Search Results (3,746)

The clinical use of 1,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D₃, is limited by its calcemic side effects and rapid metabolic degradation. To overcome these limitations, we designed novel vitamin D analogs with extended, rigidified, and branched side chains. Among them, PRI-1938, featuring a 5,6-trans triene system and 22,24-all-trans side-chain geometry, demonstrated markedly enhanced resistance to enzymatic catabolism. In vitro assays revealed that metabolic conversion of PRI-1938 by the nonselective cytochrome P450 3A4 (CYP3A4) enzyme was ca. 4-fold lower than that of the previously obtained PRI-1906 and over 9-fold lower than 1,25D3. All new analogs, including PRI-1927 and PRI-1937, exhibited significantly higher stability toward mitochondrial cytochrome P450 24A1 (CYP24A1), the vitamin D-selective catabolic enzyme, than that of 1,25D3. Molecular modeling and quantum mechanical calculations indicated that PRI-1938 adopts a highly stable conformation in the CYP24A1 active site, stabilized by four hydrogen bonds and multiple hydrophobic interactions. The spatially optimized interaction network reduces access to the catalytic heme, resulting in the lowest observed metabolic conversion. These findings highlight the critical role of the side-chain geometry in modulating metabolic stability and support the further development of PRI-1938 as a promising anticancer vitamin D analog. Full article

Although significant advances in the treatment of breast cancer have been made over the last few decades, searching for more effective prophylaxis and therapy for this type of cancer is still topical. Orphan cytochromes (CYPs) P450 are enzymes whose functions and substrates are not fully known. The overexpression of some orphan CYPs in breast cancer tissue warrants attention as a possible breast cancer prophylaxis/treatment target or biomarker. Of particular interest is CYP4Z1, which seems to be specific for breast cancer, including triple-negative breast cancer (TNBC). The currently available data indicate that inhibition of CYP4Z1 breast-specific expression may reduce the growth, progression, angiogenesis, and invasiveness of breast cancer. Although less specific, the other orphan CYPs, such as CYP2W1, CYP2S1, CYP2U1, and CYP4X1, exhibit significantly higher expression in breast tumors compared to normal tissues. The available data indicate that these CYP isoforms catalyze the hydroxylation of fatty acids. Their products, such as epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs), are considered critical modulators of cancer progression. Therefore, inhibition of the expression and activity of these orphan CYPs might be more useful in cancer treatment than in prophylaxis. This review summarizes current knowledge of orphan CYPs in breast tissue and their possible application in drug targeting or prognosis assessment. Full article

While immunophilins are well-recognized therapeutic targets, several members of this family of peptidyl-proline isomerases (PPIases) have yet to be subjected to ligand discovery efforts. In this study, we demonstrate a cost-effective means to identify ligands to the insufficiently investigated two-domain PPIase human Cyclophilin40 (Cyp40). Central to this effort was the use of beads, wherein a confocal nanoscanning (CONA) approach was used to rapidly probe candidates. Here, we describe how one can adapt the physical nature of microsized beads as a means to strategically reduce cost and ultimately make the discovery of small molecule hit and lead compounds more accessible to everyone irrespective of financial status (democratization). Full article

Cytochrome P450 enzymes (CYPs) are crucial catalysts responsible for the oxidative modification of diverse substrates, including plant hormones, antioxidants, and compounds involved in abiotic stress responses. While CYP functions in drought and salt stress adaptation have been extensively studied, their contribution to alkaline stress tolerance, particularly concerning specific cytochrome P450 genes in wild soybean (Glycine soja), remains less explored. In this study, a cytochrome P450 gene, GsCYP93D1, was identified and isolated, and its regulatory role under alkaline stress was elucidated. Transgenic GsCYP93D1 increased Arabidopsis and soybean hairy root resistance to alkaline stress, but the Arabidopsis atcyp93d1 mutant showed a reduced capacity for alkaline tolerance. Subsequent investigation showed the enhanced antioxidant defense capabilities of GsCYP93D1 transgenic plants, as evidenced by reduced superoxide radical (O₂⁻) production under exposure to alkaline stress. Furthermore, compared to the atcyp93d1 mutant, transgenic lines of GsCYP93D1 showed sensitivity to ABA. Moreover, transcript levels of genes associated with alkaline stress response and ABA signaling pathways were elevated in both GsCYP93D1 transgenic and mutant lines. Collectively, our findings demonstrate that GsCYP93D1 positively modulates plant tolerance to alkaline stress and enhances ABA sensitivity. Full article

Excessive alcohol consumption is associated with various health complications, including liver damage and systemic inflammation. Probiotic interventions have emerged as promising strategies to mitigate alcohol-induced harm, yet their mechanisms of action remain incompletely understood. This randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the protective effects of Weizmannia coagulans BC179 in chronic alcohol consumers. Seventy participants with a history of long-term alcohol intake were randomly assigned to receive either BC179 (3 g/day, 1 × 10¹⁰ CFU) or a placebo for a 30-day intervention period. Following alcohol ingestion, dynamic monitoring of blood alcohol concentration (BAC), inflammatory and oxidative stress biomarkers, and serum metabolomic profiles was conducted. BC179 supplementation significantly reduced BAC and enhanced the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), while decreasing levels of alkaline phosphatase (ALP), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Conversely, the anti-inflammatory cytokine interleukin-10 (IL-10), superoxide dismutase (SOD), and glutathione (GSH) were significantly upregulated. Levels of cytochrome P4502E1 (CYP2E1) and malondialdehyde (MDA) were also markedly reduced. Metabolomic analysis revealed significant modulation of taurine and hypotaurine metabolism, as well as downregulation of caffeine-related pathways. Collectively, these findings indicate that W. coagulans BC179 alleviates alcohol-induced discomfort by enhancing alcohol metabolism, attenuating inflammation, reducing oxidative stress, and modulating key metabolic pathways. This probiotic strain may represent a promising adjunctive strategy for managing alcohol-related health issues. Full article

Neospora caninum, as well as Toxoplasma gondii, secrete proteins that facilitate the invasion of host cells and the regulation of host immune response and metabolism. However, the localization of the secretory proteins in infected animal brains has not been studied in detail. Here, we investigate the brain and intracellular distribution of the secretory proteins in experimentally infected mice and naturally infected calves through histopathology and immunohistochemistry (IHC) to detect surface antigen 1 (NcSAG1), cyclophilin (NcCYP), profilin (NcPF), dense granule protein 6 (NcGRA6), and NcGRA7. These methods revealed that numerous tachyzoites positive for NcSAG1, NcCYP, NcPF, NcGRA6, and NcGRA7 were localized in and around the animals’ necrotic lesions, and NcGRA7 was diffusely observed in the necrotic lesions of the infected mice. Moreover, IHC revealed that NcGRA6 and NcGRA7 were distributed in the cytoplasm of infected neurons around the parasites in the infected mice and calves. This suggests that NcGRA6 and NcGRA7 might be directly related to the alteration of neuronal metabolism and activity, and that NcGRA7 might be related to the formation of necrotic lesions. Full article

The increasing demographic aging of society is a great challenge to the healthcare sector and raises the socio-economic burden. Therefore, elucidating the mechanisms of aging and developing safe effective anti-aging products to prolong people’s healthy lifespan are paramount nowadays. Panax ginseng has been highly regarded since ancient times for its ability to enhance health and prolong life. However, its main active substances of anti-aging and their mechanisms are not fully understood. In this research, Caenorhabditis elegans was used as a model organism to explore and confirm the key active substances from Panax ginseng and the mechanisms that exert anti-aging effects. Various ginsenoside compounds were evaluated based on longevity, anti-stress, physiological function, etc. Ginsenoside Re, which has powerful anti-aging activity, was screened. In the follow-up trials, transcriptomics and RT-qPCR techniques were used to investigate the mechanism of Re in exerting its anti-aging properties. Differential genes were enriched in the Insulin/Insulin-like Growth Factor-1 Signaling (IIS) pathway, the neuropeptide signaling pathway, and lipid metabolism. A significant increase in the expression levels of daf-16, sgk-1, skn-1, hsf-1, hsp-16.2, sod-3, gst-4, fil-2, lips-11, cyp-35A4, and aex-2 genes, and a significant decrease in the expression levels of daf-2, age-1, and akt-2 genes were verified. These suggest that ginsenoside Re exerts its life-extending influence by regulating lipid metabolism and the IIS pathway. Full article

Cytochrome P450 monooxygenases (P450s) are one of the most widespread enzyme superfamilies in the biological world. In insects, P450 proteins play a crucial role in the synthesis of endogenous substances and the metabolism of xenobiotics. To date, extensive research has been conducted on P450 gene-mediated detoxification and metabolism across multiple insect species. While Chironomidae species—dominant benthic organisms inhabiting diverse ecological niches and playing critical ecological roles—remain largely uncharacterized in terms of P450 protein annotation, with the exception of a single study on Propsilocerus akamusi. In this study, we expanded the annotation scope by identifying the P450 protein genes in eight additional Chironomidae species. A total of 577 P450 protein genes were annotated across the eight species, which could be classified into the following four distinct clans: 50 belonging to the CYP2 clan, 258 to the CYP3 clan, 198 to the CYP4 clan, and 71 to the Mito clan. Phylogenetic analysis using Drosophila melanogaster as an outgroup revealed that the CYP2 clan and the Mito clan are highly conserved during evolution, while the CYP3 clan and the CYP4 clan have undergone significant expansion. Most P450 proteins in Chironomidae species exhibit clear orthologous relationships with their D. melanogaster counterparts. Our research contributes to a better understanding of the evolutionary processes and the physiological functions of P450 proteins in Chironomidae species and lays the foundation for elucidating the role of P450 in environmental adaptability among the Chironomidae species inhabiting diverse habitats. Full article

Context and objective: Post-amputation pain (PAP) is an umbrella term that includes residual limb pain (RLP) and phantom limb pain (PLP), posing a significant challenge to recovery and quality of life after limb loss. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has gained interest for its potential to manage PAP, particularly in refractory cases. This narrative review explores the efficacy of ketamine for PAP and the emerging role of pharmacogenomics in guiding its use. Methods: A literature review of PubMed, Embase, and Cochrane databases was conducted, focusing on clinical trials, systematic reviews, and genetic influences on ketamine metabolism and response. Studies suggest that perioperative ketamine can reduce PAP severity and opioid use. However, outcomes vary, with some patients experiencing transient relief and others achieving prolonged benefit. Results: This variability may be linked to genetic differences in CYP2B6, CYP3A4/5, COMT Val158Met, SLC6A2, and KCNS1, which affect ketamine’s metabolism, efficacy and side effect profile. Understanding these pharmacogenomic factors could enable more personalized and effective ketamine therapy. Conclusion: Despite its promise, inconsistent dosing regimens and limited integration of genetic data hinder standardization. Further research into genotype-guided ketamine protocols may improve treatment outcomes and support precision analgesia in amputee care. Full article

Background/Objectives: DNA methylation is a critical epigenetic mechanism involved in gene expression regulation. This study examines promoter methylation of CYP2E1 in healthy liver, intestinal mucosa, as well as pathological liver samples, alongside in in vitro cell models. Methods: First, in tissue samples from the liver, duodenum, jejunum, and colon of healthy organ donors, CYP2E1 promoter methylation was quantified using the EpiTect Methyl II PCR System, while gene expression was determined by quantitative real-time PCR. Then, in vitro experiments were performed using HepG2 and Caco-2 cell lines. Cells were treated with 5-Aza-2′-deoxycytidine to induce demethylation, with subsequent analysis of CYP2E1 mRNA levels. Subsequently, promoter methylation was assessed via pyrosequencing, while gene expression was quantified using quantitative real-time PCR. Results: The analysis revealed statistically significant differences in the methylation patterns of the CYP2E1 promoter between healthy liver and gastrointestinal tissues. In cell lines, treatment with 5-Aza-2′-deoxycytidine resulted in increased CYP2E1 mRNA levels and demonstrated a strong negative correlation between promoter methylation and gene expression. However, in liver disease samples, differential methylation did not consistently translate into decreased CYP2E1 expression. Conclusions: Although in vitro experiments support a regulatory role of promoter methylation in controlling CYP2E1 expression, the clinical data indicate that additional factors may contribute to gene regulation in liver pathology. Full article

Background: Accurate assessment of CYP2C induction-mediated drug–drug interactions (DDIs) remains a challenge, despite the importance of CYP2C enzymes in drug metabolism. Limitations in available models and scarce clinical induction data have hampered quantitative preclinical DDI risk evaluation. Methods: In this study, the authors utilized an all-human hepatocyte triculture system to capture CYP2C induction using the perpetrators rifampicin, efavirenz, carbamazepine, and apalutamide. In vitro induction parameters were quantified by measuring changes in both mRNA and enzyme activities for CYP2C8, CYP2C9, and CYP2C19. These induction parameters, along with CYP-specific intrinsic clearance (CL_int) for the victim compounds, were incorporated into a physiologically based pharmacokinetic (PBPK) model, and pharmacokinetics (PK) of known CYP2C substrates were predicted with and without co-administration of perpetrator compounds using clinical dosing regimens. The results were quantitatively compared with the currently utilized mechanistic static modeling (MSM) approach and the reported clinical DDI outcomes. Results: By incorporating the measured f_m of CYP2C substrates into PBPK modeling, we observed a lower propensity to over- or underpredict the exposure of these substrates as victims of CYP2C induction-based DDIs when co-administered with known perpetrators, which resulted in an excellent correlation to observed clinical outcomes. The MSM approach predicted the CYP3A4 induction-based DDI risk accurately but could not capture CYP2C induction with similar precision. Conclusions: Overall, this is the first study that demonstrates the utility of PBPK modeling as a complementary approach to MSM for CYP2C induction-based DDI risk assessment. Full article

(1) Objective: This study aimed to systematically elucidate the molecular mechanisms by which gypenosides (GP), a major active component of Gynostemma pentaphyllum, ameliorate hypercholesterolemia by modulating the hepatic steroidogenesis pathway, and to identify key therapeutic targets. (2) Methods: We established a high-fat diet (HFD)-induced hypercholesterolemia (HC) mouse model and performed GP intervention. An integrated multi-omics approach, combining transcriptomics and proteomics, was utilized to comprehensively analyze GP’s effects on the expression of genes and proteins associated with hepatic cholesterol synthesis, transport, and steroid hormone metabolism. (3) Results: HFD induced significant dysregulation, with 48 steroidogenesis pathway-related genes and 35 corresponding proteins exhibiting altered expression in HC mouse livers. GP treatment remarkably reversed these HFD-induced abnormalities, significantly restoring the expression levels of 42 genes and 14 proteins. Multi-omics integration identified seven critical genes/proteins—Cyp3a25, Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk—that were consistently and significantly regulated by GP at both transcriptional and translational levels. Furthermore, correlation analyses demonstrated that Cyp3a25 was significantly negatively correlated with serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), whereas Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk showed significant positive correlations. (4) Conclusions: GP effectively ameliorates cholesterol dyshomeostasis through a multi-targeted mechanism in the liver. It inhibits endogenous cholesterol synthesis by downregulating key enzymes (Hmgcs1, Fdft1, Pmvk, Mvd, Fdps, Tm7sf2), promotes cholesterol efflux and transport (upregulating Abca1, ApoB), and accelerates steroid hormone metabolism (upregulating Cyp3a11, Cyp3a25). These findings provide robust scientific evidence for the development of GP as a safe and effective novel therapeutic agent for hypercholesterolemia. Full article

Background/Objective: Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool for predicting pharmacokinetics (PK) to support drug development and precision medicine. However, it has not been established for non-renal clearance pathways in patients with end-stage renal disease (ESRD), a population that bears heavy medication burden and is thereby at high risk for drug–drug–disease interactions (DDDIs). Furthermore, the pronounced inter-individual variability in PK observed in ESRD patients highlights the urgent need for individualized PBPK models. Methods: In this study, we developed a PBPK population model for ESRD patients, incorporating functional changes in key drug-metabolizing enzymes and transporters (DMETs), including CYP3A4, OATP1B1/3, P-gp, and BCRP. The model was initially constructed using the recalibrated demographic and physiological parameters of ESRD patients. Then, we used five well-validated substrates (midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin) and their corresponding PK profiles from ESRD patients taking a microdose cocktail regimen to simultaneously estimate the abundance of all these DMETs. Lastly, machine learning was employed to identify potential factors influencing individual clearance. Results: Our study suggested a significant reduction in hepatic OATP1B1/3 (75%) and intestinal P-gp abundance (34%) in ESRD patients. Ileum BCRP abundance was estimated to increase by 100%, while change in hepatic CYP3A4 abundance is minimal. Notably, simulations of drug combinations revealed potential DDDI risks that were not observed in healthy volunteers. Machine learning further identified Clostridium XVIII and Escherichia genus abundances as significant factors influencing dabigatran clearance. For rosuvastatin, aspartate aminotransferase, total bilirubin, Bacteroides, and Megamonas genus abundances were key influencers. No significant factors were identified for midazolam, pitavastatin, or atorvastatin. Conclusions: Our study proposes a feasible strategy for individualized PK prediction by integrating PBPK modeling with machine learning to support the development and precise use of the aforementioned DMET substrates in ESRD patients. Full article

Despite significant medical advancements, two major health challenges persist: antibiotic resistance in microbial pathogens and drug resistance in cancer cells. To address these issues, research has increasingly focused on discovering novel natural compounds with dual antimicrobial and anticancer activities. Among such candidates, antimicrobial peptides (AMPs) have attracted attention due to their ability to selectively target microbial and cancer cells while exhibiting minimal toxicity toward normal cells. Although Vietnam possesses rich biodiversity, including a wide range of Anura species, studies on AMPs from these organisms remain limited. In this study, a novel AMP, brevinin-1 E8.13, was identified from the skin secretion of Sylvirana guentheri, a frog species native to Vietnam. The brevinin-1 E8.13 peptide was successfully cloned, sequenced, and chemically synthesized. Functional assays revealed that brevinin-1 E8.13 possesses strong antibacterial activity against Staphylococcus aureus and exerts significant antiproliferative effects on various human cancer cell lines, including A549 (lung), AGS (gastric), Jurkat (leukemia), HCT116 (colorectal), HL60 (leukemia), and HepG2 (liver). The peptide demonstrated moderate to potent cytotoxic activity, with IC₅₀ values ranging from 7.5 to 14.8 μM, depending on the cell type. Notably, brevinin-1 E8.13 exhibited low cytotoxicity toward normal human dermal fibroblast (HDF) cells and even promoted cell proliferation at lower concentrations. Furthermore, Chemically Activated Fluorescent Expression (CAFLUX) bioassay results confirmed that the peptide significantly downregulated Cyp1a1 gene expression in HepG2 cells. Collectively, these findings highlight the therapeutic potential of brevinin-1 E8.13 as a dual-function antimicrobial and anticancer agent derived from the skin secretion of Sylvirana guentheri. Full article

This study investigates the use of food supplements (FS) among polymedicated elderly individuals and assesses potential FS–drug interaction risks. A total of 98 community-dwelling older adults were surveyed and 18.4% reported FS use. FS were mostly used for musculoskeletal and cognitive support, with 71% having potential metabolic interactions via CYP enzymes or P-glycoprotein. Monthly costs reached €55. The findings reveal a complex interaction landscape and financial burden, underscoring the need for medication reviews and health literacy efforts to ensure safer FS use in older adults. This study aligns with One Health principles by linking clinical, social, and economic aspects of aging. Full article