Sasanquasaponin (SQS) exhibits anti-inflammatory and antioxidant effects, with unknown therapeutic effects in osteoarthritis (OA).This study was conducted to verify the effects of SQS and its molecular mechanism in OA.Specifically, flow cytometry was utilized to assess cell apoptosis, and ELISA was used for evaluating the levels of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and matrix-degrading enzymes (MMP-3, MMP-13, ADAMTS-4, ADAMTS-5). The targeting effects of SQS on the MAPK and PI3K/AKT pathways were predicted using the molecular docking method.SQS rescued IL-1β-induced apoptosis in human chondrocytes (C-28/I2) in a concentration-dependent manner while suppressing the production of pro-inflammatory cytokines and matrix-degrading enzymes. Bioinformatics prediction identified reliable binding sites for SQS in key proteins of both the MAPK (p38, JNK) and PI3K/AKT (PI3K, AKT) signaling pathways. In IL 1β stimulated C 28/I2 cells, SQS suppressed the excessive activation of p38, JNK, PI3K, and AKT. Moreover, overexpression of these proteins reversed the protective effect of SQS against C-28/I2 apoptosis, as well as its inhibitory effect on the production of pro-inflammatory cytokines and matrix-degrading enzymes.Collectively, SQS alleviates OA inflammation and matrix degradation via inactivation of the MAPK and PI3K/AKT pathways.

1. Vonoprazan and imatinib may be co-prescribed in patients with acid-related disorders, but the pharmacokinetic consequences of this combination remain unclear.2. We evaluated the effects of vonoprazan on imatinib pharmacokinetics in rats and compared metabolic inhibition in human and rat liver microsomes.3. Rats (n = 6/group) received vehicle or vonoprazan (5.0 or 20.0 mg/kg) orally for 7 days, followed by imatinib (30.0 mg/kg). Imatinib and N-desmethyl imatinib were quantified by UPLC-MS/MS. Inhibition kinetics were examined in human (HLM) and rat liver microsomes (RLM).4. Imatinib AUC(0-t) increased by 37.2% and 63.7% at 5.0 and 20.0 mg/kg vonoprazan, respectively; the increase was significant at 20.0 mg/kg (p < 0.05). N-desmethyl imatinib AUC(0-t) decreased by 37.4% and 69.4% (both p < 0.05). IC50 values were 17.52 μM in HLM and 9.35 μM in RLM. Inhibition patterns were consistent with competitive inhibition in HLM and mixed-type inhibition in RLM, with apparent Ki values of 38.97 and 37.17 μM, respectively.5. Vonoprazan increased imatinib exposure in rats and inhibited microsomal metabolism. Species differences and uncertainty in the kinetic estimates limit quantitative extrapolation; clinical interaction studies are needed.

1. Linzagolix is an orally available gonadotropin-releasing hormone antagonist used to treat female-specific diseases, such as uterine fibroids and endometriosis.2. After a single dose of [[14]C]linzagolix or linzagolix to female rats and monkeys, linzagolix exhibited the absorption-distribution-metabolism-excretion characteristics of acidic drugs owing to the presence of a carboxylic acid moiety in its structure.3. Linzagolix showed low total clearance, high oral bioavailability, and high plasma exposure associated with high solubility, low metabolic clearance, and entero-hepatic circulation. Linzagolix had a low-volume distribution with limited tissue distribution associated with high plasma protein binding. These absorption-distribution-metabolism-excretion characteristics were comparable between the two species.4. After a single oral dose of [[14]C]linzagolix to rats, radioactivity was rapidly distributed to almost all tissues; however, the extent of the tissue distribution was limited and decreased in parallel with elimination from the blood.5. In both species, linzagolix was identified as the primary circulating and excretory component. The major biotransformation pathways of linzagolix were two O-demethylations and O-debenzylation. Additionally, sulphate conjugates of O-demethylated metabolites were detected in rats.6. The major excretion route of linzagolix was faecal excretion via the bile in its unchanged form.

Hearing loss is a recognised hazard of aminoglycosides and platinum chemotherapy, but the auditory risk of antifungal drugs has received far less attention. Itraconazole lists hearing loss in its prescribing information, yet dedicated peer-reviewed auditory studies appear absent.

1. Minocycline has shown therapeutic potential in neurodegeneration and ageing, but the effects of exposure during development remain poorly understood. This study investigated whether minocycline exposure restricted to development alters redox status and locomotor function in adult Drosophila melanogaster after drug withdrawal.2. A preliminary adult survival assay was used to inform dose selection. Fly eggs were cultured on standard food containing minocycline at 0.05, 0.10 or 0.20 mM from embryonic development through eclosion. Adults were then transferred to untreated food and assessed on post-eclosion day 5. Larval feeding and body-wall contraction were assessed as developmental behavioural endpoints, adult climbing performance was assessed using the negative geotaxis assay, and redox status was evaluated using FOX-reactive peroxides, nitric oxide-related measures, thiols and malondialdehyde.3. Developmental minocycline exposure reduced FOX-reactive peroxide and nitric oxide-related measures and increased thiol levels in adults. Exposure also impaired larval feeding and adult climbing performance, whereas pupation and larval crawling were not significantly altered.4. Developmental minocycline exposure was associated with altered redox status and locomotor deficits that remained evident in early adulthood following drug withdrawal. These findings support further investigation of the tissue-specific and molecular mechanisms underlying the effects of developmental minocycline exposure.

Marine organisms have fascinated scientists with their unique and unparalleled biodiversity and therapeutic potential.They are known to possess novel bioactive compounds with varied pharmacological properties that encompass anticancer, antimicrobial, anti-inflammatory, neuroprotective, antiviral, and cardioprotective properties.The review is put forth to discuss key advancements in landscapes of small molecules derived from marine sources, along with their clinical status.We also identify key challenges in marine drug discovery, such as access to marine organisms, supply chain sustainability, chemical diversity, synthesis complexity, bioavailability optimisation, and intellectual property concerns.The review also put forth the discussions on improving the drug discovery area from marine sources by considering the advancements in marine biotechnology, artificial intelligence, and interdisciplinary collaborations.Redressing these challenges and adopting emerging technologies, the potential of marine biodiversity may be harnessed for biomedical innovation and, in turn, contribute to health and promote environmental sustainability.

1. To characterise metoprolol pharmacokinetics and assess the feasibility of pharmacokinetic sampling among cisgender males, cisgender females, and transgender women receiving gender-affirming hormone therapy.2. Nine healthy volunteers (three per group) received a single 100 mg oral dose of metoprolol, and serial blood samples were collected over 12 h. Plasma metoprolol concentrations were determined using HPLC and analysed by a non-compartment model. CYP2D6 genotyping or phenotyping was not performed; therefore, the analysis was descriptive and hypothesis-generating.3. Descriptively, mean area under the concentration-time curve values were 2550 ± 126 ng·h/mL in cisgender males, 2142 ± 463 ng·h/mL in cisgender females, and 1522 ± 189 ng·h/mL in transgender participants. Mean peak plasma concentrations were 418 ± 43, 363 ± 58, and 269 ± 27 ng/mL, respectively. The corresponding elimination rates were 0.139, 0.140, and 0.268 h[-1], and mean half-lives were 4.98, 4.92, and 2.58 h, respectively.4. The observed profiles suggest between-participant variability that warrants further investigation; however, three participants per group cannot represent the respective populations, and the findings cannot be attributed to sex, gender, or hormone therapy without CYP2D6 genotype data. Larger, genotype-stratified studies with detailed hormone and body-composition measurements are required.

Present study aims to develop and assess a capecitabine-loaded nanoparticle formulation (C18) for improved oral bioavailability and targeted anticancer activity.Capecitabine nanoparticles were successfully prepared using a double emulsion solvent evaporation process. These nanoparticles were then tested for in vitro cytotoxicity using MTT assays against HT-29, HepG2 and L929 cell lines to calculate IC50 values. The pharmacokinetic properties of the medication and its nanoparticle formulation were also investigated in Wistar rats after oral administration. Validated HPLC methods were used to assess the plasma concentrations of 5-FU and capecitabine, and data was processed using PkSolver software.The nanoparticle formulation (C18) exhibited dose-dependent cytotoxicity by IC50 values of 38.91 µg/mL (HepG2) and 55.15 µg/mL (HT-29), showing superior anticancer activity compared to 5-FU. Cytotoxicity towards normal L929 cells was moderate, indicating selective toxicity. Pharmacokinetic studies revealed enhanced oral bioavailability, increased Cmax and AUC, and prolonged circulation time for the nanoparticle formulation compared to the conventional drug.Capecitabine-loaded nanoparticles demonstrated improved cytotoxic potential against cancer cell lines and favourable pharmacokinetic profiles, associate their probability as an active oral nanocarrier system for cancer therapy.

1. Pentobarbital is metabolised by cytochrome P450 (CYP) enzymes, being a model compound for evaluating CYP-mediated drug-drug interactions, has become difficult to obtain for animal studies in Japan. The metabolic pathway of thiopental (TP), a barbiturate with similar pharmacological properties, remains insufficiently characterised. This study investigated TP metabolic profile, with emphasis on CYP modulator-induced drug-drug interactions.2. TP was administered intraperitoneally to either phenobarbital (PB), chloramphenicol (CP)-pre-treated, or untreated rats. Plasma TP concentrations were quantified using HPLC-DAD and a plate reader. Hypnotic and sedative properties were assessed by time to loss of righting reflex and recovery from hindlimb paralysis. TP metabolism was further evaluated in vitro using rat liver microsomes (RLMs) and recombinant CYP enzymes, and hepatic CYP mRNA levels were quantified by real-time RT-PCR.3. Compared with TP alone, PB pre-treatment shortened TP-induced anaesthesia and decreased plasma TP concentrations, whereas CP pre-treatment prolonged the duration of action and increased plasma TP levels. TP metabolism was mediated by CYP2B1 and CYP2C11. PB pre-treatment induced CYP2B1 and enhanced TP metabolism, whereas CP pre-treatment suppressed CYP2C11, inhibited CYP2B1, and reduced TP metabolism.4. These results suggest that TP is a useful alternative model compound for investigating pharmacokinetics/pharmacodynamics and CYP-mediated drug-drug interactions.

Coumarins are plant-derived secondary metabolites widely present in foods, spices, and medicinal plants. Their limited intestinal absorption and extensive host metabolism allow a variable fraction to reach the colon, where gut microorganisms can transform them into metabolites with distinct physicochemical and biological properties.This review synthesizes current evidence on gut microbiota-mediated coumarin biotransformation, focusing on microbial taxa, metabolic reactions, structural determinants, and consequences for biological activity. Reported transformations include deglycosylation, reduction, O-demethylation, hydroxylation, deprenylation, and lactone ring opening. Recent studies have identified multiple human gut bacteria capable of coumarin reduction and implicated the NADPH-dependent reductase NemA in this process. Gut bacteria may also generate simple coumarins from dietary phenolic precursors. These transformations can modify biological activity, while coumarins and their metabolites may reciprocally influence microbial composition and metabolism.Current evidence supports gut microbiota as an important determinant of coumarin metabolism, but its physiological relevance in humans remains uncertain. Key gaps include interindividual variability, specific microbial enzymes and taxa, enterohepatic recycling, and the contribution of the gut mycobiome. Integrated microbiome, metabolomic, and pharmacokinetic approaches are needed to establish the contribution of microbiota-derived metabolites to coumarin bioactivity and safety.

Although dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown potential triglyceride-lowering effects, the clinical evidence remains inconsistent. This study aimed to determine whether the triglyceride-lowering effect observed in patients receiving dapagliflozin was associated with dapagliflozin exposure using a pharmacometric approach integrating clinical data and a preclinical model.Clinical data were retrieved from 85 Japanese patients with type 2 diabetes mellitus who received dapagliflozin 5 mg/day for 12 months. Serum triglyceride levels and plasma concentrations of dapagliflozin were analysed using a population pharmacokinetic-pharmacodynamic (PK-PD) model. In addition, dapagliflozin (0.1 or 0.2 mg/kg) was administered to poloxamer-407-induced dyslipidemia model rats to examine exposure-dependent triglyceride-lowering effects.Among the 18 patients with elevated serum triglyceride levels (≥150 mg/dL) at baseline, dapagliflozin significantly reduced triglyceride levels, with a mean reduction of 47 mg/dL at 12 months. The population PK-PD model captured 103 triglyceride measurements and revealed an exposure-dependent triglyceride-lowering effect. Consistently, a dose-dependent reduction in triglyceride levels was observed in the dyslipidemia model rats.These findings suggest that dapagliflozin exposure is associated with triglyceride-lowering effects, demonstrating an exposure-response relationship supported by pharmacometric analysis of long-term real-world data and a dyslipidemia model.

This study aimed to evaluate the bioactivation of methyl-parathion (Me-Pa) and the expression and activity of mouse cytochrome P450 (Cyp) isoforms involved, in the cauda epididymis-vas deferens (CE-VD) and testis, and in the liver for comparison.Microsomes were obtained from adult mice treated and non-treated with phenobarbital (PB), and the bioactivation of Me-Pa was indirectly evaluated by in vitro acetylcholinesterase inhibition. The protein content was evaluated by immunoblotting, and the enzymatic activities by resorufin ether-O-dealkylation and 16α- and 6β-testosterone hydroxylation. Me-Pa bioactivation was observed in the testis at a lower rate than in the liver and was detected in the CE-VD only after PB induction.The protein content and enzymatic activities associated with the Cyps evaluated were observed in all tissues in different proportions, depending on the enzyme. In all cases, protein content and enzymatic activities in the liver were higher than in reproductive tissues, except for Cyp1a2, for which constitutive expression was not observed in the CE-VD, but its associated enzymatic activity was higher compared to the testis and liver.These findings suggest that mouse reproductive tissues are metabolically active in biotransforming xenobiotics, such as Me-Pa, contributing to its toxicity.

1. Parkinson's disease (PD) involves dopaminergic dysfunction, oxidative stress, and neuroinflammation. This study evaluated an optimised astaxanthin-loaded nanoemulsion (AXTNE) in paraquat-induced experimental Parkinsonism.2. Male Wistar rats were randomly assigned to nine groups (n = 6). Parkinsonian alterations were induced by paraquat (10 mg/kg, i.p.) twice weekly for 4 weeks. Aqueous astaxanthin (AXT; 30 mg/kg), AXTNE (15 and 30 mg/kg), levodopa + carbidopa (15 + 3.75 mg/kg), and AXTNE-levodopa combinations were administered orally for 28 days. Motor function was assessed using catalepsy, locomotor activity, grip strength, postural instability, and beam-walk tests. Pooled bilateral striatal tissue was analysed for oxidative stress, inflammatory cytokines, monoaminergic neurotransmitters, and dopaminergic protein markers.3. Paraquat induced motor deficits, oxidative imbalance, increased inflammatory cytokines, reduced dopamine and noradrenaline, and altered tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and α-synuclein levels. AXTNE attenuated these alterations and reduced MDA levels measured by TBARS. AXTNE-levodopa combinations produced additional improvements across several endpoints.4. AXTNE attenuated multiple paraquat-associated Parkinsonian alterations, with generally greater numerical improvements than aqueous AXT. Combination with levodopa showed potential complementary effects. Further histopathological, pharmacokinetic, biodistribution, and mechanistic studies are warranted.

This study investigated the combined effects of zinc and cystine on reproductive damage induced by diisononyl phthalate (DiNP) in male rats.A total of 28 rats were randomly assigned to four groups (n = 7 per group) and treated for 45 days. Group 0 (Control) received physiological saline, Group G1 (positive control) received a zinc- cystine combination at a dose of 5 mg zinc + 50 mg cystine/kg body weight, Group 2 received DiNP alone (15 mg/kg body weight), whereas Group 3 received DiNP in combination with zinc (5 mg/kg body weight) and cystine (50 mg/kg body weight).Hormonal parameters, including luteinizing hormone (LH), Follicle-stimulating hormone (FSH), and testosterone, were measured. Sperm concentration, motility, speed, and vitality were also evaluated, together with testicular oxidative stress markers, including GSH, GSH-Px, MDA, and SOD.The results showed that the zinc-cystine combination significantly alleviated the reproductive and oxidative damage induced by DiNP exposure. Improvements were observed in hormonal status, sperm quality parameters, and antioxidant defence markers compared with the DiNP-treated group.These findings highlight the protective potential of zinc and cystine against environmental toxin-induced reproductive dysfunction and suggest a combined effect that may have therapeutic relevance in reducing the adverse effects associated with phthalate exposure.