BMC Pharmacology & Toxicology最新文献

Acute myocardial infarction (AMI) is a leading fatal cardiovascular disease and poses a major threat to human health. Pyroptosis, an inflammation-related programmed cell death, plays a critical role in the progression of AMI. Kaempferol is a natural flavonoid compound with a variety of pharmacological effects, which exerts a significant cardioprotective function. The role of O-GlcNAcylation, a post-translation modification, has received attention in diseases including AMI. In this research, we explored the therapeutic potential of Kaempferol to AMI due to its well-known cardioprotective effect, including its antioxidant and anti-inflammatory properties. Hypoxia/reoxygenation (H/R) model was adopted to provoke myocardial injury and AMI mice model was established. Our findings indicated that H/R lessened cell viability and contributed to the release of LDH, IL-1β and IL-18, cell pyroptosis rate, and the expression of NLRP3, active caspase 1 and GSDMD-N-terminal domain (GSDMD-N). Kaempferol mitigated myocardial damage caused by H/R through repressing cell pyroptosis. Besides, we discovered that Kaempferol restored the levels of O-GlcNAcylation by regulating the activity of OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase) in H/R-treated H9c2 cells. Notably, molecular docking revealed the binding relationship between Kaempferol and OGT. Further, we proved that knockdown of OGT abrogated the function of Kaempferol in H/R-induced pyroptosis. In AMI mice, Kaempferol relieved the myocardial tissue injury and decreased the NLRP3 and GSDME-N protein levels. More importantly, our results illustrated that OGT was responsible for the O-GlcNAcylation of GSDME at T94 site and acted as an inducing factor for GSDME phosphorylation. Namely, this study validated that Kaempferol facilitated GSDME O-GlcNAcylation to inhibit H/R-induced pyroptosis in an OGT-dependent manner.

Two straightforward, affordable, accurate, and spectrophotometric techniques gross developed to assess norfloxacin, formulations, and biological samples. The oxidation of norfloxacin will be done in technique (A) in acid solution with help of Fe(III). A wavelength of 511 nm with a correlation coefficient of 0.9879 was produced by the resulting Fe(II) coupled with 1,10-phenanthroline and the red colour complex. A uniform absorbance ranging from 1 to 30 µg/mL was discovered. Similarly, in procedure (B), in an acidic medium, Ce(IV) was added to norfloxacin. After reacting with a specific amount of methyl orange, the residual Ce(IV) is then determined. An absorbance measurement at 508 nm and a correlation coefficient of 0.9966 indicate a straight-line relationship between the two variables for concentration range is 1-15 µg/mL. The procedures were developed after a careful analysis of the several elements that influence the reaction process. After calculations, the LOD (limits of detection) and LOQ (limit of quantification) were determined to be 1.098 and 1.111 µg/mL for method A and 2.875 and 3.368 µg/mL for method B respectively. The method B has also been applied for the determination of norfloxacin in spiked human plasma and urine samples. The percentage recoveries ranged from 98.74 to 103.43% and from 98.17 to 100.85% for plasma and urine samples, respectively. Proposed techniques have been successfully used for the examination of biological fluids, formulations for medicines as well as pure norfloxacin following statistical validation through recovery studies.

Background: Sickle cell disease (SCD) is a severe genetic disorder causing anemia, pain, and organ damage, affecting millions globally. Voxelotor, approved in the United States in 2019, targeted sickle cell disease pathophysiology. Despite its therapeutic benefits, concerns remain regarding its long-term safety and potential side effects, including headaches and gastrointestinal disturbances. This study used the FDA Adverse Event Reporting System (FAERS) to assess voxelotor's safety, aiming to enhance treatment strategies and clinical decision-making in SCD management.

Methods: In this study, we utilized the FAERS to extract voxelotor-related adverse event reports from 2019 to 2024. We conducted descriptive and disproportionality analyses using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS) to identify significant adverse event signals. The reliability of voxelotor adverse drug reactions (ADRs) was further improved by comparing with hydroxyurea ADRSs. Finally, adverse reactions were divided into acute ADRS, delayed ADRs and efficacy related reports to analyze the adverse event onset time.

Results: A total of 16,677,340 case reports were collected in the FAERS database, of which 20,902 reports related to voxelotor were identified. Voxelotor induced adverse events occurred in 27 system organ categories (SOC). Key system organ classes affected were the blood and gastrointestinal systems. Notably, some adverse events, such as priapism and osteonecrosis, were not listed on the drug's label. The median adverse event onset time of acute ADRs, delayed ADRs and efficacy related reports were 1, 189.5 and 271 days, respectively.

Conclusion: This study systematically analyzed ADRs of voxelotor, highlighting the need for ongoing monitoring and further research on voxelotor's long-term safety and efficacy in treating sickle cell disease.

Background: Melasma is a common hyperpigmentation disorder that causes significant distress to patients. In the real world, it is closely associated with various medications, making the timely identification and discontinuation of causative drugs an important aspect of clinical management. This study investigates the relationship between melasma and drug exposure based on data from the FDA Adverse Event Reporting System (FAERS) database.

Methods: This study includes reports from the first quarter of 2004 to the second quarter of 2024, focusing on cases related to melasma. We employed four statistical methods to analyze the association between suspected drugs and adverse events related to melasma.

Results: Within a specific timeframe, we extracted a total of 408 adverse reaction reports related to melasma. The result shows that a higher number of cases in female patients compared to male patients. The United States had the highest number of reported cases. We identified 22 drugs that were notably associated with melasma. Among these, the contraceptive "Ethinylestradiol and norethindrone" demonstrated the strongest signal of association.

Conclusions: Melasma is associated with exposure to various medications, with a notable proportion of cases coincided with contraceptive use. The mechanisms involved include hormonal disturbances and oxidative stress.

Background: This pharmacovigilance study aims to assess adverse reactions to rotigotine based on spontaneous reports in the FDA Adverse Event Reporting System (FAERS) database, providing insights for clinical dosing.

Methods: We conducted a retrospective analysis using FAERS data from Q2 2007 to Q2 2024, employing four disproportionality analysis methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multinomial Gamma Poisson Shrinkage (MGPS). These methods were utilized to detect and evaluate adverse events (AEs) associated with rotigotine.

Results: The dataset retrieved from the FAERS, encompassing 17,522,075 reports, a subset of 7,570 AE reports specifically implicated rotigotine. Upon analysis, 172 preferred terms (PTs) exhibited significant disproportionality and were consistently identified by the four employed algorithms. Particularly, product adhesion issue(N = 1,336, ROR 115,28 [108.94-121.98], PRR 108.46 [135850.43], EBGM 103.57 [98.79], IC (5.03) [5.03]) emerged as the predominant AE. Serious and unexpected AEs, such as drug ineffectiveness(N = 651, ROR 1.32 [ 1.22-1.43], PRR 1.31 [50.04], EBGM 1.31 [1.23], IC 0.39 [-1.27]), fall incidents(N = 361, ROR 2.93 [2.64-3.25 ], PRR 2.9 [451.76], EBGM 2.9 [2.66], IC 1.54 [-0.13]), and Parkinson's disease(N = 345, ROR 51.57 [46.31-57.42], PRR 50.79 [16476.71], EBGM 49.7 [45.43], IC 5.64 [3.97], were also recorded.The majority of these AEs were reported within the initial 30 days of therapy (n = 298, 22.1%), whereas a significant number were noted after 360 days of treatment (n = 507, 36.2%). The median time to the onset of AEs was 213 days.

Conclusion: Our findings, which align with the established safety profile of rotigotine, reveal the presence of unexpected serious AEs and emphasize the importance of continued vigilance in post-marketing surveillance.

Organophosphorus poisoning (OP), a prevalent form of pesticide intoxication, induces severe multiorgan dysfunction. While combined lipid emulsion (ILE) and standard treatment (pralidoxime methiodide & atropine) demonstrate improved clinical outcomes, the therapeutic mechanisms remain elusive.

Methods: An OP rat model was established for: (1) histopathological assessment via hematoxylin-eosin (H&E) staining; (2) LPS/Toll-like receptor 4 (TLR4) quantification through flow cytometry; (3) inflammatory cytokine measurement using enzyme-linked immunosorbent assay (ELISA); and (4) cytokine mRNA analysis via reverse transcription PCR (RT-PCR). TLR4 pathway validation employed anti-TLR4 intervention.

Results: After survived 24 h, multiple organs were damaged in rats with organophosphorus poisoning. Treatment with standard treatment or only lipid emulsion slightly alleviated the symptoms of poisoning, However, when standard treatment was combined with lipid emulsion, the symptoms were significantly alleviated, and the expression level of TLR4 was significantly decreased in the ST + ILE group. After anti-TLR4 was used to block the LPS/TLR4 pathway, liver function and acetylcholinesterase(AchE) levels in rats were significantly improved(P < 0.001), lung and heart pathology improved, and inflammatory cytokines were reduced; Moreover, the expression level of TLR4 in heart and lung also decreased significantly(P < 0.01). As a result, the symptoms of organ poisoning were relieved.

Conclusion: Lipid emulsion is involved in the protective effect via the LPS/TLR4 pathway on vital organs inacute or organophosphorus poisoning.

Background: Cold ischemia-reperfusion (IR) injury is a multifactorial process detrimental to liver graft function during liver transplantation (LT). Although flushing hepatic grafts prior to reperfusion have been well explored, the optimal graft rinse solution to prevent cold IR injury remains largely undefined. The aim of this study was to evaluate whether a new rinse solution combining polyethylene glycol PM 35,000 Da (PEG35) with lactated solution (RLS) could mitigate cold IR injury in Wistar rats.

Methods: Livers were isolated, preserved for 24 h and flushed immediately before ex vivo reperfusion with either RLS or PEG35-enriched RLS. Liver injury, graft function, energy balance, autophagy, oxidative stress as well as inflammatory response were assessed.

Results: Flushing hepatic grafts with PEG35-enriched RLS resulted in decreased transaminase levels after cold ischemia. The improved graft function was evidenced by increased bile flow, enhanced BSP clearance, and reduced vascular resistance in these flushed grafts. Phospho-AMPK protein expression, as well as LC3B gene and protein expression were significantly increased compared to those unflushed and flushed only with RLS. PEG35-enriched RLS also maintained the oxidative state, as indicated by reduced activities of antioxidant enzymes and decreased MDA concentration. Additionally, this graft rinse solution down-regulated the inflammatory response by inhibiting the expression of genes involved in the HMGB-1/NF-κB/TNF-α signaling pathway.

Conclusion: These data strongly suggest that rinsing liver grafts with PEG35-enriched RLS prior to reperfusion represents a simple and cost-effective strategy to enhance liver functional recovery after cold IR injury. This approach could serve as a viable alternative to RLS in clinical applications, highlighting the need for further research to explore its broader implications.

This study aimed to investigate the protective effect of quercetin against arsenic-induced oxidative damage, inflammation, and apoptosis in mouse BALB/c 3T3 fibroblast cells (NIH-3T3). Arsenic at different concentrations of 0.05 µM (low), 0.5 µM (medium), 10 µM (high) doses were used to induce toxicity, while 120 μm quercetin was used for treatment. MTT and LDH analyses were performed to determine the effect of arsenic and quercetin on cell viability, while oxidative stress markers and antioxidant enzyme activities were measured by spectrophotometric method. TNF-α and IL-1β levels were measured by the ELISA method, Autodock programs were used for molecular docking studies. In addition, computer-based analyses of quercetin and succimer molecules were performed using SwissADME web tools. TNF-α (PDB ID: 2AZ5), IL-1β (PDB ID: 1ITB), Caspase3 (PDB ID: 2XYG), Bax (PDB ID: 4S0O), SOD (PDB ID:1CBJ), GSH-Px (PDB ID: 1GP1) and Bcl-2 (PDB ID: 1G5M) crystal structures were obtained from the Protein Data Bank. Bax and Bcl-2 levels of apoptotic genes and mRNA expression levels of Caspase-3 activity were measured using the QRT-PCR technique. TUNEL staining was performed to determine DNA fragmentations, while DAPI staining was done to visualise nuclear modifications. Quercetin has been found to significantly reduce oxidative stress, inflammation, and apoptosis in cells and exert anti-apoptotic effects. Molecular docking studies revealed quercetin shows good binding affinity with molecules with SOD, GSH-Px, Bax, Bcl-2, Caspase-3, TNF-α and IL-1β structures, and has been observed to bind with Bax and Bcl-2 with molecular docking scores of -7.5 and - 7.7 kcal/mol, respectively. These findings are supported by results showing that quercetin is effective in anti-apoptotic and anti-inflammatory processes in arsenic-induced cells under in vitro conditions. In addition, when ADME values are examined, it can be considered that quercetin is a useful and effective candidate compound in reducing arsenic toxicity, considering its higher synthetic accessibility score, better pharmacokinetic properties, and good biological transition and interaction capacities compared to succimer.

Lead is a heavy metal contaminant that can cause significant alterations in renal structure and function, resulting in nephrotoxicity. The fatty acids of royal jelly exhibit immunoregulatory, anticancer, anti-inflammatory, and antioxidant properties, which have garnered significant interest. The most prevalent among them is 10-hydroxydecanoic acid (10-HDA). Zinc oxide nanoparticles (ZnONPs) demonstrate a renoprotective effect, likely due to their antioxidant, anti-inflammatory, and antiapoptotic properties. This study evaluated the therapeutic efficacy of 10-HDA and ZnONPs, administered either as monotherapy or in combination, against lead-induced nephrotoxicity. Male rats were orally administered lead acetate (PbAc) for three months, followed by the administration of 10-HDA and/or ZnONPs for one month. Exposure to PbAc resulted in elevated renal lead concentration, as well as increased serum levels of urea, creatinine, and cystatin C. The condition resulted in damage to the renal parenchyma, characterised by degenerative glomeruli and tubules, and exhibited the highest lesion score. Nrf2 and HO-1 exhibited reduced expression and diminished antioxidant enzyme levels subsequent to PbAc poisoning. Additionally, there was an increase in the inflammatory and apoptotic signalling through the p-IKK/NF-κB axis. The administration of 10-HDA and ZnONPs significantly decreased renal lead levels and improved antioxidant capacity. Moreover, renal inflammatory markers (TNF-α, p-IKK, IL-1β, IL-6, and IL-8) and proapoptotic indicators (Bax and Caspase-3) were significantly suppressed. The combined therapy demonstrated a synergistic effect (combination index < 1). In conclusion, the results indicated that 10-HDA and ZnONPs have the potential to be a supplement or even an effective treatment to alleviate the adverse effects of lead poisoning. This is potentially attributed to their potent ameliorative actions against oxidation, inflammation, and apoptosis.

Background: Hepatotoxicity of pyrazinamide, an antituberculosis drug, limits its therapeutic use and oxidative stress has been implicated in this toxicity. This study investigated the protective effects of adenosine triphosphate (ATP), thiamine pyrophosphate (TPP), melatonin, and Liv-52, which have previously been shown antioxidant activities, on pyrazinamide-induced hepatotoxicity.

Methods: 36 albino Wistar male rats were divided into randomized six groups; healthy (HG), pyrazinamide (PZG), ATP + pyrazinamide (APZG), TPP + pyrazinamide (TPZG), melatonin + pyrazinamide (MPZG) and Liv-52 + pyrazinamide (LPZG) groups. ATP 4 mg/kg and TPP 25 mg/kg were administered intraperitoneally (IP). Melatonin 10 mg/kg and Liv-52 20 mg/kg were given orally. One hour after administration of ATP, TPP, melatonin, and Liv-52, 250 mg/kg pyrazinamide was applied orally to all rats except HG group. The treatment was repeated (1 × 1) for 4 weeks. Then, blood samples were taken for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Immediately after, the rats were euthanized with thiopental sodium (50 mg/kg, IP), and the livers were removed. The tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) also hydropic degeneration, necrosis, and apoptosis (caspase 3) were examined.One-Way ANOVA was used in biochemical analyses and Tukey test was used as post-hoc. For histopathological and immunohistochemical analysis, the Kruskal-Wallis test was used and Dunn's test as a post-hoc.

Results: Pyrazinamide increased MDA land decreased tGSH, SOD, and CAT levels in liver tissues (p < 0.001). It also increased serum ALT and AST activities and caused severe hydropic degeneration and necrosis in liver tissue (p < 0.001). ATP, TPP, melatonin, and Liv-52 significantly prevented the biochemical and histopathological changes induced by pyrazinamide (p < 0.05). On the other hand, Liv-52 was more successful than other potential protectors in protecting liver tissue from pyrazinamide damage (p < 0.05).

Conclusions: ATP, TPP, melatonin, and Liv-52 can be used to protect liver tissue from pyrazinamide-induced hepatotoxicity in rats.