Background: Traumatic brain injury (TBI) is a leading cause of mortality worldwide and often results in substantial cognitive, motor, and psychological impairments, triggering oxidative stress, neuroinflammation, and neurodegeneration. This study examined the neuroprotective effects of azithromycin (AZI) in TBI. Methods: TBI was induced in rats using the weight-drop method. Subsequently, rats received a daily intraperitoneal (I.P.) dose of AZI (150 mg/kg) for 28 days. Behavioral tests (Morris water maze, rotarod, and open field tests) were performed to assess cognitive and motor functions. Neurochemical analyses included oxidative stress markers (GSH, SOD, MDA, catalase), inflammatory cytokines (TNF-α, IL-1β), apoptotic markers (caspase-3, Bax, Bcl-2), mitochondrial complexes (complex I, II, III, IV, and V), and the transforming growth factor- beta (TGF-β) as a neurofilament marker. Histological evaluations focused on neuronal integrity in the cortex, hippocampus, and striatum. Results: Treatment with AZI significantly facilitated motor and cognitive function recovery in TBI-affected rats. At the molecular level, AZI effectively reduced oxidative stress markers, ameliorated neuroinflammation by decreasing TNF-α, IL-1β, and neuronal apoptosis, and differentially modulated mitochondrial complexes. Histological assessments revealed enhanced neuronal integrity and fewer pathological changes in AZI-treated rats compared to untreated TBI controls. Conclusions: AZI was shown to interfere with several pathways involved in TBI’s pathophysiology. While preclinical results are promising, further studies are necessary to establish the long-term safety and efficacy of AZI in a clinical setting. This research supports the potential re-purposing of AZI as a novel treatment strategy for TBI and related neurodegenerative disorders.

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways.

This study is designed to highlight the comparative efficacy of nicorandil (NO donor/K_ATP opener) vs nebivolol (β1blocker with NO-induced vasodilatory and antioxidant actions) in a rat model of unilateral ureteric obstruction (UUO) to assess whether mitigating oxidative stress, inflammatory drive, and apoptosis could modulate UUO -driven fibrogenic remolding.Moreover, their therapeutic potential was further assessed by docking analysis. Sham control group (1); UUO Group (2); Group (3): The nicorandil-treated group, in which rats received 15 mg/kg/day following ureteric obstruction for 21 days, and Group (4): the nebivolol-treated group, in which rats received 2 mg/kg/day orally following ureteric obstruction for 21 days. bioinformatically, Notable findings include nebivolol's superior binding affinity to Catalase, TGFβ1R and LOX-1 and nicorandil's higher affinity to TP53and Smad-3. These interactions suggest that both compounds may mitigate oxidative stress, inflammation, and fibrosis. Nebivolol potentially offers greater renal protection through enhanced suppression of pro-inflammatory signaling. Mechanistically, nebivolol demonstrates superior efficacy through coordinated modulation of key molecular pathways. Nebivolol disrupts the self-amplifying cycle of oxidative stress and inflammation by upregulating SIRT-1, miRNA200a expression restoring Nrf2 activity, and downregulating Keap1 re-establishing redox homeostasis. It further attenuates NF-κB-driven proinflammatory signaling and suppresses downstream PKC/p38 MAPK activation, reducing fibrotic and apoptotic responses. Concurrently, nebivolol enhances protective signaling via PPARγ, Klotho, and CREB, promoting cellular resilience and structural preservation. These multifaceted actions converge to normalize renal function, mitigate tissue injury, and maintain glomerular-tubular integrity. By targeting interconnected redox, inflammatory, and apoptotic pathways, nebivolol could emerge as a mechanistically therapeutic candidate, offering promise for repurposing in obstructive nephropathy and potentially in broader contexts of chronic kidney disease characterized by complex molecular dysregulation.