Search Results (1,299)

No. 0 diesel oil may pose a serious threat to sea cucumber (Apostichopus japonicus) aquaculture by inducing skin ulceration. This study aimed to evaluate the protective efficacy and mechanism of a previously developed inhibitor composition against diesel-induced injury. The inhibitor composition significantly alleviated skin ulceration in the experimental group (Eg), reducing the lesion area to 14.44 ± 1.79% after 96 h, compared to 33.19 ± 2.94% in the diesel-exposed control group (Cg) (p < 0.05). It effectively suppressed the overactivation of autolytic enzymes (cathepsin L and B) while enhancing the activities of acetylcholinesterase, superoxide dismutase, and catalase. Transcriptomic profiling revealed 3137 differentially expressed genes, with functional enrichment in pathways related to Notch signaling, ECM–receptor interaction, glycosaminoglycan biosynthesis, and detoxification. The upregulation of genes such as HES-C, CYP1A1, GST, and UGT may be linked to the regulation of apoptosis inhibition, xenobiotic metabolism, and antioxidant defense. Furthermore, enhanced expression of NAD kinase and PNLIPRP may indicate a potential strengthening of energy metabolism and lipid utilization during stress adaptation. This study suggests that the inhibitor composition may exert a multi-level protective effect against diesel-induced injury by coordinating tissue repair, oxidative balance, and detoxification processes, offering a potential strategy to mitigate pollution impacts in sea cucumber aquaculture. Full article

Hypecoum erectum L. is a medicinal plant known for its high content of isoquinoline alkaloids (IQAs), a class of compounds with diverse pharmacological activities. To elucidate the biosynthetic mechanisms and tissue-specific accumulation of IQAs, we integrated HPLC-MS/MS-based metabolomic analysis with RNA sequencing (RNA-seq) transcriptomic profiling across the roots, stems, and leaves of H. erectum. Metabolomic analysis identified twenty-six IQAs as differentially accumulated metabolites (DAMs) among the three tissues, while transcriptomic analysis revealed twenty-two categories of differentially expressed genes (DEGs) involved in IQA biosynthesis. KEGG pathway enrichment analysis demonstrated that nine DAMs and twenty categories of DEGs were co-enriched in the IQA biosynthetic pathway of Hypecoum erectum. Notably, seven key DAMs—Stylopine, Protopine, Magnoflorine, Corydaline, Tetrahydropalmatine, Sanguinarine, and Palmatine—preferentially accumulated in the root, concomitant with the elevated expression of eleven root-specific DEGs, including GOT1, CYP719A14, SMT, CYP719A1_2_3_13, PSOMT1, E2.1.1.116, CYP80B1, E2.1.1.128, NCS, ASP5, and BBE1. Gene–metabolite correlation network analysis further identified nine DAMs and fifteen DEGs closely associated with IQA biosynthesis, highlighting key enzymatic regulators of alkaloid accumulation. Additionally, several transcription factor (TF) families, including bHLH, NAC, and ERF families, were predicted to participate in the transcriptional regulation of IQA-related genes. Collectively, these findings demonstrate that roots are the primary site of IQA biosynthesis in H. erectum and provide a molecular framework for understanding the regulation and utilization of its medicinally active components. Full article

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood–brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG−; multi-tissue subset: n = 6 PG+, n = 21 PG−). Our data revealed a “dual-fate” mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a “metabolic sink”, passively accumulating metabolites generated in peripheral organs—such as 17-hydroxypregnanolone—despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced “metabolic segregation” within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile—combining metabolic segregation with active central buffering—defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites—several with previously established GABAergic and neuroprotective activity—without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model. Full article

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy. Full article

Background: Di(2-ethylhexyl) phthalate (DEHP) is a high-production-volume plasticizer and ubiquitous environ-mental contaminant with established endocrine-disrupting potential. While zebrafish transcriptomic studies have typically used high concentrations and long exposure windows, less is known about genome-wide responses during late embryogenesis/early larval maturation under environmentally relevant exposures. Here we profiled whole-organism transcriptomic responses to a short DEHP exposure during a developmentally sensitive transition (96–120) hours post-fertilization, hpf) and interpreted responses using differential expression, enrichment analyses, and endocrine-focused protein–protein interaction (PPI) network modeling. Methods: Wild-type AB zebrafish lar-vae (96 hpf) were exposed to DEHP at [10⁻⁹ M] or solvent control for 24 h. Larvae were pooled per replicate (25 lar-vae/pool) and processed for poly(A)-selected RNA-seq. Reads were quality-controlled, aligned to the Danio rerio reference genome, and quantified at gene- level. Differential expression was performed using DESeq2. Functional enrichment used KEGG over-representation analysis (ORA) and gene set enrichment analysis (GSEA). Zebrafish genes were mapped to human orthologs for GO/KEGG and STRING-based endocrine subnetworks, which were visualized and interrogated using STRINGdb and visNetwork. Results: Low-dose, short-term exposure does not produce large gene-level effects but induces coordinated, pathway-level transcriptional remodeling. KEGG ORA showed significant enrichment of MAPK signaling and regulation of actin cytoskeleton with additional enrichment of axon guidance and neuroactive ligand–receptor interaction. GSEA detected coordinated downregulation of KEGG neurodegeneration collections with negative normalized enrichment scores reflecting shared gene sets re-lated to mitochondrial function, proteostasis, cytoskeletal organization, and stress-response pathways. Endo-crine-focused STRING subnetworks indicated consistent downregulation of CYP19A1 within estrogen metabo-lism/biosynthesis modules and downregulation of upstream androgen biosynthetic enzymes HSD3B2 and CYP17A1, alongside upregulation of HSD17B3 and proteostasis-associated factors including DNAJA1. Endocrine network to-pology highlighted regulatory and cofactor nodes affecting receptor-linked transcription, consistent with indirect endocrine modulation rather than large receptor-transcript changes. Conclusions: In summary, this study demon-strates that exposure to low-dose DEHP during a critical period of zebrafish embryonic development is associated with modest but coordinated transcriptomic changes across multiple biological pathways. Pathway enrichment and network-based analyses highlight estrogen- and androgen-associated processes, along with broader signaling, met-abolic, and structural pathways, as transcriptionally responsive during this window. Importantly, these findings reflect molecular-level associations rather than direct evidence of functional or physiological endocrine disruption. Instead, they identify candidate pathways and regulatory networks that may be sensitive to low-level environmen-tal exposure and warrant further investigation. Collectively, this work underscores the value of systems-level tran-scriptomic approaches for detecting subtle, pathway-wide responses to environmentally relevant exposures during development. Full article

Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor, necessitating innovative multi-target strategies. Natural compounds like the triterpenoid Alisol B from Alisma orientale hold promise due to their polypharmacological potential, yet their system-level mechanisms are unclear. Using an integrated multi-omics approach (transcriptomics, proteomics, lysine acetyl-proteomics) in resistant GBM cells and validating findings in vitro and in AB strain zebrafish (Danio rerio) xenografts, we found that Alisol B induces endoplasmic reticulum stress and G2/M arrest, initiated by extensive lysine acetylation reprogramming on histones and metabolic enzymes (e.g., FASN, FDFT1). This epigenetic rewiring leads to disrupted cholesterol biosynthesis, characterized by transcriptional activation of the mevalonate pathway alongside post-transcriptional suppression of terminal enzymes (DHCR7, CYP51A1), suggestive of toxic intermediate accumulation. Alisol B also downregulated the oncogenic axis (BIRC5-FOXM1-ITGA4) and SCD5. This study delineates Alisol B’s novel multi-mechanistic action through concurrent epigenetic rewiring, metabolic dysfunction induction, and survival network dismantling. Our work elucidates the molecular pharmacology of a natural compound and provides a framework for developing polypharmacological therapies against resistant cancers, exemplifying natural products as tools to reveal new therapeutic paradigms. Full article

Background/Objectives: CEU-938, an innovative antimicrotubule prodrug bioactivated by cytochrome P450 1A1 (CYP1A1), represents a promising targeted alternative for cancer cells overexpressing this enzyme. To optimize its clinical utility and minimize off-target effects in breast cancer (BC) patients, this study aims to identify predictive biomarkers of CEU-938 efficacy. Methods: The antiproliferative activity of CEU-938 was assessed across a panel of 39 human breast cancer and non-tumorigenic cell lines. Differential expression analyses were subsequently performed to distinguish CEU-938-responsive from non-responsive cell lines using a threshold of 1000 nM. Candidate biomarkers identified through this approach were then validated by RT-qPCR and Western blot analyses. Results: CEU-938 demonstrated marked and selective antiproliferative activity across molecular subtypes of human breast cancer, with efficacy observed in approximately 40% of triple-negative breast cancer (TNBC), 70% of estrogen receptor-positive (ER⁺), and 80% of human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer cell lines, while sparing non-tumorigenic human breast cells (MCF 10A, MCF-12A, 184B5). Differential expression analysis identified five candidate biomarkers associated with CEU-938 responsiveness, namely, FOXA1 (log2-fold change (LFC) = 3.1), RAB25 (LFC = 3.8), RHOV (LFC = 2.9), PRKCH (LFC = 1.6), and HDAC9 (LFC = −1.7). Among these, FOXA1 and RAB25 robustly validated by RT-qPCR and Western blot analyses, showing strong inverse correlations with CEU-938 sensitivity (Spearman correlation coefficients of −0.82 and −0.61, respectively, at the protein level). The predictive value of FOXA1 and RAB25 was further confirmed by Western blot analyses in two independent breast cell line models, the non-responsive MCF-12A and the responsive MDA-kb2. Conclusions: Collectively, these findings identify FOXA1 and RAB25 as robust predictive biomarkers of response to CEU-938. Notably, FOXA1 and RAB25 are strongly implicated in breast cancer biology, and FOXA1 has been directly linked to the aryl hydrocarbon receptor (AHR), the main regulator of CYP1A1. These results position CEU-938 as a strong precision-therapy candidate that combines target selectivity, a favorable toxicity profile, and biomarker-enabled patient stratification, with potential clinical benefit in ER⁺ and HER2⁺ enriched tumors, as well as a subset of TNBC. Full article

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. Methods: A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including CYP2D6, CYP3A4/5, UGT1A4, UGT2B7/15, SULT1A1/2, and SULT1E1, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. Results: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with SULT1A1 copy number variation (p = 0.030) and SULT1E1 rs3736599 (p = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with UGT2B7 rs7439366 (p = 0.040) and CYP3A4 rs2242480 (p = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to SULT1A2*2 (p = 0.050), SULT1E1 rs3736599 (p = 0.016), and UGT2B15 rs4148269 (p = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. Conclusions: This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

Background/Objectives: Losartan, an angiotensin II receptor blocker (ARB) used to treat hypertension and heart failure, shows significant variability in pharmacokinetics (PK) and pharmacodynamics (PD) among individuals. Methods: In this study, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of losartan and its active metabolite, E3174, using curated data from 25 clinical trials. The model mechanistically describes the processes of absorption, hepatic metabolism, renal and fecal excretion, and pharmacodynamic blood pressure regulation. Simulation studies examined the effects of dose, hepatic and renal impairment, and genetic polymorphisms in cytochrome p450 2C9 (CYP2C9) and P-glycoprotein 1, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1), on the model. Results: The model successfully reproduced key PK/PD observations, including dose-dependent receptor blockade, attenuated responses with hepatic impairment, modest enhancement with renal impairment, and substantial variability in E3174 formation dependent on CYP2C9; the effects of ABCB1 were minimal. Specifically, dose dependency simulations confirmed the saturable nature of CYP2C9 metabolism, predicting a decreasing E3174-to-losartan ratio and a stronger, sustained suppression of blood pressure and aldosterone at higher doses. Hepatic impairment was predicted to lead to elevated losartan plasma concentrations (increased AUC) and attenuated metabolite formation, confirming the clinical need for dose reduction. Renal impairment simulations predicted stable losartan AUC but showed an overestimation of E3174 accumulation compared to observed data, where E3174 exposure remained stable. Genetic variability (CYP2C9) was the major determinant of response, with simulations confirming that reduced-function alleles lead to a 1.6- to 3-fold increase in losartan AUC and diminished blood pressure reduction. ABCB1 variability resulted in only minor modulation of systemic exposure and blood pressure effects. Conclusions: This mechanistic digital twin framework provides a quantitative basis for understanding variability in losartan therapy and supports its application in individualized dosing strategies. Full article

APETALA2/ethylene-responsive factor (AP2/ERF) transcription factors integrate phytohormone signalling with developmental programmes and specialised metabolism, yet their family-wide features and potential contributions to phenolic-acid biosynthesis remain to be systematically clarified in Salvia miltiorrhiza. In this study, we conducted a comprehensive genome-wide analysis and identified 169 SmAP2/ERF genes, which were classified into five subfamilies (AP2, ERF, DREB, RAV and Soloist). SmAP2/ERFs were unevenly distributed across chromosomes and expanded predominantly through tandem and segmental duplication, and Ka/Ks analysis indicated that tandem-duplicated pairs have mainly undergone purifying selection. Promoter analysis revealed abundant cis-acting elements related to light, phytohormones and stress responses, indicating extensive regulatory potential. Comparative phylogenetic analysis with Arabidopsis thaliana prioritised four candidates (SmAP2/ERF88, SmAP2/ERF110, SmAP2/ERF121 and SmAP2/ERF122) closely associated with specialised-metabolism regulators. These genes exhibited distinct tissue-preferential expression patterns and divergent hormone responsiveness: SmAP2/ERF88/110 were broadly inducible, whereas SmAP2/ERF121/122 responded mainly to abscisic acid and were repressed by brassinosteroids. Confocal imaging of GFP fusions confirmed nuclear localisation of all four proteins. Phytohormone treatments differentially regulated key phenolic-acid pathway genes (PAL, C4H, 4CL, TAT, HPPR, RAS and CYP98A14) and altered rosmarinic acid and salvianolic acid B accumulation. These results broaden the genome-wide understanding of the SmAP2/ERF family in Salvia miltiorrhiza. Hormone-responsive SmAP2/ERFs show expression patterns associated with hormone-dependent transcriptional changes in phenolic-acid pathway genes and with RA and SAB accumulation, providing candidates for future functional validation and metabolic engineering. Full article

Cytochrome P450 monooxygenases (CYPs/P450s) play a key role in organisms’ primary and secondary metabolism in species across all domains of life. Accurate annotation of P450 genes is crucial for identifying their functions, evolution, and, consequently, their biotechnological potential. In this study, we report the identification of an unprecedented one-nucleotide exon required for the correct assembly of CYP621A P450 genes from multiple Fusarium species. Through comparative genomic analysis of 20 orthologous CYP621A genes, supported by an intronless CYP621B1 gene from Aspergillus clavatus, we demonstrate that omission of this single-nucleotide exon disrupts exon phase compatibility and prevents reconstruction of a full-length, functional P450 protein. The micro-exon encodes the central nucleotide of the glycine codon in the highly conserved PKG motif, which is essential for maintaining the structural integrity between the EXXR and PERF motifs, a characteristic of P450 enzymes. Importantly, transcriptomic evidence from sequence read archive (SRA) data confirms accurate splicing of this one-nucleotide exon in Fusarium solani and F. acuminatum under multiple growth conditions. This work presents the second example of the smallest exon reported to date for a gene, and the first for a P450 gene or a fungal gene. The study’s findings have broad implications for genome annotation pipelines, underscoring the need for careful manual curation and improved algorithms to detect ultra-small exons in functionally constrained regions of eukaryotic genes. Full article

Background/Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to help alleviate pain and treat inflammation, but they are also recognized as common causes of severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite their clinical importance, pharmacogenetic markers to predict individual susceptibility to NSAID-induced SJS/TEN remain insufficiently defined. This study investigated associations between HLA class I and II alleles, CYP2C9 polymorphisms, and NSAID-induced SJS/TEN in a Thai population. Methods: A total of 18 patients with NSAID-induced SJS/TEN and 54 NSAID-tolerant controls were enrolled. Genotype data from 183 unrelated Thai individuals without a history of drug allergy were included as a general population control group. Genotyping was performed for HLA class I and II alleles and the CYP2C9*3 variant. Results: HLA-DQB1*03:02 was significantly associated with NSAID-induced SJS/TEN (OR = 9.23, 95% CI = 2.19–38.83, p = 0.0024, Pc = 0.0312), particularly those triggered by piroxicam (OR = 13.71, 95% CI = 2.81–66.86, p = 0.0012, Pc = 0.0156). Additional associations were identified for HLA-B*56:01 and HLA-A*68:01 in the overall NSAID-induced SJS/TEN group. The subgroup analysis suggested that these alleles, along with HLA-DRB1*04:03, were associated with an increased risk of piroxicam-induced SJS/TEN. However, these associations did not remain statistically significant after Bonferroni’s correction. No significant association was identified for CYP2C9*3. Conclusions: This study identified specific HLA alleles, particularly HLA-DQB1*03:02, as candidate pharmacogenetic risk factors for NSAID-induced SJS/TEN in a Thai population, especially in piroxicam-associated cases. However, these associations should be considered exploratory. Larger, multicenter, multi-ethnic studies are required to validate these findings and clarify their potential clinical utility. Full article

Broodiness in poultry represents a major bottleneck for reproductive performance, governed by complex remodeling of the hypothalamic-pituitary-ovarian (HPO) axis. CYP11A1, the rate-limiting enzyme in steroidogenesis, is essential for hormone synthesis; however, its spatiotemporal dynamics within the HPO axis during reproductive transitions remain unclear. Using the Wuding chicken as a model, this study characterized the expression profile and cellular function of CYP11A1. We identified a distinct “ovary-hypothalamus expression inversion” pattern: CYP11A1 expression exhibited an ovary-dominant pattern during the egg-laying period to support folliculogenesis; however, this shifted to a hypothalamus-dominant pattern during the broodiness period. This inversion indicates its active role in central neurosteroid modulation rather than a passive response to HPO axis regression. In vitro assays in granulosa cells (GCs) demonstrated that CYP11A1 overexpression significantly upregulated AKT1 and mTOR transcription, promoted the G0/G1 to S/G2/M cell cycle transition, and enhanced cell proliferation. Conversely, CYP11A1 knockdown arrested the cell cycle and suppressed the PI3K/AKT/mTOR pathway. Additionally, CYP11A1 coordinated the expression of steroidogenic genes (STAR, HSD3B1), reflecting a coupling between steroid metabolism and cell growth. These findings reveal CYP11A1 as a critical molecular node linking HPO axis remodeling, granulosa cell proliferation, and steroidogenesis, providing a potential target for molecular breeding to mitigate broodiness in indigenous chickens. Full article

Flower color, as an important trait of ornamental plants, has been a research hotspot in recent years. In this study, we selected Prunus campanulata (Maxim.) (ZH, red), P. dielsiana (Schneid.) (WH, white), and two cherry blossom varieties ‘Yanzhi Fei’ (FH, deep pink) and ‘Yanzhi Xue’ (XH, pinkish white) obtained by open-pollination hybridization as material. By means of bioinformatics methods such as metabolomics and transcriptomics, it is expected to deeply study the molecular mechanism of the gradient changes in flower color between the parents and offspring of cherry blossoms. Metabolomics analysis indicated that a total of 84 flavonoid related metabolites were identified, among which 31 were associated with the anthocyanin metabolic pathway, including three major types of anthocyanin substances: cyanidin, delphinidin, and malvidin. Transcriptome analysis showed that a total of 7712 differential genes were detected between P. campanulata and P. dielsiana; there were 3948 differential genes between P. campanulata and ‘Yanzhi Xue’, 2802 between P. campanulata and ‘Yanzhi Fei’, and 2511 between ‘Yanzhi Xue’ and ‘Yanzhi Fei’. After screening based on anthocyanin accumulation, nine key enzyme genes were obtained. Joint analysis showed that the relative expression trends of structural genes such as PAL, 4CL, CHI, DFR, and CYP75B in the samples were consistent with those of anthocyanins, and they had a high correlation with downstream metabolites. The results of this study lay a certain scientific foundation for the future directional improvement and breeding of cherry blossom colors. Full article