Search Results (1,339)

Amaryllidaceae alkaloids are of notable pharmacological relevance. For instance, galanthamine is used in the treatment of Alzheimer’s disease, while other alkaloids (lycorine, crinine, etc.) derived from Amaryllidaceae plants are also of great interest because they exhibit antitumour, antiviral, antibacterial, antifungal, antimalarial, analgesic and cytotoxic properties. Phenolic acids comprise a group of natural bioactive substances that have commercial value in the cosmetic, food and medicinal industries due to their antioxidant, anticancer, anti-inflammatory and cardioprotective potential. In the present study, the effect of temperature (15, 20, 25 and 30 °C) on Amaryllidaceae alkaloid and phenolic acid biosynthesis in Leucojum aestivum in vitro plant cultures was investigated. The highest diversity of alkaloids (i.e., galanthamine, crinan-3-ol, demethylmaritidine, crinine, 11-hydroxyvitattine, lycorine, epiisohaemanthamine, chlidanthine) was noted in plants cultured at 30 °C. By contrast, ismine and tazettine were only present in plants cultured at 15 °C. Temperatures of 20 °C and 30 °C were found to stimulate galanthamine accumulation. The highest lycorine content was noted in plants grown at temperatures of 15 and 30 °C, and it was negatively correlated with the expression of the gene that encodes the cytochrome P450 96T (CYP96T) enzyme which catalyses a key step in the biosynthesis of different types of Amaryllidaceae alkaloids. This observation may reflect temperature-induced shifts in metabolic flux among different branches of Amaryllidaceae alkaloid biosynthesis. The observed stimulating effect of a 15 °C temperature on the chlorogenic, caffeic, p-coumaric, sinapic, ferulic and isoferulic acid content was in line with the highest expression of a gene that encodes the tyrosine decarboxylase (TYDC) enzyme, which is involved in plant stress response mechanisms. At 30 °C, however, the highest content of the caffeic, vanillic, p-coumaric and isoferulic acids was noted. Full article

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC₅₀ vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025. Full article

Salt stress is a major agricultural issue. A promising modern agriculture method is the foliar treatment of zinc oxide nanoparticles (ZnONPs). This approach has shown promise in boosting challenged tomato yields, fruit quality, and leaf extract antibacterial activity against pathogens. A greenhouse experiment was conducted. The previously synthesized and characterized ZnONPs were used to alleviate the harmful effects of NaCl stress. Tomato fruit weight from different treatments was determined, and the gas–liquid chromatography device was used to observe the changes in fatty acid production. The antimicrobial activities of the aqueous and diethyl ether extracts from tomato leaves were determined against six bacterial and six fungal strains. The plants that were salinity-stressed and sprayed with 0.075 and 0.15 g/L ZnONPs showed a better improvement compared to the salinity-stressed plants. Also, the sprayed plants that were not stressed at all showed promising results compared to the control and the other different treatments. Through the process of molecular docking, it was shown that caffeic acid, ferulic acid, p-coumaric acid, sinapic acid, and apigenin-7-glucoside are essential chemicals that possess antibacterial and antifungal effects against the DNA Gyrase inhibitor and the sterol 14-alpha demethylase (CYP51) enzyme, respectively. It is concluded that salt stress can negatively affect the growth, quality, and variant plant features. However, the foliar application of ZnONPs is able to overcome those adverse effects in the stressed plants, and enhance the non-stressed as well. 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

Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article

Due to the neuroprotective and antioxidant properties, phenylethanoid glycosides (PhGs) are valuable plant-derived compounds. Traditional extraction methods are constrained by low yields and limited resources, prompting the integration of synthetic biology and enzyme engineering technologies for sustainable production. This review summarizes the advances in the microbial synthesis of PhGs, emphasizing the elucidation of biosynthetic pathways, enzyme engineering modifications of glycosyltransferases and acyltransferases, and strategies for optimizing microbial cell factories in Escherichia coli and Saccharomyces cerevisiae. Significant advancements encompass the efficient synthesis of verbascoside and echinacoside in S. cerevisiae, as well as the comprehensive elucidation of the echinacoside biosynthetic pathway in Cistanche spp., including the identification of key steps catalyzed by a rhamnosyltransferase, a CYP450 hydroxylase, and a terminal glucosyltransferase that enable pathway reconstruction in S. cerevisiae. We conduct a systematic analysis of methods to address the biosynthetic bottlenecks via protein engineering, including rational design and directed evolution, as well as the metabolic engineering strategies such as precursor enhancement and cofactor recycling. Additionally, we investigate the synthesis of non-natural PhG analogues and the prospective integration with AI-assisted design, emphasizing the significant potential of microbial systems in overcoming the supply challenges for medicine-food homologous ingredients. Full article

Low temperature during early spring severely impairs maize germination, leading to significant yield losses. To elucidate the mechanisms underlying cold tolerance at the germination stage, we compared two cold-tolerant maize inbred lines (AM and CM) with a cold-sensitive line (BM) under control (25 °C) and chilling (6 °C) conditions. Phenotypic observations showed that AM and CM maintained high germination rates and exhibited enhanced coleoptile elongation under cold stress, whereas BM displayed substantial growth inhibition. Cold-tolerant lines accumulated less malondialdehyde and showed markedly higher SOD and POD activities, indicating a stronger antioxidant defense. Transcriptome profiling revealed that cold tolerance is associated with a more robust transcriptional response in AM and CM, characterized by significant activation of the phenylpropanoid and flavonoid biosynthesis pathways. Among the differentially expressed genes, the class III peroxidase gene ZmPER5 was strongly upregulated in AM and CM but only weakly induced in BM, suggesting its central role in reinforcing the cell wall structure and enhancing ROS-scavenging capacity under chilling conditions. Other lignin- and flavonoid-related genes, including ZmHCT4 and ZmCYP75, also exhibited genotype-specific induction patterns consistent with cold tolerance. qRT-PCR validation confirmed the RNA-seq expression trends. These results demonstrate that maize cold tolerance during germination relies on the coordinated enhancement of antioxidant enzyme activity, activation of phenylpropanoid-derived lignin biosynthesis, and accumulation of protective flavonoids. The identified candidate genes, especially ZmPER5, provide valuable targets for improving cold tolerance in maize breeding. 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

AflatoxinB1 (AFB1) is a hepatotoxic mycotoxin whose bioactivation by cytochrome P450 (CYP450) enzymes generates reactive metabolites that drive oxidative stress, inflammation, and apoptosis. Propolis is a bee-derived product with antioxidant and immunomodulatory properties. To investigate whether propolis supplementation attenuates AFB1-induced hepatic injury by modulating inflammatory mediators, Nrf2–HO-1 signaling, mitochondrial apoptosis, and CYP450 expression in rats, twenty-four male Sprague-Dawley rats were randomly allocated to four groups (n = 6): control, AFB1 (25 µg/kg/day), propolis (250 mg/kg/day), and AFB1 + propolis. Treatments were given by oral gavage for 28 days. Hepatic IL-1β, IL-6, TNF-α, Nrf2 and HO-1 levels were measured by ELISA. Histopathology was assessed on H&E-stained sections. Bax, Bcl-2, caspase-3, CYP1A2, CYP3A4, CYP2C19 and cytochrome P450 reductase expressions were evaluated immunohistochemically and quantified by ImageJ. Data were analyzed using one-way ANOVA with Tukey’s post hoc test. AFB1 significantly increased hepatic IL-1β and IL-6 and reduced Nrf2 levels, while propolis supplementation restored Nrf2, elevated HO-1 and significantly lowered IL-6 compared with AFB1 alone (p < 0.05). AFB1 induced marked hydropic degeneration, sinusoidal congestion, and mononuclear infiltration, alongside increased Bax and caspase-3 and decreased Bcl-2 expression; these changes were largely reversed in propolis-treated groups. AFB1 upregulated CYP1A2, CYP3A4 and cytochrome P450 reductase, whereas propolis co-treatment significantly suppressed their expression without affecting CYP2C19. Propolis supplementation attenuated AFB1-induced liver injury through coordinated anti-inflammatory, antioxidant, anti-apoptotic and metabolic regulatory effects, notably via restoration of Nrf2–HO-1 signaling and down-regulation of key CYP450 isoenzymes. Propolis may represent a promising natural dietary strategy against AFB1-associated hepatotoxicity, warranting further translational research. Full article

Cytochrome P450 (CYP450) monooxygenases are a class of enzymes containing conserved heme-binding functional domain. They contribute to a wide range of biosynthetic processes, serving a pivotal function in plant resistance to abiotic stress. To date, little is known about the CYP450s of Chlamydomonas reinhardtii. In our study, a total of 37 crP450 genes were identified from C. reinhardtii based on domain and sequence alignment, unevenly distributed on 12 chromosomes with 4 pairs of tandem replications shared among family members. Most of these genes contained 10 or more introns and encoded CYP450 proteins with an average of 593 amino acids and 3–9 conserved motifs. CYP450 enzymes were mainly distributed in the chloroplasts, cytoplasms, mitochondria, and cytoplasmic membranes. There were numerous light, jasmonic acid, abscisic acid, and salicylic acid response elements located in the upstream of gene coding sequences, suggesting that these genes could be modulated by plant hormones. Transcriptome analysis uncovered distinct expression patterns of crP450 genes under various stress conditions, with the 37 crP450 genes grouped into 9 clusters. In summary, this study presented a genome-wide characterization of CYP450 genes in C. reinhardtii, providing a strong foundation for further exploration into their biological functions. 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

Root rot disease severely threatens tropical fruit production, leading to plant mortality and reduced yields; however, the mechanisms of host defense responses and pathogen infection remain poorly understood. In this study, Fusarium acutatum was isolated from diseased Annona squamosa roots and identified through morphological features and ITS phylogeny (99.8% identity). Infection triggered a marked activation of antioxidant defenses, with elevated POD, SOD, PAL, PPO, and CAT activities. Transcriptomic and TMT-based quantitative proteomic analyses identified 23,791 and 74,403 differentially expressed genes (DEGs) and 367 and 609 differentially expressed proteins (DEPs) in root at 5 and 10 days post inoculation, respectively, relative to the control. These DEGs and DEPs were consistently enriched in pathways involving redox regulation, protein synthesis and processing, ubiquitin-mediated proteolysis, phenylpropanoid and flavonoid metabolism, cell wall remodeling, plant–pathogen interaction and MAPK signaling. Integrated transcriptomic–proteomic correlation analysis showed clear positive associations between key defense-related genes and proteins, suggesting that phenylpropanoid metabolism and reactive oxygen species (ROS) scavenging play central roles in resistance. Key genes such as CHI2, CHS, and CYP were strongly induced and validated by qPCR, supporting coordinated activation of the defense systems. Furthermore, F. acutatum exhibited upregulation of 50 pathogenic-related proteins, including 4 cell wall-degrading enzymes (e.g., CBH1, pectate lyase), 5 metabolic regulation or signal transduction enzymes (e.g., gabD, TPI, and ENO) and 3 potential effectors, suggesting coordinated pathogen strategies for host colonization. Collectively, this study provides comprehensive multi-omics insight into the molecular mechanisms underlying A. squamosa defense against F. acutatum and offers candidate targets supported by omics evidence, serving as a theoretical reference for the management of root rot. Full article

Background: Genetic studies have found that a germline BRCA1 gene mutation is the origin of highly increased cancer risk. Clinical studies have suggested that increased cancer risk in type-2 diabetes may be attributed to unhealthy lifestyle factors and bad habits. Purpose: Patients with either BRCA1 gene mutation or type-2 diabetes similarly exhibit increased cancer risk, insulin resistance, and fertility disorders. It was suggested that these three alterations derive from a common genomic failure, and its recognition may shed light on the unsolved secret of cancer. Results: (1) Germline mutations on ESR1, BRCA1, and CYP19A genes encoding estrogen receptor alpha (ERα), genome safeguarding BRCA1 protein, and CYP19 aromatase enzyme cause genomic instability. BRCA1 and ESR1 gene mutations specifically cause breast cancer, while error in the CYP19A gene leads to cancers in the endometrium, ovaries, and thyroid. (2) ERα, BRCA1, and CYP19 aromatase proteins are transcription factors creating the crucial DNA stabilizer circuit driven by estrogen regulation. Liganded ERα drives a second regulatory circuit to also control cell proliferation, in partnership with various growth factors. In a third regulatory circuit, liganded ERα drives cellular glucose supply in close interplay with insulin, IGF-1, and glucose transporters. (3) Impaired expression or activation of each transcription factor of the triad leads to defective estrogen signaling and endangers regular cell proliferation, insulin sensitivity, and fertility. (4) Impaired estrogen signaling caused by either genetic or lifestyle factors alarms the hypothalamus, which issues neural and hormonal commands throughout the body to restore estrogen signaling. (5) When the compensatory actions cannot restore estrogen signaling, the breakdown of genomic regulation leads to cancer initiation. (6) Lifestyle factors that upregulate estrogen signaling decrease cancer risk, while downregulating estrogen signaling increases it. Conclusions: Increased cancer risk, insulin resistance, and infertility all originate from defective estrogen signaling. Full article

Backgrounds: While the conditionally essential amino acid taurine is known to confer hepatoprotection against injury through anti-inflammatory and antioxidant mechanisms, it remains unclear whether it plays an active role in the process of hepatocarcinogenesis. Emerging research portrays taurine as a double-edged sword in oncology, with its capacity to either inhibit or facilitate carcinogenesis being contingent upon the specific tumor microenvironment. Objectives: Investigating the effect of taurine on hepatocellular carcinoma progression and its underlying mechanisms. Methods: A hydrodynamic tail vein injection (HDT) model of primary hepatocellular carcinoma was established in mice to validate the effects of taurine and its downstream bile acid synthesis pathway on liver cancer progression. Subsequent RNA sequencing analysis was performed to investigate the molecular pathways through which taurine exerts its functions. Results: Supplementation of taurine or overexpression of its transporter SLC6A6 significantly accelerated HCC development in vivo. Inhibition of taurine transporter abrogated the tumor-promoting effects of the bile acid synthesis enzymes CYP7A1 and BAAT. This suppression may be mediated through the blockade of the cell cycle, p53 signaling pathway and metabolic pathways. Conclusions: Our findings demonstrate that taurine plays a vital role in the tumor-promoting activities of HCC. 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