Whereas our previous single-dose study characterized the distinct pharmacokinetic (PK) profile of enteric-coated sustained-release (ECSR) aspirin compared with enteric-coated (EC) aspirin, featuring prolonged absorption and reduced variability, its pharmacodynamic (PD) effects under multiple-dose conditions remain unknown. This study was designed to compare the multiple-dose PK and PD profiles of 50 mg ECSR aspirin versus 100 mg EC aspirin. An open-label, randomized, two-sequence, crossover study was conducted in 12 healthy Chinese male subjects. Participants received either 100 mg EC or 50 mg ECSR aspirin daily for 10 consecutive days. PK parameters and PD biomarkers, including serum thromboxane B2 (TXB2), urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 2,3-dinor-6-keto prostaglandin F1α (2,3-dinor-6-keto PGF1α), were assessed. PK analysis revealed that dose-normalized systemic exposure to the parent drug (acetylsalicylic acid, ASA) for the ECSR formulation was only 37
Diabetic hepatopathy is a major complication of type 2 diabetes mellitus characterized by metabolic dysregulation, oxidative stress, inflammation, and emerging evidence of ferroptosis-mediated liver injury. Icariin (IC), a bioactive flavonoid, exhibits hepatoprotective potential; however, its clinical applicability is limited by poor bioavailability. Liposomal nanoformulation represents a potential approach to modify IC delivery and enhance its pharmacological efficacy. Ninety rats were randomly assigned to six groups (n = 15/group): Control, IC, IC-LNPs, NA–STZ, NA–STZ + IC, and NA–STZ + IC-LNPs. Type 2 diabetes was induced by nicotinamide (120 mg/kg, i.p.) followed 15 min later by streptozotocin (60 mg/kg, i.p.). Five days after diabetes confirmation, diabetic treatment groups received IC or IC-LNPs at an IC-equivalent dose of 80 mg/kg/day, i.p., for eight consecutive weeks. Hepatic injury was assessed through biochemical parameters, oxidative stress markers, inflammatory cytokines, ferroptosis-related markers, and histopathological and ultrastructural analyses. NA–STZ administration induced significant metabolic dysfunction, including hyperglycemia, insulin depletion, dyslipidemia, weight loss, and elevated hepatic enzyme levels. IC treatment significantly improved these parameters, while IC-LNPs produced a more pronounced protective effect. Diabetic induction was associated with reduced hepatic NRF2 and HO-1 levels, accompanied by reduced levels of GSH, SOD, CAT, and GPX, and increased oxidative stress markers (MDA and H₂O₂). IC-LNPs more effectively restored antioxidant defenses and redox homeostasis than free IC. Moreover, NA–STZ increased NF-κB and COX-2 expression and the inflammatory mediators TNF-α, IL-6, and IL-1β, which were markedly reduced by IC-LNP treatment. Importantly, diabetic hepatopathy was associated with alterations in ferroptosis-related markers, evidenced by iron accumulation (Fe²⁺), upregulation of ACSL4 and TFR1, and downregulation of GPX4 and SLC7A11. IC-LNPs significantly attenuated these alterations, consistent with modulation of ferroptosis-related processes. Histopathological and ultrastructural analyses confirmed severe hepatic damage in diabetic rats, whereas IC-LNPs markedly preserved hepatic architecture. IC-LNPs provided greater protection than free IC against NA–STZ-induced diabetic hepatopathy, associated with attenuation of oxidative stress and inflammation and modulation of NRF2/HO-1, NF-κB/COX-2, and ferroptosis-related markers. These findings support the potential of liposomal IC as a preclinical approach for diabetic liver injury; however, pharmacokinetic, biodistribution, safety, and further mechanistic studies are required before its therapeutic or translational potential can be established.
The therapeutic potential of antibody-drug conjugates (ADCs) is frequently undermined by the emergence of resistance to conventional payloads, which predominantly exert their effects through the disruption of intracellular targets such as microtubules or nuclear DNA. In pursuit of therapeutic agents capable of bypassing these established resistance pathways, we turned our attention to the engineered bacterial pore-forming toxin, pneumolysin ΔA146 (PLY ΔA146). To evaluate its intrinsic cytotoxic potential independent of antibody-mediated delivery, we generated a recombinant fusion protein (CPP-PLY ΔA146) for direct cellular assessment. This construct demonstrated proficient cellular internalization into both HER2-positive SK-BR-3 and triple-negative MDA-MB-231 breast cancer cell lines. Subsequent functional analysis revealed a potent and concentration-dependent suppression of cell proliferation, yielding half-maximal inhibitory concentrations (IC₅₀) of approximately 1.140 µM and 1.433 µM, respectively, after a 72-hour exposure. Mechanistically, the observed cytotoxicity was fundamentally linked to the induction of programmed cell death. This was substantiated by a convergence of evidence: a significant elevation in Annexin V-positive populations, conclusive detection of DNA strand breaks, the cleavage and consequent activation of caspase-8 and caspase-3 along with a corresponding increase in their catalytic activities, a decisive shift in the Bax/Bcl-2 equilibrium toward a pro-apoptotic phenotype. Collectively, these results delineate a defined and efficacious pro-apoptotic mechanism for PLY ΔA146, one that is functionally discrete from the modalities of current ADC mainstays. These results provide an in vitro proof-of-concept for PLY ΔA146 as a potential candidate payload for future ADC development, proposing a strategic avenue to surmount existing limitations and potentially augment the efficacy of targeted oncological interventions.
Despite advances in surgery and chemotherapy over recent decades, epithelial ovarian cancer remains the most lethal gynecologic malignancy. Cinchonine, a natural compound traditionally utilized for its anti-inflammatory and anti-malarial properties, has demonstrated anti-tumor activity through multiple pathways. However, its therapeutic potential in epithelial ovarian cancer remains largely unexplored. This study evaluated the anti-tumor effects of cinchonine in epithelial ovarian cancer using both in vitro and in vivo models. In vitro, cinchonine significantly inhibited cell proliferation, induced G0/G1 phase arrest, and promoted apoptosis in selected epithelial ovarian cancer cells. In vivo, cinchonine markedly suppressed tumor growth in an epithelial ovarian cancer xenograft model, with efficacy similar to that of positive control. Histopathological examination revealed no evident toxicity in major organs following cinchonine treatment, whereas cisplatin was associated with mild early toxicity. Integrated transcriptomic and network pharmacology analyses identified the calcium signaling pathway as a key mechanistic axis underlying the effects of cinchonine. Consistent with these findings, in vitro experiments demonstrated that cinchonine significantly increased intracellular calcium ion concentrations in epithelial ovarian cancer cells. Moreover, inhibition of calcium signaling with the specific inhibitor verapamil markedly attenuated the anti-proliferative and pro-apoptotic effects of cinchonine. Collectively, these findings suggest that cinchonine has therapeutic potential for the treatment of epithelial ovarian cancer.
Tinnitus is a prevalent and often persistent symptom that imposes a substantial psychological and functional burden. Beyond disease-related mechanisms, accumulating real-world observations suggest that tinnitus may also emerge as a manifestation of drug-related adverse events. However, systematic, cross-database evidence characterizing tinnitus-associated drug safety signals remains limited. This study identified 21 systemic medications previously reported in association with tinnitus and retrieved post-marketing reports from the FDA Adverse Event Reporting System (FAERS) (2004–2025) and the WHO VigiAccess database. After data cleaning and standardization, disproportionality analyses were performed using four complementary algorithms (reporting odds ratio, proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multi-item Gamma–Poisson Shrinker). Drug-event pairs meeting predefined thresholds were considered signals. We further conducted sex-stratified analyses, quantified the relative contribution of age, sex, and body weight to adverse events using an XGBoost model, and examined time-to-onset patterns with Weibull shape parameter modeling. Across databases, tinnitus-related adverse event signals were not randomly distributed but instead converged within specific system organ classes and formed recognizable clusters at the Preferred Term level, particularly within neuropsychiatric and musculoskeletal domains. Most reports originated from adult and older adult populations, with females being more frequently represented. Tinnitus appeared as a recurrent positive signal across multiple therapeutic categories, and a considerable proportion of signals overlapped between FAERS and VigiAccess, supporting robustness while revealing complementary differences between the databases. After stratification, several signals persisted across sexes, whereas age explained the greatest proportion of variability compared with sex and body weight. Moreover, time-to-onset analyses consistently suggested an early-failure risk pattern, in which adverse events occurred predominantly shortly after treatment initiation and then declined. Integrating two large pharmacovigilance databases, we mapped consistent risk signals for tinnitus across multiple medications. These findings support closer monitoring during early treatment and offer real-world evidence to guide safer prescribing and future mechanistic research.
Retinal pigment epithelial (RPE) cells are vulnerable to hypoxia-related and oxidative stress. Cobalt chloride (CoCl₂) is widely used as a chemical hypoxia mimetic; however, an appropriate concentration window for producing measurable RPE injury without the more extensive damage associated with higher concentrations remains incompletely defined. Aldehyde dehydrogenase 2 (ALDH2) contributes to reactive-aldehyde detoxification and cellular stress defense. ARPE-19 cells were exposed to 0, 10, 100, 500, 1000, or 2000 µM CoCl₂. Scratch-wound recovery and representative morphology were evaluated for up to 72 h, and relative CCK-8 metabolic activity was quantified at 24, 48, and 72 h. The 500 µM condition was selected for molecular and pharmacological experiments based on the integrated dose-response profile. Culture-supernatant 4-HNE and VEGF-A were measured by ELISA, whereas HIF-1α, ALDH2, and BAX were assessed by Western blotting. Alda-1 and Daidzin were used as an ALDH2 activator/chemical chaperone and an enzymatic inhibitory comparator, respectively. CoCl₂ caused concentration- and time-associated impairment of scratch-wound recovery. Wound closure was largely preserved at 0–100 µM, whereas 500–2000 µM produced wound-closure failure. The CCK-8 profile showed that 500 µM retained a nonmaximal metabolic signal compared with the substantially greater late reductions observed at 1000 and 2000 µM. Thus, 500 µM represented the lowest tested concentration producing significant functional injury while avoiding the more extensive injury phenotype observed at higher concentrations. Under 500 µM CoCl₂, HIF-1α increased early, ALDH2 protein abundance decreased, and culture-supernatant 4-HNE and VEGF-A increased at the later time point. Alda-1 improved wound recovery and restored ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype and shifted extracellular stress-marker readouts in an unfavorable direction. CoCl₂ produced a concentration-resolved, hypoxia-related and aldehyde-associated RPE injury phenotype. Alda-1 improved wound recovery and increased ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype. These findings support ALDH2-associated aldehyde-detoxifying defense as a modulatory component of CoCl₂-induced RPE stress.
Programmed cell death ligand 1 (PD-L1) inhibitors are important agents for lung cancer immunotherapy. However, they frequently cause cutaneous toxicity in clinical practice, which compromises therapeutic compliance. Current studies mostly focus on immune cells, while the direct role of keratinocytes remains unclear. In this study, we used the PD-L1 small-molecule inhibitor BMS-1 as a tool compound to investigate its potential targets and non-immune mechanisms of keratinocyte toxicity by integrating network toxicology, molecular dynamics simulations, and in vitro experiments. In the present study, potential targets responsible for cutaneous toxicity induced by PD-L1 inhibitors were predicted using public databases. Gene ontology and pathway enrichment analyses were performed via the DAVID database. Key targets were identified from the established protein-protein interaction (PPI) network and further validated in conjunction with differentially expressed genes derived from the GEO database. The binding interactions between PD-L1 inhibitors and core targets were verified by molecular docking, molecular dynamics simulation, and in vitro cellular experiments. A total of 246 potential targets associated with cutaneous toxicity induced by the PD-L1 inhibitor BMS-1 were identified via network toxicology. GO and KEGG analyses revealed that these targets were mainly enriched in pathways related to inflammation, proliferation and apoptosis. Following screening with multiple algorithms and validation using GEO datasets, ALB, EGFR and MMP9 were recognized as core targets. Molecular docking demonstrated that the docking scores of BMS-1 to all three targets were below − 5 kcal·mol⁻¹, and 100 ns molecular dynamics simulations confirmed stable conformations of the complexes. MM/PBSA theoretical binding free energy calculations further revealed an affinity ranking of MMP9 > ALB > EGFR, with van der Waals interactions serving as the dominant driving force and polar solvation energy consistently contributing a desolvation penalty. Interaction fingerprint analysis indicated that van der Waals packing and π‑interactions of hydrophobic and aromatic residues were central to complex stabilization, with MMP9 exhibiting the most favorable binding potential through its strong hydrophobic network.Cellular assays indicated that BMS-1 suppressed HaCaT cell proliferation, elevated mRNA expression of IL‑1β and TNF‑α, and regulated target gene expression: downregulating ALB while upregulating EGFR and MMP9. The small-molecule PD-L1 inhibitor BMS-1 induces HaCaT cell injury by suppressing ALB and promoting EGFR and MMP9 expression. These results provide a mechanistic hypothesis for BMS-1 related keratinocyte damage, but caution should be exercised when extrapolating to clinically approved PD-L1 antibodies, as their pharmacokinetic and immunomodulatory profiles differ substantially. Further studies are warranted to validate the relevance of these targets in clinical cutaneous adverse reactions.
Sepsis is a life-threatening condition driven by dysregulated immune and inflammatory responses, leading to multi-organ dysfunction, including liver injury. This study investigated the pharmacological and toxicological effects of limonene (LM) and limonene-loaded nanoliposomes (LM-LNPs) in a lipopolysaccharide (LPS)-induced model of hepatic injury in male Albino rats. LPS caused hepatic damage marked by elevated liver enzymes, dyslipidemia, oxidative and nitrosative stress, and suppression of the Nrf2/HO-1 axis, alongside activation of TLR4/NF-κB signaling, increased cytokines, and apoptosis. Histological findings confirmed severe injury. LM treatment partially ameliorated these alterations, whereas LM-LNPs demonstrated significantly greater hepatoprotective efficacy. Specifically, LM-LNPs restored liver function biomarkers, improved lipid profiles, enhanced endogenous antioxidant defenses, and reactivated the Nrf2/HO-1 pathway, while suppressing TLR4/NF-κB-mediated inflammatory responses. This resulted in reduced cytokine production, attenuated oxidative damage, and modulation of apoptosis, with preservation of hepatic architecture. Immunohistochemical analysis further confirmed upregulation of NRF2 expression and downregulation of NF-κB in hepatic tissues. Notably, nanoliposomal encapsulation improved the pharmacokinetic and biopharmaceutical properties of limonene, including controlled release, enhanced intestinal permeability, increased systemic bioavailability, and improved hepatic tissue distribution. In conclusion, LM-LNPs exert potent hepatoprotective effects against LPS-induced sepsis-like inflammatory liver injury through coordinated modulation of oxidative stress, inflammatory signaling, and apoptosis, highlighting their potential as a nano-enabled pharmacological strategy for managing inflammation-associated liver damage. Not applicable.
Abstract Background Arsine poisoning is a rare but life-threatening condition characterized by severe hemolysis. Clinical data on its management remain limited. This study describes the clinical features, diagnostic approach, and treatment experience of 12 patients from a single arsine poisoning incident. Methods Clinical data from the 12 patients were retrospectively collected. Presenting symptoms, diagnostic findings, and treatment strategies were summarized. Results Ten of the 12 patients survived. Arsenic was detected in cleaning wastewater and in the red blood cells of four patients, and, together with clinical hemolysis, supported the diagnosis of arsine poisoning. Common symptoms included headache, nausea, vomiting, abdominal pain, dizziness, chest tightness, and hematuria; headache, nausea, and vomiting frequently co-occurred. All patients received high-dose methylprednisolone, vitamin C + B6, and chelation therapy. The two non-survivors additionally received mechanical ventilation, therapeutic plasma exchange, dialysis, methylene blue, and transfusions; they died on day 3 from progressive cardiovascular failure secondary to acute hemolysis. Five other patients underwent therapeutic plasma exchange and dialysis and ultimately survived. Conclusions This case series highlights the clinical presentation, diagnostic workflow, and management of arsine poisoning in a well-characterized patient cluster. Early recognition and timely intervention may facilitate clinical management. The findings are descriptive and limited by the retrospective design and small sample size.
Whether aspirin is comparable to low molecular weight heparin (LMWH) in preventing venous thromboembolism (VTE) after major orthopedic surgery remains controversial. This meta-analysis aims to systematically evaluate the efficacy and safety of aspirin versus LMWH for the prevention of deep vein thrombosis (DVT) following major orthopedic surgery. Randomized controlled trials (RCTs) comparing aspirin with LMWH in patients undergoing major orthopedic surgery (including total hip arthroplasty and total knee arthroplasty) from inception to August 2025 were systematically searched in electronic databases including PubMed, Cochrane Library, EMbase, CNKI, WanFang, and VIP. Literature was managed using EndNote X9, and meta-analysis was performed using RevMan 5.3 software. Primary outcome measures included pulmonary embolism (PE), DVT, major bleeding events, minor bleeding events, wound complications, all-cause mortality within 90 days postoperatively, and postoperative blood loss. A total of 13 RCTs involving 13,411 patients were included, with 7,160 patients in the aspirin group and 6,251 in the LMWH group. The overall meta-analysis showed a significantly higher incidence of PE in the aspirin group than in the LMWH group (OR = 1.61, 95
Previous research has shown that cardiovascular events are more prevalent among type 2 diabetes mellitus (T2DM) patients; therefore, it is vital to reduce cardiovascular risk factors in this population. Randomized controlled trials (RCTs) investigating the effects of coenzyme Q10 (CoQ10) supplementation on cardiovascular risk factors have reported inconsistent findings. As a result, we intended to assess the effects of CoQ10 supplementation on lipid and glucose profiles, blood pressure, oxidative stress, and inflammation in patients with prediabetes and T2DM. A systematic literature search was carried out using electronic databases, including PubMed, Web of Science, and Scopus, from inception to May 2025to identify eligible RCTs evaluating the effect of CoQ10 supplementation on cardiovascular risk factors. We used STATA software to combine the individual study results for all outcomes studied. Heterogeneity tests of the selected trials were performed using the I2 statistic. All analyses were performed using random-effects models to account for potential between-study heterogeneity, and pooled data were determined as the weighted mean difference with a 95
The association between hyperlactatemia (HLA) and linezolid concentrations in elderly patients remains poorly understood. This study aimed to explore the associations among linezolid trough concentrations, HLA, and clinical outcomes in elderly patients. Elderly patients receiving linezolid treatment at four tertiary hospitals in Beijing between May 2021 and June 2023 were enrolled. Linezolid concentrations and arterial lactate levels were dynamically monitored, and risk factors for HLA and mortality were analyzed to develop a clinical prediction model. A total of 231 patients were studied, among whom 116 (50.2
Mastodynia is a common symptom in women with fibrocystic breast disease and can substantially impair quality of life. Although vitamin E is frequently used for symptom relief, the potential additional analgesic effect of fluoxetine remains unclear. This study aimed to compare the analgesic effect of fluoxetine plus vitamin E with that of vitamin E plus placebo in women with mastodynia associated with fibrocystic breast disease. This double-blind, randomized clinical trial enrolled 78 women with mastodynia associated with fibrocystic breast disease who attended clinics affiliated with Shahrekord University of Medical Sciences, Shahrekord, Iran. Participants were randomly assigned (1:1) to receive either vitamin E (400 IU/day) plus fluoxetine (10 mg/day) or vitamin E (400 IU/day) plus placebo for 8 weeks. Randomization was computer-generated, allocation was concealed using identical medication packaging, and participants, investigators, and outcome assessors were blinded to treatment allocation. The primary outcome was breast pain intensity, assessed using the Visual Analog Scale (VAS) at baseline and at 1 and 2 months after treatment initiation. Secondary outcomes included breast heaviness, breast itching, and adverse events. Data were analyzed using repeated-measures analysis of variance and appropriate categorical tests. Seventy participants (35 per group) completed the study and were included in the analysis. Baseline demographic and clinical characteristics were comparable between the two groups. Repeated-measures analysis of variance demonstrated significant effects of treatment group (F (1,68) = 11.056, P = 0.001), time (F (2,136) = 164.321, P < 0.001), and the group-by-time interaction (F (2,136) = 60.996, P < 0.001) on breast pain intensity. No significant between-group differences were observed at baseline or after 1 month of treatment; however, after 2 months, breast pain intensity was significantly lower in the fluoxetine plus vitamin E group than in the vitamin E plus placebo group (P < 0.001). Breast heaviness was also significantly less frequent in the combination therapy group after 1 month (P = 0.009). Three participants in the fluoxetine group discontinued treatment because of adverse events, and no serious adverse events were reported in either group. The addition of fluoxetine to vitamin E improved breast pain after 8 weeks compared with vitamin E plus placebo in women with mastodynia associated with fibrocystic breast disease. These findings suggest that fluoxetine may be a useful adjunctive treatment; however, larger multicenter randomized trials with longer follow-up are needed to confirm its efficacy and safety. Iranian Registry of Clinical Trials (IRCT20200205046381N1), registered on February 28, 2020.
Tricin has attracted increasing attention due to its diverse pharmacological properties, highlighting its considerable potential for clinical application. However, its potential for drug–drug interactions (DDIs) and its inhibitory effects on human cytochrome P450 (CYP450) enzymes remain unclear. This study aimed to explore the effect of tricin on CYP450s. The inhibitory effect of tricin on CYP450s was evaluated by an in vitro study using human pooled live microsomes (HLMs). Tricin, CYP450 enzymes, and the corresponding substrates were co-incubated with HLMs using a NADPH-generating system, and the HLMs incubated without tricin or positive inhibitors served as the negative control. Corresponding inhibitory parameters were obtained by incubating tricin (0-100 µM) with the specific substrates at different concentrations. Tricin showed a selective inhibitory effect on the activities of CYP1A2, 2D6, and 3A4, with the IC50 values of 12.760 µM, 14.050 µM, and 6.925 µM for CYP3A4 with testosterone as substrate, and 8.070 µM for CYP3A4 with midazolam as substrate, respectively. It was revealed that tricin competitively inhibited the activities of CYP1A2 (Ki=5.641 µM) and 2D6 (Ki=6.247 µM) while non-competitively inhibited the activity of CYP3A4 (Ki=2.876 µM). The activity of CYP3A4 was also inhibited by tricin in a time-dependent inhibition (TDI) manner with a KI of 1.418 µM and a Kinact of 0.029 min⁻¹. In vitro HLM study indicated the competitive inhibition of tricin on CYP1A2 and 2D6, while non-competitive inhibition and TDI on CYP3A4, thereby informing its potential for clinical drug interactions. Not applicable.
Desmopressin has been associated with hyponatremia-in clinical practice; however, postmarketing real-world evidence on its safety signals, susceptible populations, and time-to-onset (TTO) patterns remains limited. This study aimed to characterize desmopressin related adverse event signals in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS,2004Q1–2025Q4) and the Canadian Vigilance Adverse Reaction Database (CVARDD), focusing on hyponatremia. Signal detection was performed using four disproportionality analysis methods (reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker), with concurrent positivity across all four methods required for signal confirmation. Subgroup analyses were conducted by age and sex. For cases with complete dates, TTO was calculated and modeled using the Weibull distribution. Among 19,906,480 deduplicated reports, 3,878 listed desmopressin as the primary suspect drug. The strongest signals were observed for metabolism and nutrition disorders, particularly hyponatremia-related events (e.g., Hyponatraemia, Blood sodium decreased, Water intoxication, Hyponatraemic encephalopathy), often accompanied by seizures and other serious neurologic events. Age was the main source of heterogeneity: hyponatremia-related RORs were markedly higher in patients aged ≥ 60 years. TTO analysis showed an early-failure pattern, with 60
Lead is a ubiquitous environmental and industrial toxicant known to cause reproductive toxicity and neurotoxicity via the induction of oxidative damage and modulation of neurotransmitters. On the other hand, oleuropein and alpha-lipoic acid have independently been reported to demonstrate antioxidant and neurotransmitter modulatory activities. Here, we evaluated the protective role of oleuropein/alpha lipoic acid in lead-induced reproductive toxicity and neurotoxicity in Drosophila melanogaster. A 7-day survival analysis was carried out, and subsequently, flies were exposed to vehicle, lead acetate (20 mg/kg diet), and/or oleuropein and alpha lipoic acid (0.1 mg/kg diet) for 7 days. Oleuropein and alpha lipoic acid restored lead-induced weight loss and suppression of reduced glutathione, superoxide dismutase, and catalase activities, as well as elevated malondialdehyde contents. In addition, oleuropein and alpha lipoic acid ameliorated lead-induced increases in acetylcholinesterase and monoamine oxidase activities and reductions in acetylcholine, dopamine, and serotonin in flies. Additionally, lead-induced disruption of climbing activity, courtship and mating latencies, mating duration, copulation success rate, and emergence rate were ameliorated by oleuropein and alpha lipoic acid in D. melanogaster. Overall, oleuropein and alpha lipoic acid attenuated lead-induced reproductive toxicity and neurotoxicity in D. melanogaster. Thus, oleuropein/alpha lipoic acid is a promising candidate for further investigation against lead-induced toxicity.
Lung transplantation (LT) is the definitive treatment for end-stage chronic respiratory failure. Despite improvements in surgical and perioperative care, fungal infections remain a major complication in LT recipients, and antifungal prophylaxis with liposomal amphotericin B (L-AmB) is commonly used. However, evidence on the safety of L-AmB administration in LT recipients remains limited. This retrospective observational study aimed to assess the profile of renal, hepatic and hematologic safety, and the incidence of hypersensitivity adverse events following prophylactic L-AmB use in LT recipients. A retrospective, single-center observational study of adult patients (≥ 18 years) who underwent their first bilateral LT at the University Hospital of Padua (Italy), between January 2020 and March 2025. All patients received intravenous L-AmB (3 mg/kg/day for 5 days) as postoperative antifungal prophylaxis. Adverse effects were assessed based on acute kidney injury (AKI), liver toxicity, hematotoxicity, and infusion reactions. Laboratory values were collected at baseline, on days 1, 2, 3, 7, and 14 post-L-AmB initiation. 189 LT recipients were screened and 140 enrolled. Concerning safety profile, AKI occurred in 55 (39
Contamination of pharmaceutical syrups with ethylene glycol (EG) and diethylene glycol (DEG) has led to serious poisoning incidents worldwide, highlighting the necessity for strong regulations and reliable testing methods. A gas chromatography-mass spectrometry (GC-MS) method was developed and validated in accordance with ICH Q2(R2) guidelines. The method was developed for pharmaceutical syrup matrices and validated using multiple commercially available products, supporting its applicability for routine regulatory surveillance. It exhibited excellent linearity, with r² of 0.9991 for EG and 0.9963 for DEG. The detection (LOD) and quantification (LOQ) limits were 0.02
Fazamorexant, a dual orexin receptor antagonist (DORA) targeting insomnia, demonstrated in vitro metabolism via CYP3A4. Thus, the effects of CYP3A4 inhibitors on the pharmacokinetics, safety, and tolerability of fazamorexant were investigated. In this single-center, open-label, non-randomized, fixed-sequence study, 24 healthy subjects received a single oral dose of fazamorexant (20 mg) alone on D1, followed by a 6-day regimen of the CYP3A4 weak inhibitor ticagrelor (90 mg twice daily, Days 2 to 7) to reach steady state, with a second dose of fazamorexant co-administered on Day 6. Area under the plasma concentration–time curve from time zero to infinity (AUC0–inf), maximum plasma concentration (Cmax), time to Cmax (Tmax), and other relevant pharmacokinetic parameters were derived from plasma concentrations of fazamorexant collected at prespecified time points. Adverse events (AEs) were recorded. CYP3A4 weak inhibition by ticagrelor (90 mg, twice daily) increased the Cmax of fazamorexant by approximately 14
Titanium dioxide (TiO2) is widely present in a variety of food and personal care products, leading to frequent human exposure primarily via oral ingestion. Although the oral bioavailability of TiO2 nanoparticles is generally considered low, the gastrointestinal tract represents the primary site of exposure and may undergo local molecular and metabolic disturbances following repeated contact. In this study, we investigated the impact of TiO2 exposure on gene expression and cellular metabolism in intestinal epithelial cells using integrated transcriptomic and metabolomic approaches. Transcriptomic analysis identified differentially expressed genes associated with disruptions in cellular components, molecular functions, and biological processes, collectively pointing to mechanisms underlying TiO2-induced cytotoxicity. Metabolomic profiling further revealed that TiO2 exposure perturbed key metabolic pathways, as evidenced by significant alterations in critical metabolites—including acetylcholine, glutathione, cytosine, deoxyadenosine, and pantothenic acid—indicative of broad metabolic dysfunction. Notably, integrative correlation analysis demonstrated that TiO2 disrupts lipid metabolism, amino acid metabolism, nucleotide metabolism, energy metabolism, and redox homeostasis. In conclusion, our findings elucidate the metabolic mechanisms driving TiO2-induced intestinal toxicity. Moreover, this work underscores the power of integrated transcriptomic-metabolomic analysis as a robust strategy for mechanistic toxicological evaluation and risk assessment of nanomaterial exposure.
