Search Results (567)

WRKY transcription factors play critical roles in plant growth, development, metabolism, and stress responses. In this study, we performed the first genome-wide characterization of the WRKY gene family in Bupleurum chinense, using a T2T-level assembly of the autotetraploid genome. A total of 303 BcWRKY genes were identified and found to be unevenly distributed across four subgenomes. Phylogenetic and structural analyses revealed that segmental duplications after polyploidization drove lineage-specific expansion of the family. Meta-transcriptome analysis demonstrated that BcWRKY genes exhibited tissue-specific expression patterns and dynamic responses to stress, suggesting functional diversification. Under drought, waterlogging, methyl jasmonate, and ABA treatments, the contents of saikosaponins A and D significantly increased. This increase was accompanied by transcriptional activation of multiple BcWRKY genes. Correlation analysis between ten BcWRKYs and ten saikosaponins biosynthetic associated genes (BcBASs, BcCYPs, and BcUGTs) identified BcWRKY22, BcWRKY33, and BcWRKY46 as potential regulators of saikosaponin metabolism under stress conditions. Our study provided a comprehensive framework for understanding BcWRKY gene evolution and secondary metabolic regulation in polyploid medicinal plants. It also offered candidate genes for breeding B. chinense cultivars with high saikosaponin content. Full article

Glycosylation serves as an effective strategy to enhance the solubility, bioavailability, and pharmacological activity of polyhydroxyphenols. In this study, we explored the glycosylation of natural and natural-inspired phenolic compounds using the glycosyltransferase AbCGT and evaluated the anti-renal fibrotic potential of the resulting glycosides. Among them, 1,3,5,8-tetrahydroxyxanthone 5-O-β-D-glucopyranoside (2-1a), synthesized via the regioselective 5-O-glycosylation of demethylbellidifolin, demonstrated significant anti-renal fibrotic activity. In contrast, its homologous glycosyltransferase, UGT73AE1, predominantly glycosylated demethylbellidifolin at the 3-OH position. Molecular docking studies revealed the structural basis for this regioselectivity difference. To enhance the production of 2-1a, we established a UDP-glucose (UDPG) recycling system by coupling AbCGT with Glycine max sucrose synthase (GmSuSy) and subsequently optimized the reaction conditions. Furthermore, targeted mutagenesis of AbCGT informed by molecular docking analysis identified a F138A mutant that enhanced glycosylation yield by 2.3-fold. This work develops a novel glycosyltransferase-based catalytic system and identifies a new compound with potential anti-renal fibrotic activity. Full article

The impact of genetic variation in sickle cell patients plays a significant role in opioid therapy individual response and pain management. This review aims to provide a comprehensive overview of the importance of exploring genetic variability and its impact on pain management in patients with sickle cell disease. It also explores opioid therapy variability and opioid Safety. With respect to literature, the polymorphisms in the key metabolic enzymes CYP2D6, UGT2B7, and COMT, as well as variations in the OPRM1, are important modifiers of the pharmacokinetics and pharmacodynamics of opioids. Variations in the COMT gene can influence how the body manages certain brain chemicals and how pain is experienced, while changes in the OPRM1 gene can alter how well opioids bind to their receptors. They help determine how opioids are broken down in the body, how well they attach to pain receptors, and how pain is felt by someone with sickle cell disease. Patients with reduced-function and ultra-rapid CYP2D6 alleles have a modified metabolism of codeine and tramadol, which presents either a reduced analgesic response or a risk for increased toxicity. These observations support the case for the need for tailored opioid prescriptions in a population that is genetically diverse, as well as the risk of not having standardized pain measurement, and the absence of clinical implementation. There remains the risk of unrecognized pharmacogenomics, lack of data, and personalized opioid descriptions persist. Future research should focus on integrating genetic testing into clinical practice to optimize opioid selection, personalize medicine, minimize adverse effects, and ensure each patient receives treatment that is both effective and safe to enhance quality of life for individuals with sickle cell disease. Full article

Background: The UGT1A1 gene is associated with the toxicity caused by SN38, the cytotoxic component of Sacituzumab govitecan (SG) used in the treatment of metastatic triple-negative breast cancer (mTNBC), among other approved indications. In this study, we aimed to analyze the effect of UGT1A1*28 allele on the safety and, secondarily, the effectiveness of SG in mTNBC. Methods: This was a multicenter, ambispective study that included patients treated with SG for mTNBC. Genotyping for UGT1A1*28 was performed using real-time polymerase chain reaction (PCR). Adverse events (AEs) of grade ≥ 2 during the first three cycles were compared between patients who were homozygous mutant (UGT1A1*28/*28) and those with wild-type (WT) or heterozygous genotypes. Effectiveness between the two groups was also compared using progression-free survival (PFS) and overall survival (OS) assessed with the Kaplan–Meier method. Results: A total of 81 patients were included: 37.0% were WT, 55.6% heterozygous, and 7.4% homozygous mutant. All UGT1A1 *28/*28 patients experienced grade ≥ 2 AEs (100% vs. 69.3%; p = 0.109), with a statistically significant association in the case of febrile neutropenia (33.3% vs. 6.7%; p = 0.025), and a trend towards higher rates of anemia and diarrhea (50.0% vs. 17.3%; p = 0.053). Genotype did not influence PFS or OS; however, dose reductions were associated with better survival outcomes. Conclusions: This real-world study shows a correlation between toxicity and the presence of the UGT1A1*28 mutation in patients treated with SG for mTNBC. Improving treatment tolerability through dose reductions may enhance SG effectiveness. These findings support the implementation of UGT1A1 genotyping in routine clinical practice. Full article

Astragalus membranaceus is a model of traditional ‘homologous nature of medicine and food’. Its stems and leaves have been proven to have a variety of biological activities. In this study, high-throughput sequencing technology was used to sequence transcriptomics and metabolomics A. membranaceus stems and leaves at different growth stages (flowerless stage, flower bud stage, flowering stage, green fruit stage, mature fruit staged, and withering stage), and a regulation analysis was conducted on its differentially expressed genes and differentially accumulated metabolites. The results showed that five hub genes, PAL, CHI, AMIE, CAD, and PRX, were found to play a central regulatory role in flavonoid biosynthesis. The combined analysis of transcriptomics and metabolomics constructed a flavonoid metabolic regulatory network during the growth and development of A. membranaceus stems and leaves. At the same time, based on the significant antioxidant activity of isoquercitrin, three genes that may be related to isoquercitrin biosynthesis were screened, namely IF7MAT, FG3, and UGT78D2. The results of this study provide insights into the biosynthesis and comprehensive development and utilization of flavonoids in A. membranaceus. Full article

The liver is the central organ in metabolism; however, modeling hepatic diseases remains limited by current experimental models. Animal models frequently fail to predict human liver physiology, while primary hepatocytes rapidly dedifferentiate in culture. We performed comprehensive transcriptomic profiling of induced pluripotent stem cells (iPSCs) differentiation into hepatocyte-like cells (HLCs) under two-dimensional (2D) and three-dimensional (3D) culture conditions. RNA sequencing analysis revealed the sequential activation of lineage-specific markers across major developmental stages: definitive endoderm (FOXA2, SOX17, CXCR4, CER1, GATA4), posterior foregut (PROX1, GATA6), and hepatoblasts (HNF4A, AFP). Comparative analysis demonstrated a markedly enhanced hepatic gene expression of 3D organoids, as demonstrated by a 33-fold increase in HNF4A expression and elevated levels of mature hepatocyte markers, including ALB, SERPINA1, and UGT2B15. However, the 3D cultures retained fetal characteristics (290-fold higher AFP expression) and exhibited significantly impaired metabolic function, with CYP3A4 expression levels reduced by 2000-fold compared to the adult human liver. This partial maturation was further supported by a moderate correlation with adult liver tissue (ρ = 0.57). We demonstrated high reproducibility across five biologically distinct iPSCs lines, including those derived from patients with rare monogenic disorders. The establishment of quantitative benchmarks provides a crucial tool for standardizing in vitro liver models. Furthermore, we delineate the specific limitations of the current model, highlighting the need for further protocol optimization to enhance metabolic maturation and P450 enzyme activity. Functional validation of metabolic activity (CYP enzyme assays, albumin secretion) was not performed; therefore, conclusions regarding hepatocyte functionality are based on transcriptomic evidence. Full article

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches. Full article

Background/Objectives: This study evaluates the relationship between UGT1A9 polymorphisms, cardiac biomarker patterns, and clinical presentations in patients admitted to the Pamukkale University Emergency Department with cardiac symptoms. Methods: A total of 207 consecutive patients presenting with chest pain, dyspnea, palpitations, or other cardiac complaints were initially enrolled. Patients with incomplete clinical data or unsuccessful genotyping were excluded prior to analysis, and all remaining samples were included in the final evaluation. UGT1A9 *1, *2, and *3 alleles were genotyped using allele-specific PCR and TaqMan^® assays. Patients were classified into wt/wt, wt/*3, and *3/*3 groups. Statistical analyses included Kruskal–Wallis, Mann–Whitney U, and chi-square tests. Results: Genotype distribution was 64% wt/wt, 32% wt/*3, and 4% *3/*3. CK-MB levels differed significantly across genotypes (p = 0.006), with the highest in wt/*3 carriers. Troponin I levels showed no genotypic differences (p = 0.533). UGT1A9*3 carriers exhibited elevated CK-MB with relatively low Troponin I, suggesting possible statin-associated muscle injury rather than true myocardial necrosis. Conclusions: UGT1A9 polymorphisms, particularly UGT1A9*3, influence CK-MB variability and may confound the assessment of myocardial injury. Troponin I remains unaffected by genotype. Incorporating UGT1A9 pharmacogenetic testing may contribute to a better understanding of biomarker variability and support future research toward personalized therapeutic strategies. Full article

Kratom alkaloids are classified as aromatic pentacyclic indole and substituted carbonyl oxindole alkaloids. This study investigates the metabolism and interactions of indole alkaloids using in silico tools, including ADMET Predictor 13.0™, to assess pharmacokinetic and metabolic profiles. The analysis examined absorption, distribution, metabolism, and excretion (ADME), focusing on cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzyme interactions, drug transporters, and clearance. Most indole alkaloids showed strong substrate interaction and inhibition of CYP3A4 (79–99% confidence) and induction of CYP1A2 (up to 94% confidence). Among UGT enzymes, UGT1A1 demonstrated the highest substrate affinity (97%), while none interacted with UGT2B15. All alkaloids showed strong P-glycoprotein (Pgp) interaction but minimal inhibition of BCRP. Mitralactonine exhibited the highest skin permeability, and Mitralactonal showed maximal jejunal permeability. Most indole alkaloids demonstrated significant blood–brain barrier penetration (up to 99% confidence) and compliance with Lipinski’s rule of five. Predictive modeling indicated notable effects on hepatic microsomal clearance parameters. This investigation offers the first comprehensive in silico ADMET profiling of kratom indole alkaloids, uncovering their CYP3A4 inhibition potential and metabolic liabilities to prioritize candidates for safer therapeutic development, though limited by model biases, applicability domain restrictions, and inability to fully capture biological complexity, stereochemistry, or interindividual variability necessitating experimental in vitro and in vivo validation. Full article

Background: Rosa chinensis, commonly known as the Chinese rose, is one of the most economically significant ornamental plants worldwide. The Rosa chinensis cultivar ‘Rainbow’s End’ notably transitions in color from yellow to red throughout its blooming phase; however, the chemical and molecular foundations underlying this floral color transformation remain inadequately understood. Methods: This study used the petals of the Rosa ‘Rainbow’s End’ cultivar at four developmental stages (R1, R2, R3, and R4) for targeted metabolomic and transcriptomic analyses. Results: Targeted metabolomic analyses revealed that the majority of anthocyanidin metabolites were highest at stages R2 and R3 and lowest at R1 and R4. In contrast, most carotenoid metabolites reached their highest levels at R1 and declined continuously from R2 to R4. These results were consistent with the color phenotype of Rosa ‘Rainbow’s End’ petals and suggested that both anthocyanins and carotenoids play critical roles in flower color variation. Specifically, an upregulation of CHS, ANS, and UGT genes in the anthocyanin biosynthesis pathway was observed in R2 and R3, coinciding with the expression of two MYB transcription factors (MYB14 and MYB54). Conversely, consistent downregulation of PSY, PDS, Z-ISO, ZDS, CHYB, and NCED genes in the carotenoid biosynthesis pathway was detected in R2 to R4 and was associated with four MYB transcription factors (MYB20, MYB43, MYB44, and MYB86). Conclusions: Rosa ‘Rainbow’s End’ is an excellent model for studying variations in flower color. The expression patterns of the identified structural genes involved in anthocyanin and carotenoid biosynthesis pathways, along with the related MYB transcription factors, were aligned with the levels of metabolite changes in the petals of four flowering stages. These genes and transcription factors are likely responsible for the color shifts in Rosa ‘Rainbow’s End’. This study clarifies the mechanisms underlying color changes in Rosa ‘Rainbow’s End’ and provides a theoretical basis for future flower breeding efforts. Full article

Background: Lonicera macranthoides is a valuable traditional Chinese medicinal plant, enriched in secondary metabolites that exert significant therapeutic effects against specific diseases. However, the differences in the accumulation of key metabolites across various tissues of this plant remain poorly understood. Methods: This study analyzed the transcriptomes and metabolomes of three key tissues (flowers, leaves, and fruits) in Lonicera macranthoides. Results: Transcriptome sequencing identified 7321 differentially expressed genes (DEGs) common to flowers, fruits, and leaves. Among the top 20 KEGG pathways enriched by these DEGs, metabolic pathways and biosynthesis of secondary metabolites were prominently represented. At least 70 CYP genes and 12 UGT genes were differentially expressed, with a greater proportion of these genes being up-regulated in flowers or fruits. DEGs involved in flavonoid biosynthesis include CHI, CHS, and FLS, with most of these genes being up-regulated in fruits. Metabolomics analysis identified 4961 metabolites across the three tissues. KEGG pathway classification of these DAMs showed that a large proportion are involved in metabolic pathways and secondary metabolite biosynthesis. Conjoint analysis of the transcriptomic and metabolomic data revealed that the most significantly enriched were metabolic pathways and biosynthesis of secondary metabolites. Integrative analysis of DEGs and DAMs indicated that flowers and fruits are likely key tissues for the biosynthesis of hederagenin-based saponins, while fruits may serve as critical organs for flavonoid biosynthesis. Conclusions: This study provides novel insights into the tissue-specific differential accumulation of metabolites in Lonicera macranthoides, and lays a crucial foundation for further investigating the underlying molecular regulatory mechanisms. Full article

Common ragweed, Ambrosia artemisiifolia L., a noxious invasive plant, produces novel secondary metabolites. However, it attracts soybean aphid, Aphis glycines, a significant pest of soybean, to feed on it. Elucidating the molecular mechanisms of A. glycines adaptation to A. artemisiifolia may help identify target genes useful for pest management. High-throughput transcriptome sequencing identified 4250 differentially expressed genes (DEGs), with 2399 upregulated and 1851 downregulated. KEGG pathway enrichment analysis suggested that these DEGs were significantly involved in core detoxification-related pathways, including metabolism of xenobiotics by cytochrome P450, drug metabolism, ascorbate and aldarate metabolism, and pentose and glucuronate interconversions. Further analysis revealed significant upregulation of 17 UDP-glycosyltransferase (UGT) genes, with AgUGT342B2, AgUGT343B2, AgUGT344J2, AgUGT344L2, and AgUGT344N2 showing 6.34-, 6.22-, 2.14-, 3.98-, and 7.49-fold higher expression, respectively, than in A. glycines fed on soybean. Bioassays demonstrated that A. glycines reared on A. artemisiifolia exhibited significantly reduced sensitivity to three common insecticides, imidacloprid, thiamethoxam, and lambda-cyhalothrin, with LC₅₀ values increasing by 5.8-fold, 2.8-fold, and 3.6-foldhigher, respectively, than those reared on soybean. These findings indicate that feeding on A. artemisiifolia induces UGT gene family upregulation in A. glycines, conferring cross-resistance to multiple insecticide classes. This study reveals a molecular mechanism linking host adaptation to insecticide resistance, highlighting the ecological and evolutionary consequences of invasive plant-herbivore interactions. Full article

Colorectal cancer (CRC) remains the third leading cause of mortality among cancer patients in developed countries. Each new study in this field can contribute to better detection, diagnosis, and treatment of this disease. Our study aimed to assess transcriptional activity of genes associated with the biotransformation of xenobiotics and endobiotics in all three phases in the CRC adenocarcinoma, including correlations between them, as well as the aromatic hydrocarbon receptor (AhR) pathways. Based on transcriptome analysis (1252 mRNAs) of the CRC tissue and healthy colon, the upregulation or downregulation of 46 significant mRNAs was presented. The study also revealed the downregulation of AKR7A2 and upregulation of SLC5A6 and SLC29A2, previously undistinguished and potentially therapeutically valuable in CRC. The diagnostic potential of ADH1C, GGT5, NQO2, and SLC25A5 was demonstrated. It was stated that the AHR, EPHX1, GSTP1, and SLC25A32 did not correlate in healthy intestinal tissue whereas AHCY, ALDH1A1, NNMT, GSTM4, UGT2B17, and SLCO1B3 did not correlate in CRC. The disturbed transcriptional activity of genes related to the biotransformation process at all stages of CRC suggests that this may be the cause of its occurrence; the genes ought to be taken into account in preventive strategies and the treatment of patients. 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

Myofibrillar protein (MP) aggregation in solutions with NaCl concentrations below 0.3 M results in poor solubility. Ultrasound-assisted glutaminase treatment (UGT) was applied to improve MP solubility in a low-salt solution (containing 0.1 M NaCl). The solubility increased with ultrasonic power and time, peaking at 44.34% (480 W, 15 min) and reaching 61% after UGT. Subsequently, the effect of post-sonication heat treatment (60 °C, 30 min) on the physicochemical and structural characteristics of ultrasound-enzyme treated MP (UEMP), prepared under specific ultrasonic conditions (480 W, 20 min), was systematically investigated. The findings revealed that UEMP exhibited higher hydrophobicity, sulfhydryl content, and turbidity, but reduced particle size, ζ-potential, and fluorescence, suggesting disulfide disruption and exposure of hydrophobic residues. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed weakened high-molecular weight bands and intensified low-molecular weight bands. Fourier-transform infrared spectroscopy confirmed these structural rearrangements, with a blue-shifted amide A band and decreased amide I intensity. Heating further increased the hydrophobicity and fluorescence without altering the size, ζ-potential, or molecular weight. The red shift in the amide A band suggests reinforced local ordering. Rheology analysis showed non-Newtonian shear-thinning behavior, which was unchanged by UGT or heating. Collectively, UGT with moderate heating enhances MP solubility and thermal stability by disrupting stabilizing bonds and modulating the structure. Full article