Search Results (1,270)

Acne vulgaris is a chronic inflammatory dermatosis where conventional therapies often face limitations in efficacy and safety, necessitating the development of microbiome-targeted interventions. This study investigated the immunomodulatory potential of microbiome-derived tryptophan metabolites as a novel therapeutic strategy for Cutibacterium acnes (C. acnes)-induced inflammation, focusing on the aryl hydrocarbon receptor (AHR) pathway. We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. acnes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model. In vitro, ILA and IPA significantly suppressed C. acnes-driven inflammatory mediators, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, and Cyclooxygenase-2 (COX2), whereas IAA demonstrated limited efficacy. In vivo, ILA treatment exhibited superior therapeutic activity, markedly reducing inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression. Transcriptomic analysis confirmed that ILA attenuates inflammatory signaling (e.g., IL-17 and TNF pathways) while upregulating AHR-responsive genes such as Cytochrome (CYP) 1A1 and CYP1B1. Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical formulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management. Full article

Thamnaconus septentrionalis is an emerging commercially important aquaculture species in China, distributed extensively in the Indo-West Pacific Ocean. Recently, because of the seriously declining population and considerable economic potential of this aquaculture fish, increasing attention has been paid to the conservation and development of T. septentrionalis. Artificial fish breeding is essential and has become progressively implemented on local farms in China, which benefits the protection of T. septentrionalis resources and facilitates the development of its fishery industry. Previous studies have demonstrated that temperature could significantly influence ovary development in T. septentrionalis. However, the potential molecular mechanisms underlying the influence of temperature on testis development in T. septentrionalis have been scarcely studied. Thus, this study comprehensively explores the effects of temperature on testis development in T. septentrionalis using histological observation and transcriptomic techniques. Histological and transmission electron microscopy analyses indicated that T. septentrionalis testes, undergoing a rise in temperature, developed from phase III to IV. Transcriptomic analysis identified 315 differentially expressed genes, including 200 upregulated and 115 downregulated genes. Moreover, rising temperatures may enhance testis development by regulating steroid hormone biosynthesis, cellular senescence, and nucleotide metabolism. The upregulation of four genes (hsd11b2, cyp11b, cyp11a, and hsd17b3) involved in the steroid hormone biosynthesis process may significantly contribute to the increased level of testosterone and 11-keto-testosterone. This study is the first to elucidate the potential molecular mechanism involved in T. septentrionalis testis development induced by temperature, offering valuable and novel insights for its artificial breeding and fishery resources conservation. Full article

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

Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include (1) enhanced activity of anticancer drug efflux mechanisms (MRP1); (2) suppressed activity of anticancer drug influx mechanisms (ENT-1); (3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); (4) influence of the tumor microenvironment (GRP94), etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan–Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group, n = 1, 5%: AKR1B1(+)/AKR1B10(−), 5-year overall survival (OS), 100%; Intermediate prognosis-1 group, n = 9, 5%: AKR1B1(−)/AKR1B10(−) plus MRP1(−), 5-year OS, 68%; Intermediate-2 prognosis group, n = 6.3%: AKR1B1(−)/AKR1B10(−) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; and Poor prognosis group, n = 3, 16%: AKR1B1(−)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n = 2. Conclusions: The Urayasu classification for ALL is considered reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy. Full article

Background/Objectives: Flavonoids are widely used as lead structures in drug discovery, and their pharmacological and metabolic properties are strongly influenced by structural features such as positional isomerism. This study aimed to compare the metabolic profiles and underlying mechanisms of two isoflavone-based positional isomers, ACF-02 (2-(4-hydroxy-3-methoxyphenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-4H-chromen-4-one) and ACF-03 (2-(3-hydroxy-4-methoxyphenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-4H-chromen-4-one). Methods: The metabolic pathways of synthetically prepared ACF-02 and ACF-03 were investigated using an in vitro incubation system with human liver microsomes (HLMs) supplemented with an NADPH-regenerating system, followed by liquid chromatography–high-resolution tandem mass spectrometry (LC–HRMS/MS) analysis. Metabolites were identified based on LC–HRMS/MS data and molecular networking-based node connectivity with the parent compounds. Major metabolites were further characterized by CYP phenotyping using recombinant CYP450 isoforms, and the potential for drug–drug interactions of ACF-03 was evaluated using a CYP probe substrate cocktail approach. Results: HLM incubation of ACF-02 and ACF-03 produced both hydroxylated and O-demethylated metabolites, with O-demethylation as the predominant pathway; notably, the most abundant O-demethylated metabolite differed in an isomer-dependent manner, occurring at the B₂ ring for ACF-02 and at the A ring for ACF-03, with distinct CYP isoform involvement. Molecular networking supported the relationships between the parent compounds and their metabolites, and both compounds exhibited relatively high metabolic stability with limited CYP inhibition. Conclusions: Despite differing only in the position of a single methyl substituent, ACF-02 and ACF-03 exhibited distinct isomer-dependent metabolic profiles. These findings demonstrate that even subtle positional isomerism can significantly influence metabolic behavior and should be carefully considered during lead optimization and drug design. 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

Salvia miltiorrhiza Bunge is a traditional Chinese medicinal plant whose roots are rich in water-soluble phenolic acids. Rosmarinic acid and salvianolic acid B are representative components that confer antibacterial, antioxidant, and cardio-cerebrovascular protective activities. However, these metabolites often accumulate at low and unstable levels in planta, which limits their efficient development and use. This review summarises recent advances in understanding salvianolic acid biosynthesis and its transcriptional regulation in S. miltiorrhiza. Current evidence supports a coordinated pathway composed of the phenylpropanoid route and a tyrosine-derived branch, which converge to generate rosmarinic acid and subsequently more complex derivatives through oxidative coupling reactions. Key findings on transcription factor families that fine-tune pathway flux by regulating core structural genes are synthesised. Representative positive regulators such as SmMYB111, SmMYC2, and SmTGA2 activate key nodes (e.g., PAL, TAT/HPPR, RAS, and CYP98A14) to promote phenolic acid accumulation. Conversely, negative regulators such as SmMYB4 and SmMYB39 repress pathway genes and/or interfere with activator complexes. Major regulatory features include hormone-inducible signalling, cooperative regulation through transcription factor complexes, and emerging post-transcriptional and post-translational controls. Future directions and challenges are discussed, including overcoming regulatory redundancy and strong spatiotemporal specificity of transcriptional control. Integrating spatial and single-cell omics with functional genomics (e.g., genome editing and rational TF stacking) is highlighted as a promising strategy to enable predictive metabolic engineering for the stable, high-yield production of salvianolic acid-type compounds. Full article

In today’s world, unhealthy living habits have contributed to the rise in metabolic disorders like hyperlipidemia. Recognized as a popular edible and medicinal mushroom in China and various eastern nations, Ganoderma lucidum is a promising high-value functional and medicinal food with multiple biological activities. Our earlier research has demonstrated that G. lucidum polysaccharides (GLP) showed distinct lipid-lowering abilities by enhancing the response to oxidative stress and inflammation, adjusting bile acid production and lipid regulation factors, and facilitating reverse cholesterol transport through Nrf2-Keap1, NF-κB, LXRα-ABCA1/ABCG1, CYP7A1-CYP27A1, and FXR-FGF15 pathways, hence we delved deeper into the effects of GLP on hyperlipidemia, focusing on its structural characterization, gut microbiota, and fecal metabolites. Our findings showed that GLP changed the composition and structure of gut microbiota, and 10 key biomarker strains screened by LEfSe analysis markedly increased the abundance of energy metabolism, and cell growth and death pathways which were found by PICRUSt2. In addition, GLP intervention significantly altered the fecal metabolites, which enriched in amino acid metabolism and lipid metabolism pathways. The results of structural characterization showed that GLP, with the molecular weight of 12.53 kDa, consisted of pyranose rings and was linked by α-type and β-type glycosidic bonds, and its overall morphology appeared as an irregular flaky structure with some flecks and holes in the surface. Collectively, our study highlighted that the protective effects of GLP were closely associated with the modification of gut microbiota and the regulation of metabolites profiles, thus ameliorating dyslipidemia. Full article

Background/Objectives: This review integrates evolutionary, metabolic, genetic, and nutritional perspectives to explain how sterol-derived vitamin D pathways shape human physiology and inter-individual variability in vitamin D status. Methods: The literature on sterol and vitamin D metabolism across animals, plants, fungi, and algae was synthesized with data from metabolomics databases, genome-wide association studies, RNA-seq resources (including GTEx), structural biology, and functional genomics. Results: Vitamin D₂ and vitamin D₃ likely emerged early in evolution as non-enzymatic photochemical sterol derivatives and were later co-opted into a tightly regulated endocrine system in vertebrates. In humans, cytochrome P450 enzymes coordinate vitamin D activation and degradation and intersect with oxysterol production, thereby linking vitamin D signaling to cholesterol and bile acid metabolism. Tissue-specific gene expression and regulatory genetic variants, particularly in the genes DHCR7, CYP2R1, CYP27B1, and CYP27A1, contribute to population-level differences in vitamin D status and metabolic outcomes. Structural analyses reveal selective, high-affinity binding of 1,25-dihydroxyvitamin D₃ to VDR, contrasted with broader, lower-affinity ligand recognition by LXRs. Dietary patterns modulate nuclear receptor signaling through distinct yet convergent ligand sources, including cholesterol-derived oxysterols, oxidized phytosterols, and vitamin D₂ versus vitamin D₃. Conclusions: Sterol and vitamin D metabolism constitute an evolutionarily conserved, adaptable network shaped by UV exposure, enzymatic control, genetic variation, and diet. This framework explains inter-individual variability in vitamin D biology and illustrates how evolutionary and dietary modulation of sterol-derived ligands confers functional flexibility to nuclear receptor signaling in human health. Full article

Hemibagrus guttatus is a large omnivorous fish of significant economic value, listed as a Class II protected species in the National Key Protected Wildlife List in 2021 in China. To provide a theoretical foundation for the artificial breeding of H. guttatus, this study employs high-throughput transcriptome sequencing of testes and ovaries to elucidate the molecular regulatory pathways involved in sex differentiation. Because H. guttatus exhibits no obvious sexual dimorphism even during the breeding season, the distinctive contribution of this study compared with previous gonadal-transcriptomic investigations in other Siluriformes lies not only in documenting sex-biased genes but also in providing a molecular foundation for developing non-lethal sex-identification methods for this morphologically indistinguishable species. A total of 303,192,896 raw reads were obtained, with an effective data rate of 98.4%, indicating high sequencing quality. Differential expression analysis identified 8694 genes, including 6369 upregulated in testes and 2325 upregulated in ovaries. Among these, 88 genes were functionally annotated as sex-related, with 62 testis-biased genes such as spata17, sox9, and dmrt1, and 26 ovary-biased genes including cyp19a, wnt8, and sox12. KEGG pathway enrichment analysis revealed that the TGF-β signaling pathway, insulin secretion, and steroid hormone biosynthesis may play crucial roles in gonadal development and differentiation in H. guttatus. The expression patterns of key genes such as hsd11b1, amh, and insl3 were validated by quantitative real-time PCR, showing consistency with the transcriptome results. These findings lay a molecular foundation for understanding the regulatory mechanisms of sex differentiation in H. guttatus, and provide candidate genes for further investigation into the genetic basis of gonadal development, which is essential for improving artificial reproduction and selective breeding practices. Full article

Background: Intestinal failure-associated liver disease (IFALD) is a serious complication in patients receiving parenteral nutrition, often exacerbated by inflammation, lipid overload, and oxidative stress. Nobiletin (NOB), a polymethoxylated flavone, is known for its anti-inflammatory and lipid-regulating properties. Methods: We employed an in vitro model using THLE-2 human hepatocytes and primary human cholangiocytes exposed to Intralipid (INT) and lipopolysaccharide (LPS) to simulate IFALD conditions. NOB was tested at non-toxic concentrations (10 and 25 µM) to assess its protective effects. MTT viability assays, multiplex bead-based immunoassays (MAGPIX), RT-qPCR, and Western blotting were used to evaluate changes in inflammation markers, gene expression, and protein signaling. Moreover, ALT and AST activities were used to assess hepatocellular injury. Results: NOB maintained high cell viability in THLE-2 hepatocytes and cholangiocytes, confirming its low cytotoxicity. NOB normalized ALT and AST activities in both tested cell lines, but the effect reached statistical significance only for ALT in cholangiocytes. Under IFALD-like conditions (LPS+INT), NOB significantly preserved metabolic activity in both cell types. In THLE-2 and cholangiocytes, NOB markedly reduced the phosphorylation of pro-inflammatory proteins JNK, NF-κB, and STAT3, indicating a broad inhibition of inflammatory signaling. Moreover, in THLE-2 cells, NOB upregulated lipid metabolism-related genes (PRKAA2, CYP7A1, and ABCA1) and decreased oxidative stress, thereby enhancing the nuclear translocation of Nrf2 and increasing SOD1 level, which supports the activation of antioxidant defenses. Conclusions: NOB exhibits hepatoprotective properties under IFALD-like conditions in vitro, likely through modulation of inflammation-related signaling and lipid metabolism pathways. Full article

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020–31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug–drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug–disease–drug interactions and glycemic risk, and inform individualized dosing strategies. 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

Transforming growth factor β (TGF-β) superfamily members are critical in teleost sex determination and differentiation. Tgfb2b is an important TGF-β ligand gene exhibiting dominant expression in the ovary of Chinese tongue sole (Cynoglossus semilaevis), yet its function in sex regulation remains unclear. In the present study, the gene expression pattern, transcriptional regulation, and knockdown effect were examined. Its expression persisted and showed a gradual increase throughout ovarian development from 3 months to 1.5 years post-hatching. In situ hybridization (ISH) revealed that the gene was distributed across oocytes at stages I–III, while scarcely detectable in the testis. The transcriptional factors CCAAT/enhancer binding protein α (C/EBPα) and Jun proto-oncogene AP-1 transcription factor subunit (c-Jun) could repress the activity of tgfb2b promoter. In vitro knockdown of tgfb2b in C. semilaevis ovarian cells led to downregulation of its downstream genes (e.g., smad1 and smad2) as well as other sex-related genes (e.g., foxl2 and esr2b). Moreover, multi-omics analysis indicated that, in C. semilaevis gonads, a miRNA named novel-m0083-3p showed an opposite expression pattern with tgfb2b and might have a binding site with the gene. By dual-luciferase assay, tgfb2b was validated to be directly targeted and suppressed by the miRNA. These results demonstrate that tgfb2b plays a significant role in ovarian differentiation and development. Further functional and molecular studies on the interplay between tgfb2b and the foxl2–cyp19a–esr axis will help elucidate the regulatory network underlying sex development in teleost. 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