data fell within the 5th and 95th percentiles of the virtual patient simulation results. Additionally, for most simulations, the area under the concentration-time curve (AUC) and peak concentration (C_max) were within 0.5- to 2-fold of the observed values. Sensitivity analysis indicated that the reduced expression of metabolizing enzymes increased plasma concentrations of drugs, which was a major factor contributing to the elevated drug exposure in patients with cirrhosis. The clinical dosing regimens of the CYP2C19 substrate omeprazole and the CYP3A4 substrate ondansetron were optimized for use in cirrhotic patients. Conclusions: The developed PBPK model successfully predicted the pharmacokinetics of CYP2C19 and CYP3A4 substrates in both healthy individuals and cirrhotic patients and can be effectively used for dose optimization in cirrhotic populations. Full article