Basic & Clinical Pharmacology & Toxicology最新文献

Central nervous system tuberculosis (CNS-TB) represents a critical form of extrapulmonary tuberculosis, characterized by high mortality and morbidity. The infection of microglia by Mycobacterium tuberculosis (Mtb) is a crucial factor in the progression of CNS-TB. Ferroptosis plays a significant role in various neurological disorders. However, it remains unclear whether Mtb can induce ferroptosis in microglia and what mechanisms underlie this process. This study demonstrated that Mtb H37Rv infection can induce ferroptosis in microglia, which is characterized by the accumulation of ferrous ions, increased levels of lipid ROS, depletion of glutathione, enhanced lipid peroxidation and reduced expression of Slc7a11 and Gpx4. Additionally, Mtb infection upregulated Sp1 expression, and Sp1 knockdown led to a suppression of ferroptosis induced by Mtb. Mechanistically, we found that Sp1 enhanced the transcription of Mettl14. Subsequently, the N6-methyladenosine modification mediated by Mettl14 stabilized the mRNA of Acsl4, ultimately inducing ferroptosis. Mettl14 also was found to enhance the stability of Sp1 mRNA, establishing a positive regulatory feedback loop. Moreover, knockdown of Acsl4 attenuated Sp1- or Mettl14-mediated ferroptosis in Mtb-infected microglia. Overall, our findings establish a connection between Mtb infection and ferroptosis and delineate a novel mechanism through which H37Rv induces ferroptosis in microglia via the Sp1-Mettl14-Acsl4 axis, offering new insights into the pathogenesis of CNS-TB.

Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1–mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1–mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by central nervous system demyelination, leading to sensory and motor dysfunction. Previous studies have demonstrated that the kappa opioid receptor agonist nalfurafine (Nalf) reduces disease severity and promotes remyelination in the experimental autoimmune encephalomyelitis (EAE) model of MS. However, the pharmacokinetics of Nalf and its optimal administration route for clinical translation remain unexplored. To investigate Nalf's pharmacokinetics and identify an effective oral delivery strategy, we successfully optimized a liquid chromatography–mass spectrometry (LC–MS) method for detecting Nalf in plasma and brain tissues of mice treated via intraperitoneal (ip) or oral administration. Nalf exhibited similar pharmacokinetic profiles following both ip and oral administration, with the oral route achieving almost 70% bioavailability and a longer elimination half-life compared to ip. Nalf effectively reached the brain and significantly reduced a range of disease parameters in EAE in a dose-dependent manner. Our findings demonstrate that oral administration of Nalf is pharmacokinetically favourable and effectively reduces disease disability and promotes remyelination in the EAE model. This study supports the clinical development of oral Nalf as a potential treatment for MS, offering an effective and noninvasive alternative to injections.

Vincristine (VCR) is a common drug used for this purpose. Apilarnil is a substance known for its antioxidant, antidiabetic and chemoprotective properties with positive effects on the reproductive system. In this study, the effects of apilarnil against testicular damage in vincristine-treated rats were investigated. For this purpose, 35 male Sprague–Dawley rats were used in the study. The rats were divided into five groups as control, VCR, APL, VCR + APL 200 mg/kg of body weight and VCR + APL 400 mg/kg of body weight. VCR was administered intraperitoneally between days 1–6 and 9–14, while APL was administered by oral gavage for 14 days. After the study, rats were sacrificed, testicular tissues were removed and examined biochemically and histopathological, and epididymis tissue was used for spermatological analysis. VCR administration induced oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis in testicular tissue, leading to changes in testicular histology and decreased epididymal sperm quality. APL administration, on the other hand, suppressed oxidative stress, apoptosis, ER stress and inflammation while preserving testicular histology and preventing the decrease in epididymal sperm quality. In conclusion, APL has protective effects against the damage caused during chemotherapy.