BMC Pharmacology & Toxicology最新文献

The liver has a tremendous regeneration potential, yet chronic liver injury poses a life-threatening condition if not managed appropriately. Apocynin, an NADPH oxidase inhibitor, has been a central focus of attention in recent years due to its significant antioxidant/anti-inflammatory potentials. In this study, we evaluated the acute toxicity and hepatoprotective effects of Apocynin against thioacetamide (TAA)-induced liver fibrosis in rats. Liver fibrosis was induced by 200 mg/kg TAA three times/week for two months, along with treatment with distilled water (positive control), silymarin (reference, 50 mg/kg), or apocynin (50 and 100 mg/kg/day). Hepatic tissues were screened for histopathological, biochemical, and immunohistochemical changes, while hepatic homogenate was examined for the antioxidant contents (catalase, CAT; superoxide dismutase, SOD) and MDA levels. Apocynin treatment showed significant hepatoprotective effects against TAA-hepatotoxicity, evidenced by reduced hepatic tissue alterations with a slight fibroplasia, reduction of hepatomegaly, less hepatic nodules/necrosis, and recovered hepatic function. Additionally, apocynin administration reduced oxidative stress by lowering pro-oxidants (MDA) and up-regulating antioxidants (SOD and CAT). Furthermore, the anti-apoptotic and anti-fibrotic effects of apocynin were confirmed by reduced pro-apoptotic P53 proteins and β-catenin (tissue proliferation/aggregation enhancer). Apocynin treatment ameliorated ECM generation (lowered collagen bundles/fibrous septa) and reduced inflammatory (less TNf-α and IL-6 cytokines) mediators, all of which restored liver functional parameters (ALT, AST, ALP, and albumin). Apocynin attenuated TAA-mediated liver fibrosis by its modulatory potentials on several cytoprotective mechanisms associated with the oxidative stress/inflammation, making it a viable therapeutic source for liver fibrosis.

Inorganic arsenical compounds, such as arsenic trioxide (ATO), are toxic environmental contaminants that occur widely in soil, water, and biological systems. Besides, zinc oxide nanoparticles (ZNPs) have been recently incorporated in various industrial and medicinal applications. Thus, their co-existence in the environment could widely occur. This study examined the potential protective activity of gallic acid (GA, 20 mg/kg b. wt) against the harmful impacts of 60-day co-exposure to ATO (8 mg ATO/kg b. wt) and ZNPs (100 mg ZNPs/kg b. wt) on the kidneys of rats. The results indicated that ZNPs and/or ATO exposure resulted in increased serum levels of markers associated with renal damage, an imbalance in electrolytes (sodium, potassium, and calcium), diminished levels of antioxidant enzymes in the kidneys, and an increased malondialdehyde (MDA) concentration. Furthermore, ZNPs and/or ATO co-exposed rats demonstrated markedly increased levels of renal zinc (Zn) and arsenic (As), accompanied by pronounced histopathological alterations, including interstitial nephritis, renal tubular necrosis, and vascular wall thickening. Immunohistochemical analysis revealed that exposure to ZNPs and/or ATO reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while increasing that of heat shock protein 90 (HSP90) in kidney tissues. Co-exposure to ZNPs and ATO produced more pronounced alterations, including increased serum uric acid and creatinine, decreased sodium levels, reduced renal GPx activity, increased MDA content, greater renal accumulation of As and Zn, and diminished Nrf2 expression, compared with individual exposures, suggesting additive toxic effects. However, GA notably reduced renal tissue damage, oxidative stress, and disturbances in renal function and electrolyte balance in rats co-exposed to ZNPs and ATO. Conclusively, the study found that exposure to ZNPs and ATO, especially when combined, was toxic to the kidneys, leading to impaired renal function through increased oxidative stress and disrupted electrolyte balance. However, GA effectively protected kidney health at the administered doses by counteracting these effects through its antioxidant properties and by modulating cellular defense mechanisms involving Nrf2 and HSP90.

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide known for its wide-ranging effects on epilepsy, neuropathic pain, and migraines. However, its precise influence on plasmalemmal ionic currents, including their magnitude and gating kinetics, remains uncertain. Therefore, a reassessment of the regulatory effect of TPM on ionic currents in electrically excitable cells is warranted.

Methods: With the aid of patch clamp technology, we investigated the effects of TPM on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from GH₃ lactotrophs.

Results: We observed that TPM exhibited a concentration-dependent inhibition of both transient (I_Na(T)) and late (I_Na(L)) components of I_Na, activated by brief depolarizing stimuli. At low concentration, TPM did not show any noticeable effect on I_Na(T); however, it was effective in reducing I_Na(L) amplitude. TPM caused a leftward shift in the midpoint of the steady-state inactivation curve of I_Na(T) without altering the gating charge. Importantly, the overall current density versus voltage relationship of I_Na(T) remained unaltered during TPM exposure. Intriguingly, the reduction in I_Na(T) induced by TPM could not be reversed by subsequent additions of flumazenil or chlorotoxin. Furthermore, TPM suppressed the density of the hyperpolarization-activated cation current (I_h). Simultaneously, the activation time course of I_h slowed in the presence of TPM. Moreover, TPM exposure decreased the hysteretic strength activated by double triangular ramp voltage, a change partially reversed by oxaliplatin. In current-clamp potential recordings, spontaneous action potentials were susceptible to suppression in the presence of TPM.

Conclusions: Collectively, these findings strongly suggest that TPM's effects on I_Na and I_h have the potential to impact the functional activities and electrical behaviors of excitable cells.

Histone deacetylases (HDACs) are enzymes responsible for removing acetyl groups from histone proteins, resulting in chromatin condensation and the repression of genes. They regulate the expression of genes, the cell cycle, and multiple cellular processes. Hydroxamic acid is a well-recognized moiety characterized by its potent zinc-binding ability, making it an effective inhibitor of HDACs. A novel hydroxamic acid-based molecule, N¹-(2,2'-bipyridin-6-yl)-N⁸-hydroxyoctanediamide (compound 3B), was previously synthesized, and the anticancer properties of the compound were examined in vitro in our laboratory. No prior toxicological study has been performed on this compound. Therefore, the current investigation focused on the acute oral toxicity of compound 3B in female BALB/c mice, adhering to OECD 423 guidelines. In this study, compound 3B was given orally at 300 mg/kg body weight (b.w.) or 2000 mg/kg b.w. The food consumption and body weight of the mice did not differ significantly between the control and treated groups. Variations were observed in the levels of a few of the biochemical markers. Histopathological examination revealed inflammatory infiltration and lesions in a few vital organs. The comprehensive investigation revealed that compound 3B exhibited moderate toxic effects at a relatively high dosage of 2000 mg/kg in few organs and caused alterations in biochemical markers; however, it did not result in any mortality, indicating that the LD₅₀ value exceeded 2000 mg/kg. Compound 3B can be administered at concentrations less than 2000 mg/kg for subsequent studies.

Background: Erectile dysfunction (ED) is a common male sexual disorder with a multifactorial etiology. The exposure to endocrine-disrupting chemicals (EDCs) has been increasingly linked to reproductive health disorders in both men and women. EDCs can interfere with hormonal signaling and physiological homeostasis, but their specific roles and mechanisms in contributing to ED remain inadequately elucidated.

Methods: Network toxicology and enrichment analysis were used to identify potential targets and signaling pathways involved in ED induced by EDCs. Single-cell sequencing was conducted to analyze the expression profiles of these targets in corpus cavernosum tissue. Key regulatory molecules were identified through protein-protein interaction (PPI) network analysis. Core targets were selected using three machine learning algorithms to evaluate the association between EDCs and ED. Molecular docking simulations were further employed to verify the binding affinity between EDCs and target proteins, elucidating potential mechanisms of action.

Results: A total of 186 potential targets were identified. Single-cell sequencing revealed their expression characteristics. PPI analysis identified key regulatory molecules, and machine learning approaches pinpointed two core targets: CTNNB1 and HIF1A. Molecular docking confirmed that most EDCs exhibit stable binding to CTNNB1 and HIF1A, suggesting the involvement of associated signaling pathways in the development of ED.

Conclusions: This study systematically characterizes the molecular pathways through which EDCs contribute to ED, with CTNNB1 and HIF1A emerging as central players. The identification of these core targets provides a theoretical foundation for developing targeted interventions against environment-related ED and underscores the importance of mitigating EDC exposure in public health strategies.