Xenobiotica最新文献

Hyperthyroidism is primarily characterised by excessive secretion of thyroid hormones and abnormal proliferation of thyroid follicular cells. Graves' disease is the most prevalent and is classified as an autoimmune thyroid disorder. However, as a typical triterpenoid compound, the mechanism of oleanolic acid in treating hyperthyroidism remains unclear. Therefore, this study aims to explore the effects and mechanisms of oleanolic acid on hyperthyroidism.The rats were divided into six groups. During the experiment, the body weight of the rats was measured weekly, and their clinical signs were monitored daily. After the administration was completed, the changes in various indicators of the rats were detected through ELISA, HE staining, immunohistochemistry, TUNEL assay, and Western blot experiments.After treatment with methimazole or oleanolic acid, it was found that the rats' body weight increased, their clinical symptoms returned to normal basically, the pathological damage of the thyroid tissue in hyperthyroid rats was significantly reduced, and the adverse effects were also reversed. Furthermore, LPS treatment can reverse the therapeutic effect of oleanolic acid on hyperthyroidism in rats.Oleanolic acid could regulate hormone levels and alleviate oxidative stress in rats with hyperthyroidism by inhibiting the TLR4/NF-κB pathway.

Infertility related to men is a major global issue. Due to the high costs and side effects of chemical drugs, interest has shifted towards medicinal bioactive compounds. Linalool, a terpenoid found in many plants, shows potential in reducing inflammation and oxidative stress. This study investigated the protective effects of linalool against CCl₄-induced testicular toxicity in rats.Twenty-four rats were divided into four groups: normal control, linalool only, CCl₄ only, and linalool plus CCl₄ treatment. Linalool (25 mg/kg) was administered for 14 days, with CCl₄ given as a single dose on day 14. Forty-eight hours later, testes were collected to assess oxidative stress markers and histopathological changes.CCl₄ significantly reduced antioxidant enzyme activity and total antioxidant capacity, while increasing malondialdehyde (MDA) levels (p < 0.001). Linalool treatment significantly improved antioxidant markers (p < 0.01) and decreased MDA levels (p < 0.001) compared to the CCl₄ group. Histological analysis showed that linalool ameliorated CCl₄-induced structural damage in testicular tissue.These findings suggest linalool protects against testicular toxicity by preventing excessive free radical accumulation and subsequent oxidative damage, highlighting its potential as a therapeutic agent for male infertility associated with oxidative stress.

Achieving and characterizing steady-state drug concentrations is an essential objective for evaluating exposure-response relationships in preclinical pharmacology. This study assessed the pharmacokinetics (PK) of Fulvestrant, Imipramine, and Brivaracetam using cassette dosing. In vitro liver stability assays with mouse liver microsomes and hepatocytes, both individually and in combination, showed no significant drug-drug interactions. Single-dose subcutaneous (SC) PK studies in CD-1 mice provided absorption, clearance, and distribution parameters to model infusion rates targeting steady-state concentrations (C_ss). A 168-hour SC cassette infusion via Alzet osmotic pumps was used to validate predictions. Brivaracetam had the highest exposure and lowest clearance, while Imipramine showed rapid elimination. Compartmental modeling accurately predicted infusion doses, targeting C_ss of 60 ng/mL. Observed C_ss values were lower than predicted, with Imipramine showing the closest match. All compounds reached steady-state within 24-36 hours, and clearance/exposure rankings were consistent across models and experiments. This integrated approach combining SC PK profiling, modeling, and cassette infusion enabled model-informed dose prediction and qualitative validation, which can support early PK evaluation and formulation development in drug discovery.

Norwogonin, a bioactive flavonoid with anti-inflammatory and anticancer potential. Its interactions with cytochrome P450 enzymes remain uncharacterised. This study aimed to investigate the effect of norwogonin on the activity of P450s.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 min incubation) were conducted with form-specific probe substrates. Metabolites were quantified via High Performance Liquid Chromatography (HPLC).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, characterised 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.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.

Xevinapant, an oral IAP (inhibitor of apoptosis protein) inhibitor, was clinically investigated for the treatment of various cancers. A novel metabolite of xevinapant, oxidated D-1143-MET1 (oxMET1), was identified in the human mass balance study, which had not been detected in previous non- and clinical studies but represented almost 10% of the total drug exposure after single-dose administration and was therefore pinpointed for its structural and initial nonclinical characterization.Using high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy after a semi-preparative isolation of oxMET1 it was possible to determine its definitive structure.OxMET1 exhibited only negligible inhibitory activity on cIAP1 in vitro, and thus, taking the low unbound fraction in human plasma into account, contribution to in vivo efficacy was considered low.In addition, coverage of human exposure could be shown in plasma samples from toxicity studies performed with preclinical species, so oxMET1, although likely major, was not a disproportionate circulating metabolite in humans. Based on these findings, this metabolite did not raise safety concerns according to the MIST guidelines, however it warrants further characterisation of its drug-drug interaction (DDI) potential. The integrated workflow presented here highlights the importance of metabolite characterization in drug development.

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.A whole-body inhalational chamber has been utilised to expose mice to different doses of Aroclor 1232 for single 6-h 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 behaviour using Irwin scale, and monoamine levels at 4 h, which is the Tmax.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. Behaviour scores were statistically significant at Tmax (3-5 h).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.

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.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 pre-treatment 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).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).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.

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.

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.

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.