Xenobiotica最新文献

1. Plantamajoside was reported to possess blood pressure-lowering effects. This study explores how plantamajoside affects the pharmacokinetics of nifedipine, providing valuable insights for clinical drug use.2. This study examined the effect of plantamajoside on nifedipine pharmacokinetics. Sprague-Dawley rats (n = 6 per group) were administered nifedipine orally, either alone or after pretreatment with plantamajoside. Blood concentrations of nifedipine were measured using liquid chromatography-tandem mass spectrometry. The effects of plantamajoside on nifedipine metabolic stability and cytochrome P450 3A (CYP3A) activity were evaluated in rat liver microsomes (RLMs).3. Co-administration of nifedipine with plantamajoside altered its pharmacokinetics, including elevated peak plasma concentration (C_max), increased area under the concentration-time curve (AUC)_(0-t), prolonged elimination half-life (t_1/2), and reduced apparent clearance (CL/F). In vitro, plantamajoside enhanced the metabolic stability of nifedipine, extending its t_1/2 and lowering intrinsic clearance. Plantamajoside also inhibited CYP3A activity in RLMs (half maximal inhibitory concentration, IC₅₀ = 13.96 μM; inhibition constant, K_i = 7.10 μM).4. The increased nifedipine exposure in rats could be attributed to the inhibition of CYP3A-mediated metabolism by plantamajoside. Given the role of orthologous CYP3A4 in humans, this interaction may enhance antihypertensive efficacy but could also increase the risk of severe hypotension clinically.

1. Norwogonin, a bioactive flavonoid with anti-inflammatory and anticancer potential. Its interactions with cytochrome P450 enzymes remain uncharacterized. This study aimed to investigate the effect of norwogonin on the activity of P450s.2. The inhibitory effects of norwogonin on P450 forms (1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) were evaluated using pooled human liver microsomes (HLMs). Dose-dependent inhibition assays (0 - 100 μM norwogonin) and time-dependent studies (0 - 30 minutes incubation) were conducted with form-specific probe substrates. Metabolites were quantified via High Performance Liquid Chromatography (HPLC).3. Norwogonin selectively inhibited 2C9, 2D6, and 3A4 (IC₅₀: 13.05 ± 4.62, 11.33 ± 2.21, and 7.52 ± 0.61 μM, respectively), with 3A4 exhibiting the highest sensitivity. Kinetic analysis revealed distinct inhibitory mechanisms of norwogonin: non-competitive for 3A4 (K_i = 3.755 μM) and competitive for 2C9 (K_i = 6.879 μM) and 2D6 (K_i = 6.028 μM). Time-dependent inhibition (TDI) of norwogonin was observed exclusively for 3A4, characterized by increasing suppression with prolonged incubation (K_I = 2.323 μM^-1, K_inact = 0.035 min^-1), while 2C9/2D6 inhibition remained static over time.4. Norwogonin selectively inhibited 2C9, 2D6, and 3A4 via distinct mechanisms, with time-dependent 3A4 suppression suggesting the potential interactions, necessitating caution in co-administered therapies.

Introduction: Polychlorinated Biphenyls pose hazards to humans as environmental and occupational workplace pollutants, despite which, though they are regulated in India, their use is not yet banned.

Methodology: A whole body inhalational chamber has been utilized to expose mice to different doses of Aroclor 1232 for single six-hour durations. The plasma and brain samples were used to estimate the corresponding congeners of PCBs (PCB 77 and PCB 180) and calculate their pharmacokinetic parameters. These variables were then correlated with mouse behavior using Irwin scale, and monoamine levels at 4 hours, which is the Tmax.

Results: A definite dose-dependence of PCB kinetic parameters was identified in plasma and brain. PCB 77 exhibited more accumulation in brain than plasma, whereas PCB 180 accumulated more in plasma than brain. The changes in the mood and miscellaneous domains on the Irwin scale were due to higher brain PCB 77; changes in autonomic functions were due to higher plasma PCB 180 levels. Behavior scores were statistically significant at Tmax (3-5 hours).

Discussion: Generally, DA reduced at Tmax for each dose level; 5-HT increased exponentially as Tmax approached for each dose level; and NA followed U-shaped dose response, the dip being correlated at Cmax.

To investigate the protective mechanism of Astragaloside IV (AS-IV) in diabetic retinopathy(DR).A streptozotocin-induced diabetic rat model was established and divided in to three groups: control, DR, and DR + AS-IV. Retinal injury was assessed using optical coherence tomography (OCT). Retinal proteomes were profiled using 4D-DIA proteomics. Candidate genes were validated using quantitative PCR (qPCR).302 differentially expressed proteins were detected. Venn diagram analysis revealed three down-regulated proteins in the DR group: Gnal, Dennd1a, and Snx13, and two up-regulated proteins: Ogn and Mylpf. AS-IV treatment reversed the expression of Dennd1a and Gnal while downregulating Ogn, Mylpf, and Snx13. PPI analysis revealed limited direct connectivity among the five proteins but identified 10 additional interactors, including MYLK, ADCY9, and RAB35. GO analysis indicated involvement in muscle contraction, muscle myosin complex, and phosphatidylinositol phosphate binding and structural molecule activity. KEGG analysis highlighted calcium signalling as a key pathway. Molecular docking demonstrated stable interactions between AS-IV and Dennd1a, Ogn, and Snx13 proteins. qPCR confirmed significant regulation of Dennd1a and Ogn, while Snx13 and Mylpf changes were not significant.AS-IV exhibited protective effects against diabetic retinal injury by modulating Dennd1a and Ogn, implicating calcium signalling and structural pathways in its therapeutic mechanism.

Norovirus is a leading cause of acute gastroenteritis worldwide, yet no approved antivirals currently exist.In this study, we employed in silico approaches to evaluate apigenin derivatives as potential inhibitors of norovirus RNA-dependent RNA polymerase (RdRp). Seventy-three compounds were initially retrieved from the ZINC database, of which 36 satisfied Lipinski's Rule of Five and were advanced for detailed analysis.Pharmacokinetic predictions revealed high intestinal absorption and favourable drug-likeness profiles for most derivatives, with limited central nervous system penetration, desirable for targeting gastrointestinal infections.Molecular docking identified ZINC14636470 (A1) as the top candidate with strong binding affinity (-9.9 kcal/mol) and key hydrogen bond interactions at the RdRp active site.Molecular dynamics simulations confirmed the stability of the A1-RdRp complex (RMSD = 0.20 ± 0.03 nm; Rg = 2.39 ± 0.02 nm).While AMES predictions flagged some derivatives as potentially mutagenic, scaffold optimisation may mitigate these risks. Apigenin derivatives, particularly A1, demonstrate promising inhibitory potential against norovirus RdRp, combining favourable pharmacokinetic properties with stable enzyme binding. These findings provide a computational foundation for subsequent in vitro and in vivo validation, supporting the development of natural flavonoid-based scaffolds as antiviral leads against norovirus.

Solute carrier (SLC) transporters are key players in drug pharmacokinetics and are notably involved in drug-drug interactions; their potential interactions with new molecular entities must be evaluated during pharmaceutical development for regulatory purposes.Various fluorescent probes substrates for SLCs have been characterised. This review summarises the nature of these dyes and their application in vitro for investigating interactions between drugs or other chemicals and main 'regulatory' SLCs that handle anionic or cationic compounds. The advantages and limitations of using fluorescent probes for SLC studies are discussed.Fluorescent probe-based SLC assays enable the identification and characterisation of xenobiotic-mediated inhibition of SLC activity through cis-inhibition assays. They also facilitate the study of fundamental properties, polymorphisms, and regulatory pathways of SLCs, as well as the characterisation of SLC substrates via trans-stimulation or competitive counterflow assays.Dye-based SLC activity assays are more cost-effective and less labour-intensive than conventional methods relying on radiolabeled substrates or liquid chromatography-tandem mass spectrometry. They are also fully compatible with high-throughput screening.Limitations of fluorescent dye-based SLC assays include the relatively low specificity of fluorescent probes, substrate-dependent variability in SLC inhibition, and limited performance of trans-stimulation or competitive counterflow assays for identifying SLC substrates.

SGLT2 inhibitors(SGLT2i) inhibit glucose reabsorption in renal proximal tubules, promote urinary glucose excretion, and lower blood glucose. They also protect cardiovascular, renal, and nervous systems, though mechanisms remain unclear.Mitochondria are key organelles for energy metabolism, redox balance, and calcium regulation, playing a critical role in chronic disease pathogenesis and progression.SGLT2i improve mitochondrial function by enhancing quality control, modulating energy metabolism, strengthening antioxidant defenses, and maintaining calcium homeostasis.These mitochondria-centered mechanisms may underlie SGLT2i protection of cardiovascular, renal, and neurological systems. This review summarizes these effects and discusses therapeutic implications.

Tacrolimus is a novel immunosuppressor for its significant anti-inflammation and immune activity, which would induce hyperglycaemia, increasing its combination with hypoglycaemic drugs.Pachymic acid has been demonstrated to possess the pharmacological activity of anti-hyperglycaemia. Tacrolimus combining pachymic acid was investigated, aiming to guide the prescription of patients taking tacrolimus.In rats, 1.2 mg/kg tacrolimus was combined with three dosages of pachymic acid (50, 100, and 200 mg/kg) with the single dosage of tacrolimus as control. The blood glucose of rats with different medications was monitored and the pharmacokinetic changes of tacrolimus were assessed. Tacrolimus significantly increased the blood glucose of rats. Pachymic acid increased C_max, AUC, and t_1/2 and reduced the clearance rate of tacrolimus in rats, and the effects were promoted by its increasing dosage. The metabolic stability of tacrolimus in rat liver microsomes was also improved by pachymic acid, both of which enhanced its hyperglycaemic effect in rats. Significant inhibition of CYP3A1/2 by pachymic acid was observed with the IC₅₀ value of 12.25μM.Co-administration of tacrolimus with pachymic acid induced adverse interactions, suppressing the metabolism and enhancing the hyperglycaemic effect of tacrolimus through inhibiting CYP3A1/2.

Phytopharmacology has become a key approach for developing new therapeutic strategies by utilising the diverse bioactive properties of plant-derived compounds to treat complex diseases, including cardiovascular disorders. Myocardial ischaemia-reperfusion (I/R) injury presents a major challenge in the management of acute myocardial infarction by worsening myocardial damage through oxidative stress, apoptosis, and cellular senescence. Carvacrol, a monoterpenoid phenol present in plants such as Origanum vulgare, possesses potent antioxidant and anti-inflammatory properties. This study investigates carvacrol's cardioprotective effects in an H9C2 cardiac myoblast model of I/R injury.Cardiac myoblast cells were exposed to an ischaemic buffer to simulate I/R conditions, with carvacrol administered at a sub-cytotoxic dose of 12.5 µg/mL prior to exposure. Carvacrol significantly enhanced cell viability by 77.37% restoration, reduced lactate dehydrogenase (LDH) release (from 330.5 ± 25.3 to 160.8 ± 15.7 U/mL, p < 0.01), suppressed reactive oxygen species (ROS) production, inhibited caspase-3 and -8 activities, and mitigated cellular senescence as evidenced by reduced β-galactosidase staining. Additionally, carvacrol restored the expression of the myogenin gene, which was downregulated by ischaemic injury.These findings highlight carvacrol's antioxidant, anti-apoptotic, anti-senescence, and gene-regulatory properties, positioning it as a promising therapeutic candidate for mitigating myocardial I/R injury.

We aimed to expound the effects of different doses of dexmedetomidine (Dex) combined with stellate ganglion block (SGB) on postoperative pain, sleep quality, and serum orexin A levels in patients undergoing general anaesthesia for laparoscopic radical resection for colorectal cancer (CRC).This prospective randomised controlled trial enrolled 320 CRC patients, randomly assigned to four groups (n = 80): control (0.9% NaCl + SGB), and three Dex groups receiving low, medium, or high Dex infusion (0.2, 0.4, and 0.6 µg/kg·h, respectively) combined with SGB. Postoperative pain [Visual Analogue Scale (VAS), postoperative days 1-3], insomnia [Athens Insomnia Scale (AIS), before and after surgery], serum orexin-A levels (enzyme-linked immunosorbent assay), and adverse events were assessed and compared.All Dex groups showed lower VAS scores (postoperative days 1-3), postoperative AIS scores, and serum orexin-A levels than the control group (p < 0.05). These improvements were dose-dependent, with the high-dose group demonstrating the most significant effects. The incidence of adverse events was lower in the Dex groups, with no significant differences across dosage levels (p > 0.05).Dex at 0.6 µg/kg·h combined with SGB provides optimal postoperative analgesia, improves sleep quality, lowers serum orexin-A, and does not significantly increase adverse events.