Search Results (4,149)

Tuberculosis (TB) remains a major public health challenge in Peru, where interindividual variability in treatment response and drug-induced hepatotoxicity may be influenced by host genetic background. This study aimed to characterize clinically relevant polymorphisms in NAT2, CYP2E1, and SLCO1B1 in a cohort of TB patients from Southern Peru, a genetically underrepresented Andean population. Thirty-five adults receiving first-line therapy (isoniazid and rifampicin) underwent targeted Sanger sequencing of key functional variants among these three genes. NAT2 acetylator phenotypes were predominantly intermediate (68.6%), followed by rapid (20%) and slow (11.4%) profiles, with high minor allele frequencies for rs1041983 and rs1801280. CYP2E1 functional promoter variants were infrequent, whereas SLCO1B1 exhibited notable allelic heterogeneity, suggesting potential variability in rifampicin transport. Comparative analysis with previously reported Peruvian data revealed regional differences in acetylator distribution, supporting population-specific pharmacogenomic stratification. Although clinical toxicity outcomes were not evaluated, the high prevalence of reduced acetylation genotypes suggests a substantial proportion of patients may benefit from genotype-informed isoniazid dosing strategies. These findings provide foundational data for implementing precision medicine approaches using affordable and targeted technologies in TB management within Andean populations and support the integration of pharmacogenomics into national TB control programs. Full article

Traditional one size fits all pharmacotherapy often yields suboptimal clinical outcomes, preventable adverse drug reactions (ADRs), and significant drug waste, imposing substantial economic and ecological burdens on healthcare systems. This review evaluates the transformative potential of pharmacogenomics (PGx) testing, particularly cytochrome P450 (CYP) gene variants, as a foundation for an ecosystem-centric accountability framework for green pharmacy and links human metabolic variability to specific environmental outcomes. Personalized CYP profiling is shown to minimize the environmental release of unused drugs and potentially ecotoxic metabolites into aquatic ecosystems, in contrast to standard uniform drug use approaches. The limitations of ethnicity-based dosing models, which rely on population genetic variation, are examined in the context of increasing global genetic admixture. It is argued that individual genetic profiling, conceptualized as a PGx-Green Passport, provides a reliable safety standard that accounts for individual differences, thereby enhancing efficiency and well-being in a globalized society. By integrating clinical data, including real-world evidence on hospital utilization, with sustainability frameworks, this review demonstrates that PGx-guided therapy is not only a tool for clinical efficiency but also a fundamental requirement for systematically achieving environmentally sustainable healthcare. Full article

Background/Objectives: Having longer mesocotyls is beneficial for the deep-sowing tolerance of rice, which is important for seedling establishment. Methods: Here, we performed transcriptome analysis of the elongating mesocotyl of Zhengdao 209 in response to three different sowing depths to identify the pivotal genes regulating rice mesocotyl elongation. Results: Three groups with different mesocotyl lengths were compared using transcriptome analysis, and 60 common differentially expressed genes were detected. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these genes are primarily involved in phenylpropanoid biosynthesis, cutin suberine and wax biosynthesis, the plant mitogen-activated protein kinase signaling pathway, diterpenoid biosynthesis, cyanoamino acid metabolism, carbon fixation in photosynthetic organisms, flavonoid biosynthesis, and glutathione metabolism. Furthermore, weighted gene co-expression network and hierarchical clustering analyses showed that most of the differentially expressed genes are implicated in phenylpropanoid biosynthesis, carbon metabolism, photosynthesis antenna proteins, and plant–pathogen interactions. Among the genes involved in phenylpropanoid biosynthesis processes, the expression levels of OsPHT3 and LOC_Os04g59260 increased, while OsCCR1, OsPGIP4, and LOC_Os01g45110 expression decreased with increasing sowing depth. Among the genes involved in the mitogen-activated protein kinase signaling pathway, the expression levels of LOC_Os07g03319 and LOC_Os07g03580 increased, while LOC_Os07g03409 decreased with increasing sowing depth. Among the genes involved in diterpenoid biosynthesis processes, the expression levels of OsCYP76M5 and OsCYP71Z2 decreased, while OsCYP71Z21 increased with increasing sowing depth. Furthermore, the expression levels of these genes were analyzed using quantitative real-time polymerase chain reaction, which confirmed the transcriptome analysis results. Conclusions: This study identified candidate genes governing rice mesocotyl length and provides novel insights into the molecular regulatory mechanisms underlying mesocotyl elongation in rice. Full article

Cancer is an alarming health concern and economic burden in both developed and developing countries. Recently, there has been a growing demand for new alternative medications with more effectiveness and fewer harmful effects. During the past decades, a set of chemotherapeutic agents has been developed to fight against a large spectrum of cancer types. Unfortunately, their use is associated with a high level of toxicity; they are expensive, also, and their deployment is restricted by the emergence of cellular resistance. Plant-based components are garnering attention due to their low toxicity, selectivity, efficiency, and ease of accessibility. Alkaloids are one of these targeted compounds. Indeed, they are a highly diverse group with basic heterocyclic nitrogen-containing alkaloids that exhibit potent anticancer effects against a large panel of solid and liquid tumors, such as lung, breast, leukemia, liver, and colon cancer. The main molecular mechanisms involved in alkaloids’ anticancer effect are the induction of apoptosis via the extrinsic and intrinsic pathways, DNA damage, and the inhibition of cell cycle progression. Amazingly, these auspicious compounds exhibited strenuous inhibitory effects against a whole range of key enzymes involved in cancer progression and metastasis, such as Cytochrome P450 (CYP450), Cyclooxygenase-2 (Cox-2), Lysine-Specific Demethylase 1 (LSD1), Poly [ADP-ribose] polymerase (PARP), and topoisomerase, mainly through two action modes, namely irreversible and reversible inhibition. Furthermore, several conventional extraction methods have been developed to extract bioactive compounds from natural matrices, such as Soxhlet and hot water extraction. However, these techniques have many drawbacks, as they require a large amount of organic solvents, which not only affect human health but also generate severe environmental issues. To overcome these limitations, multiple eco-extraction techniques have emerged as potential alternatives to traditional extraction methods such as ultrasonic extraction, microwave-assisted extraction, and supercritical fluid extraction. In fact, they are considered eco-friendly and efficient technologies with less time and solvent consumption. Overall, this review aims to provide an updated overview of the most prominent anticancer alkaloids that have not been well reviewed already, as well as the main green extraction techniques relevant to the extraction of antineoplastic alkaloids. Full article

The purpose of our study was to assess if spinacetin (SPC), a flavonoid found in spinach, can alleviate the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicative of the development of hemorrhagic cystitis. The animal experiments were conducted in female Wistar rats. The cohort of 60 animals was grouped as follows: I—control, II—CYP group, III—SPC group, and IV—CYP + SPC group. The cystometry and biochemical analyses were performed after a fortnight of SPC administration. SPC was found to restore normal cystometric parameters in CYP-induced cystitis and, similarly, it normalized c-Fos expression changes in the central micturition regions. SPC further prevented a massive increase in the bladder wall thickness/permeability due to exposition to CYP administration. CYP instillation resulted in the elevation of biomarkers found in urine (brain-derived neurotrophic factor, BDNF, and nerve growth factor, NGF), and in the bladder detrusor muscle (Rho kinase and vesicular acetylcholine transporter, VAChT), which were successfully restored after administration of SPC. As for the biomarkers in the bladder urothelium, the CYP-induced increases in TNF-α, IL-1β, IL-6, calcitonin gene-related peptide (CGRP), malondialdehyde, 3-nitrotyrosine, insulin-like growth factor-binding protein 3 (IGFBP-3), occludin, organic cation transporter 3 (OCT-3), orosomucoid-1 (ORM1), pituitary adenylate cyclase receptor 1 (PAC1), synaptosomal-associated protein 23 (SNAP23), SNAP25, and synaptic vesicle glycoprotein (SV2A) levels were attenuated by SPC. Finally, CYP administration resulted in a decrease in the heparin-binding EGF-like growth factor (HB-EGF), hemopexin (HPX), T-H protein, and tight junction protein (Z01), and we noted the successful restoration of all these changes in concentrations after application of SPC. In summary, SPC robustly mitigated cyclophosphamide (CYP)-induced cystometric dysfunction and biochemical alterations characteristic of iatrogenic hemorrhagic cystitis. These findings position SPC as a compelling therapeutic candidate and warrant further translational investigation for the management of CYP-induced bladder injury. Full article

Ethnopharmacological relevance. Withania somnifera (L.) Dunal, widely used in traditional medical systems such as Ayurveda, Unani, and Middle Eastern folk medicine, is valued for its adaptogenic, anti-inflammatory, neuroprotective, antimicrobial, and anticancer properties. These activities are primarily attributed to withanolides, with Withaferin A recognized as one of the most bioactive constituents. Although traditional preparations often rely on the root, leaf use provides a more sustainable alternative and may yield significant quantities of active metabolites. Identifying efficient, modern extraction technologies that can enhance the recovery of bioactive compounds from leaves is essential for developing effective, standardized ethnopharmacological formulations. Materials and methods. Plants of W. somnifera grown from seeds were subjected to different environmental conditions (control, drought, cold, yeast extract treatment). Leaves were extracted using Pressurized Cyclic Solid–Liquid Extraction (PCSLE) with hydroalcoholic solvents and compared with conventional infusion of dried leaves. Extracts were fractionated with solvents of varying polarity and analyzed by TLC, HPLC, and NMR for quantification of Withaferin A. Expression levels of key withanolide-biosynthetic genes (CAS, SMT1, DWARF1, CYP71, CYP76) were assessed using qRT-PCR. Antimicrobial activity of pure Withaferin A, aqueous extract, and hydroalcoholic PCSLE extract was evaluated through MIC and MBC assays against Gram-positive and Gram-negative strains. Cytotoxic activity was measured via MTT assays in six human cancer cell lines after 3, 6, and 24 h of treatment. Results. PCSLE yielded substantially higher levels of Withaferin A than traditional infusion, especially in medium-polarity fractions (chloroform and ethyl acetate), with concentrations reaching 0.70% in fresh leaf mass (4.8% dry weight), compared to 0.11% obtained by infusion. Gene expression analysis revealed that 24-week-old plants exhibited the highest transcription of withanolide-biosynthetic genes, and drought stress significantly upregulated CAS, SMT1, DWARF1, CYP71, and CYP716, indicating enhanced metabolic flux toward withanolide production. Hydroalcoholic PCSLE extracts showed broad-spectrum antimicrobial activity, with MIC and MBC values comparable to pure Withaferin A and demonstrating bactericidal effects against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes. The aqueous extract showed activity only against Gram-positive strains. Cytotoxicity assays demonstrated an optimistic, dose-dependent reduction in cell viability across all tumour cell lines treated with the hydroalcoholic PCSLE extract, closely mirroring the activity of pure Withaferin A and consistently exceeding the effect of the aqueous extract. IC50 values confirmed the high bioactive content of PCSLE extracts and suggested mechanisms like those known for Withaferin A. Conclusions. PCSLE proved to be a highly efficient extraction technology for obtaining leaf extracts rich in Withaferin A, outperforming conventional extraction methods while exploiting sustainable plant tissue. Developmental stage and drought stress significantly modulated the expression of genes involved in withanolide biosynthesis, highlighting agronomic strategies capable of enhancing metabolite production. Hydroalcoholic PCSLE extracts exhibited antimicrobial and cytotoxic activities comparable to pure Withaferin A, supporting their relevance as promising therapeutic candidates. These findings advocate for the use of W. somnifera leaves as a sustainable source of bioactive compounds and demonstrate that advanced extraction technologies can contribute to the development of innovative ethnopharmacological preparations for antimicrobial and anticancer applications. Full article

Caffeine (CAF) is one of the most widely consumed psychoactive substances worldwide. It is primarily metabolized to paraxanthine (PAR), theobromine (THR), and theophylline (THY). While CAF metabolism has been extensively characterized in humans and rodent models, corresponding data in zebrafish (Danio rerio) larvae remain limited. This study provides a comprehensive characterization of CAF biotransformation in zebrafish larvae using validated LC-QQQ-MS for quantitative metabolite profiling and FTIR imaging for spatially resolved tissue distribution mapping. Zebrafish larvae at 4 days post fertilization (dpf) were exposed to CAF at concentrations of 15, 25, and 50 mg/L for 18 h. The LC–MS/MS analysis demonstrated dose-dependent conversion of CAF to PAR (up to 4.54%), THR (up to 1.32%), and THY (up to 0.27%). The PAR/CAF and THR/CAF ratios increased as CAF concentration rose, while the THY/CAF ratio declined. In parallel, FTIR imaging was applied to visualize the spatial distribution of CAF and selected metabolites in larval tissue sections, confirming the presence of CAF, PAR, and THR and revealing their localization within the tissue. However, THY was not detected by this method. Metabolite localization differed across larval tissues, indicating compartmentalized metabolic processes. This study provides the first comprehensive characterization of CAF metabolism in zebrafish larvae, revealing low but detectable CYP450-mediated metabolic activity prior to full hepatic maturation. The findings support the utility of zebrafish larvae as a model for developmental pharmacokinetic studies. Full article

Background/Objectives: Children and young people (CYP) with a learning disability are at higher risk of living with overweight and obesity and may consume fewer fruits and vegetables compared to the general paediatric population. They are more likely to experience eating and drinking difficulties, restrictive eating, and mealtime behavioural challenges. The school environment is considered an ideal setting to improve CYP’s dietary intakes. The primary objective was to identify existing interventions to support healthier food choices for CYP attending specialist schools. Secondary objectives considered intervention development, fidelity and outcomes. Methods: A scoping review and narrative synthesis. Eligible studies were identified from bibliographic databases (e.g., Medline, Embase, PsychInfo) and grey literature (e.g., Clinicaltrials.gov, the Cochrane Library). A two-stage screening process was used. Intervention components were mapped according to the TIDieR-PHP and AACTT frameworks. Results: Seven studies, reported in ten records, were included. Interventions included modifications to the dining environment, sensory exploration, health promotion and social reinforcement. Interventions were implemented across the school day: lunchtime (n = 2), breaktime (n = 3) and other times (n = 2). Studies mainly focused on adolescents. There was some mixed evidence of increased consumption of fruits and vegetables, whole grains and water. Due to small sample sizes and heterogeneity, definitive conclusions are limited. A key finding is the lack of interventions to improve CYP’s food choices in specialist schools. Conclusions: This review highlights a crucial need for the development of multi-component interventions co-produced with stakeholders to promote healthy food choices and improve the dietary intakes of CYP attending specialist schools. Full article

Cyflumetofen (CYF) and its main metabolite, trifluoromethyl benzoic acid (B-1), both of which contain a trifluoromethyl group, are increasingly used in agriculture due to their high stability and efficacy. Structurally, these molecules share several physicochemical features with per- and polyfluoroalkyl substances (PFASs), including endocrine disruption and reproductive toxicity. This study aims to evaluate the reproductive toxicity effects of CYF and its metabolites using adult zebrafish as a model organism. The results indicate that exposure to CYF and B-1 at environmentally relevant concentrations for 21 days causes hormonal disruption and abnormal gonadal development in fish; moreover, as the concentrations increase, CYF and B-1 significantly impair the reproductive capacity of zebrafish and lead to developmental abnormalities in their offspring. Based on the ratio of E2/T and the alteration of key genes in the HPG axis, such as cyp17a2 and cyp11c1, it is hypothesized that CYF and B-1 disrupt hormonal homeostasis via the HPG axis. Notably, male fish were more susceptible when exposed to CYF or B-1, exhibiting sex-specific differences. RNA-seq analysis revealed that CYF/B-1 promotes Ca²⁺ release from the zebrafish brain and induces steroid hormone dysregulation based on the HPG axis via genes such as hsd17a and gnrh. In summary, this study provides key insights into the reproductive toxicity of CYF and its major metabolite, highlighting their risks to the environment and human health. Full article

Temperature and humidity are critical abiotic factors shaping the survival and adaptation of insect pests. However, the molecular mechanisms underlying high-temperature tolerance under contrasting humidity conditions remain poorly understood, particularly in globally invasive species such as the tomato pinworm, Tuta absoluta. Previous studies have examined individual stressors, leaving interactive thermo-hygrometric effects on gene expression and survival insufficiently resolved. Here, we assessed the contribution of cytochrome P450 genes to thermal adaptation under low- and high-humidity conditions using transcriptome profiling combined with nanocarrier-mediated RNA interference (RNAi). Third-instar larvae were exposed to high temperature under low humidity (HT-LH: 40 °C, 50% RH) or high humidity (HT-HH: 40 °C, 75% RH) for eight hours. Survival declined from 97.5% in the control to 74.16% under HT-LH and 68.33% under HT-HH conditions. Transcriptome analysis revealed extensive differential gene expression, with 464 genes upregulated and 565 downregulated in HT-LH, and 1145 upregulated and 1166 downregulated in HT-HH. Functional annotation highlighted pathways linked to metabolic regulation, proteostasis, and detoxification, including multiple cytochrome P450-associated processes. RT-qPCR confirmed the upregulation (3–5 fold) of four P450 genes (CYP6AB327, CYP6ABF1b, CYP6AE214, and CYP9A306c) under high temperature across both humidity regimes. RNAi-mediated silencing of these genes significantly reduced larval survival, demonstrating their functional role in thermal-hygrometric stress tolerance across. Cytochrome P450 genes underpin the adaptive capacity of the tomato pinworm to high-temperature stress across contrasting humidity conditions, highlighting RNAi-based disruption of P450 function as a promising avenue for sustainable pest management under climate change scenarios. Full article

Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut–liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota–bile acid–TGR5 (GPBAR1) axis. Methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g/kg/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO₂), and heat production (p < 0.05). It also reduced serum ALT (p < 0.001) and AST levels (p < 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p < 0.001 and p < 0.01, respectively). Consequently, systemic accumulation of non-12α-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred—known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p < 0.05) and activated adipose TGR5-cAMP/PKA/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders. Full article

Objectives. The aim of our study was to track changes in ODQ scores in adolescents with depressive episodes taking sertraline, depending on CYP2C19 polymorphisms. Methods. This study included 88 adolescents (88% were female) aged 12–17 who were prescribed sertraline. Emotional blunting was assessed using the Oxford Depression Questionnaire (ODQ) scale when the antidepressant was prescribed, after one, three, and 8 weeks, taking into account other medications used. Part 3 of the ODQ scale assessed the changes that occurred after the prescription of an antidepressant. All patients were genotyped for CYP2C19*2, *3, and *17. Based on genotypes, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65[50;79] points) compared with after 8 weeks (38.5[32.5;56.5] points). Part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73[56;83] vs. 59[44;71] points) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5[41.5;68] vs. 45.5[36;54] points). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusions. There was no increase in emotional blunting according to the ODQ score among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carrier status of CYP2C19 gene variants and the development of apathy induced by antidepressants. Full article

Maclekarpine E is a minor alkaloid from Macleaya species with reported in vitro anti-inflammatory activity, but its in vivo metabolism remains unexplored. This study investigated the metabolic fate of maclekarpine E in rats and evaluated the potential pharmacological relevance of its metabolites. Maclekarpine E was orally administered to male Sprague-Dawley rats (250 mg/kg). Plasma, urine and feces were collected and analyzed by UPLC-Q-TOF-MS/MS. CYP phenotyping was performed using recombinant human enzymes. Molecular docking against ABCG2 and ABCC2 was conducted to assess potential interactions of all fecal compounds with these efflux transporters. Network pharmacology was employed to predict potential anti-ulcerative colitis-related targets of the metabolites, generating hypotheses for future experimental validation. Nineteen phase I metabolites were identified. Biotransformations included ring-opening, demethylation and oxidation. All 19 metabolites were detected in feces, nine in plasma and two in urine. No phase II conjugates were observed. CYP2C19 was the only significantly active isoform under the tested conditions, mediating approximately 16.5% substrate depletion (p < 0.05). All 20 fecal compounds bound ABCG2 (ΔG < −5.0 kcal/mol); 19 bound ABCC2. Network pharmacology yielded 57 overlapping targets with ulcerative colitis, enriched in PI3K-Akt and MAPK pathways. This study provides the first comprehensive metabolic profile of maclekarpine E in rats. The compound undergoes CYP2C19-mediated oxidation and is predominantly excreted into feces. Its fecal metabolites are potential ABCG2/ABCC2 substrates and may target UC-associated pathways based on network pharmacology predictions, warranting further experimental validation. Full article

Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of continuous BaP at environmentally relevant concentrations (0.1 and 1.0 µM) and interrogated the resulting phenotypes using an integrated multi-scale framework encompassing functional toxicology, RT-qPCR, RNA-seq, phospho-kinase/NF-κB arrays, and organotypic air–liquid interface (ALI) cultures. Cells maintained metabolic competence throughout, evidenced by sustained CYP1A1 and CYP1B1 induction at both acute (4 h) and chronic (12-week) timepoints, while accumulating genotoxic stress as demonstrated by dose-dependent nuclear γ-H2AX foci formation and ATM phosphorylation (Ser1981). RNA-seq revealed a dose-dependent transcriptional shift: 0.1 µM BaP yielded 119 differentially expressed genes (DEGs; |log2FC| ≥ 1, FDR < 0.05), whereas 1.0 µM generated 255 DEGs. Downregulated transcripts were enriched for extracellular matrix and cell-adhesion programs (COL14A1, ADAMTS2, CSMD3, CADM3), while upregulated genes encompassed inflammatory, calcium-signaling, and vesicle-trafficking modules (NFATC4, CSF2RA, SYT1, PCLO). Phospho-kinase/NF-κB arrays confirmed a p53/NF-κB signaling nexus, with concurrent activation of MAPK/ERK (Thr202/Tyr204) and PI3K/Akt (Ser473) pathways. Despite persistent genotoxic stress, cells did not acquire anchorage-independent growth and remained non-tumorigenic in vivo. Critically, ALI organotypic cultures derived from BaP-exposed cells exhibited histological dysplasia, nuclear pleomorphism, and disrupted apical-basal polarity. These findings mechanistically link chronic BaP exposure to an initiation-like preneoplastic state and establish a validated 2D/3D multi-omics platform for PAH-driven lung carcinogenesis research. Full article

Background: Warfarin pharmacogenomics is critical due to its narrow therapeutic index and significant interpatient variability. While machine learning (ML) can predict anticoagulation control status (ACS), its “black-box” nature limits clinical translatability. Explainable Artificial Intelligence (XAI) addresses this by providing interpretable insights. This study applied ML and XAI to a warfarin pharmacogenomic dataset to predict poor ACS and explain model decisions. Methods: A post hoc analysis was conducted on a cross-sectional dataset of 232 patients receiving warfarin for ≥6 months. Data included age, gender, interacting drugs, SAMe-TT2R2 score, and genotypes for CYP2C9, VKORC1, and CYP4F2. Poor ACS was defined as time in therapeutic range (TTR) < 70%. The dataset was split into training (70%) and testing (30%) cohorts. Three models, Random Forest, XGBoost, and Logistic Regression, were developed and evaluated using AUC-ROC, sensitivity, and specificity. XAI techniques, including permutation importance and SHapley Additive exPlanations (SHAP), were employed for global and local interpretability. Results: Of 232 patients, 141 (60.8%) had poor ACS. XGBoost and Random Forest demonstrated comparable predictive accuracy (AUC-ROC: 0.67), outperforming Logistic Regression. Sensitivity was 0.83 and 0.79 for XGBoost and Random Forest, respectively. However, specificity was modest for both ensemble methods (Random Forest: 0.48; XGBoost: 0.41) and extremely low for Logistic Regression (0.04), indicating poor discrimination, particularly for identifying patients with adequate anticoagulation control. Globally, important predictors included the age, SAMe-TT2R2 score, CYP2C9 (*2/*2), female gender, and VKORC1 (C/T). XAI revealed predictions were primarily driven by VKORC1, CYP4F2, SAMe-TT2R2 scores, and drug interactions. Concordance between XAI predictions and actual ACS was 78% for adequate and 88.6% for poor ACS. SHAP analysis showed VKORC1 provided a stable risk signal (mean absolute SHAP: 1.44 ± 0.49 in concordant cases), while CYP2C9 was a high-variance, high-impact driver of discordance (mean SHAP: 3.44 ± 3.79 in discordant cases). Conclusions: ML models, particularly ensemble methods, show modest ability to predict poor warfarin control with limited ability to correctly identify patients with adequate control from our dataset. XAI transforms these models into interpretable tools, with SHAP analysis attributing predictions to specific genetic and clinical features. While predictive accuracy remains modest, this approach enhances transparency and provides a foundation for generating hypotheses that may ultimately support clinical decision-making in pharmacogenomic-guided warfarin therapy. Full article