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Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies.
Although microRNAs have been investigated, the reno-protective role of microRNA-205 (miR-205) in cyclophosphamide (CPA)-induced nephrotoxicity has not yet been explored. Therefore, this study evaluated the influence of buspirone on miR-205 and its downstream target EGLN2, focusing on oxidative and ER stress as key drivers of renal injury. This represents a significant gap in nephrotoxicology and epigenetic Toxicology research. Animals were randomly allocated among four groups (n = 8), including the normal control group and the CPA group that received one intraperitoneal injection of CPA at 200 mg/kg on day 7. Buspirone at 5 or 10 mg/kg per day was administered by oral gavage for ten consecutive days, whereas CPA injected on the seventh day. At experimental completion, blood samples and renal tissues were subjected to analysis using biochemical, histopathological, immunohistochemical, Western blotting, and qRT-PCR techniques. CPA induced marked renal dysfunction, reflected by elevated SCr, BUN, NGAL, and KIM-1, with evident histopathological damage. This was accompanied by miR-205 suppression, EGLN2 upregulation, impaired Nrf2 signaling, increased PC levels, and stimulation of PERK/eIF2α/ATF4/CHOP-linked ER stress signaling ( p < 0.01). Concurrently, activation of JNK1, Fos, and NF-κB increased inflammatory cytokines, and initiated caspase-dependent apoptotic signaling ( p < 0.01). Buspirone pretreatment mitigated these alterations, accompanied by increased miR-205 expression, reduced EGLN2 expression, enhanced Nrf2-associated antioxidant defenses, and attenuation of ER stress, inflammation, and apoptosis, thereby preserving renal function and tissue integrity. These findings highlight the preventive renoprotective potential of buspirone against CPA-induced nephrotoxicity and underscore the relevance of miR-205/EGLN2 signaling in renal stress responses. Future toxicokinetic and toxicodynamic studies should evaluate buspirone’s safety in tumor treatment.
Findings indicate that PLGA-MIN/CUR coatings represent a promising multifunctional strategy for enhancing implant surface performance and preventing or managing peri-implantitis.
