Targeting oxidative stress-NLRP3-apoptotic-steroidogenic axis in doxorubicin-induced testicular toxicity: protective efficacy of ferulic acid niosomes

Protective Effects of Icariin-Loaded Nanoliposomes against Methotrexate-Induced Testicular Toxicity via Modulation of NRF2/NF-κB and Ferroptosis Signaling.

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, its clinical use is limited by severe testicular toxicity associated with oxidative stress, inflammation, apoptosis, and ferroptosis. Therefore, the present study investigated the protective effects of icariin-loaded nanoliposomal formulation (ICA-LNPs) against MTX-induced testicular injury in rats compared with crude icariin (ICA). Sixty adult male Sprague Dawley rats were randomly allocated into six groups: control, ICA, ICA-LNPs, MTX, MTX+ICA, and MTX+ICA-LNPs. MTX administration markedly impaired reproductive function, evidenced by significant reductions in testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sperm count, motility, and viability, together with increased sperm abnormalities. MTX also disrupted the NRF2/HO-1/NQO1 signaling pathway, suppressed antioxidant defenses, and elevated oxidative stress markers. In addition, MTX significantly activated NF-κB-mediated inflammatory responses, enhanced apoptotic and ferroptotic pathways, increased iron accumulation and ACSL4 expression, and reduced GPX4 and SLC7A11 expression in testicular tissue. Histopathological examination further confirmed severe degeneration of seminiferous tubules and impaired spermatogenesis. Treatment with ICA-LNPs significantly ameliorated these alterations and demonstrated superior protective efficacy compared with crude ICA. ICA-LNPs restored reproductive hormones, improved semen quality, enhanced antioxidant status, suppressed inflammatory mediators, reduced apoptosis and ferroptosis-related markers, and preserved normal testicular histoarchitecture. Furthermore, GPX4 immunoreactivity was markedly increased, whereas ACSL4 expression was significantly reduced following ICA-LNPs treatment. In conclusion, ICA-loaded nanoliposomal formulation effectively attenuated MTX-induced testicular toxicity and was associated with reduced oxidative stress, inflammation, apoptosis, and ferroptosis, highlighting its potential as a promising therapeutic strategy for preserving male reproductive function.

Nicotinamide Riboside Attenuates Cisplatin-Induced Hepatorenal Toxicity Through Restoration of NAD+ Homeostasis and Nrf2/NQO1-Dependent Antioxidant Signaling

Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD+ homeostasis.

Quinic acid attenuates cisplatin-induced acute kidney injury by modulating inflammatory cytokines, oxidative stress, apoptosis, and the Nrf2/HO-1/NQO1 pathway in rats.

BACKGROUND The nephrotoxicity induced by cisplatin (Cis) is mediated by oxidative stress, inflammation, and apoptosis, which limit the clinical utility of this commonly used chemotherapeutic drug. Natural polyphenolic compounds such as quinic acid (QA) have cytoprotective and antioxidant properties. This study evaluated the protective effect of QA against cisplatin-induced acute kidney injury (AKI) in rats and its impact on the associated oxidative, inflammatory, apoptotic, and Nrf2/HO-1/NQO1 pathways. METHODS Forty male Wistar rats were randomly divided into five groups (n = 8): Control, Cis (7.5 mg/kg, i.p.), Cis + QA was administered orally at doses of 25, 50, or 100 mg/kg once daily for 14 days before the cisplatin challenge. Biochemical markers (BUN, creatinine, KIM-1, NGAL), oxidative stress indices (MDA, NO, GSH, TAC, SOD, CAT, GPx), inflammatory cytokines (TNF-α, IL-1β), apoptotic gene expression (Bax, Bcl-2, Caspase-3), and Nrf2 pathway proteins (Nrf2, HO-1, NQO1) were assessed. Renal histopathology was evaluated using blinded scoring. RESULTS Cisplatin caused severe renal dysfunction, oxidative imbalance, inflammation, and apoptosis, along with the suppression of Nrf2/HO-1/NQO1 signaling. QA, particularly at doses of 50 and 100 mg/kg, significantly improved serum renal markers, restored antioxidant capacity, reduced MDA and NO levels, downregulated TNF-α and IL-1β, modulated apoptotic gene expression toward cell survival, and enhanced Nrf2-pathway protein levels. Histological injury scores were significantly lower in groups treated with QA.The antioxidant, anti-inflammatory, anti-apoptotic, and Nrf2-pathway-modulating properties of quinic acid markedly attenuate cisplatin-induced AKI. Further mechanistic and translational research on QA to evaluate its potential as a nephroprotective adjunct is warranted.

Hesperidin mitigates DEHP-induced nephrotoxicity through anti-oxidant, anti-apoptotic, and anti-inflammatory pathway modulation: Evidence from Nrf2/HO-1/Keap-1, Bax/Bcl-2/caspase-3, and TLR4/NF-κB axis activation

Objective(s): This study aimed to assess the protective role of hesperidin (HSP), a citrus flavonoid, against di-(2-ethylhexyl) phthalate (DEHP)-induced kidney toxicity in rats, focusing on oxidative stress, apoptosis, inflammation, and anti-oxidant defense pathways. Materials and Methods: Thirty-five male rats were randomly assigned into five groups (7 per group): control group, DEHP-treated group (1 g/kg), DEHP + HSP (100 mg/kg) group, DEHP + HSP (200 mg/kg) group, and HSP-alone group, and treated orally for 10 consecutive days. Kidney tissues were collected for biochemical assays, including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Gene expression of Nrf2, Keap1, HO-1, Bax, Bcl-2, Caspase-3, TLR-4, and NF-κB was analyzed using real-time PCR, and protein levels were evaluated using Western blotting. Results: DEHP significantly increased oxidative damage and the expression of inflammatory and apoptotic markers, while decreasing anti-oxidant parameters. Co-treatment with HSP, particularly at 200 mg/kg, restored anti-oxidant balance, reduced lipid peroxidation, and down-regulated the expression of TLR-4, NF-κB, and Caspase-3. Moreover, HSP increased Bcl-2 levels and enhanced Nrf2/HO-1 signaling, as confirmed by both gene and protein expression data. Conclusion: HSP demonstrates dose-dependent renoprotective effects against DEHP-induced nephrotoxicity in rats. The protective mechanism involves anti-oxidant enhancement and inhibition of oxidative stress-induced inflammation and apoptosis, supporting the therapeutic potential of HSP in managing phthalate-related renal injury.

Liposomal Nano-Curcumin Attenuates Cisplatin-Induced Hepatotoxicity in Rats with Concomitant Regulation of Wnt/β-Catenin/GSK-3β and Nrf2 Signaling

Objective: This research examined the effectiveness of liposomal N-Curcumin (N-Cur) against Cis-diamminedichloroplatinum (CDDP)-induced hepatotoxicity, specifically examining its ability to influence the Wnt/β-catenin/GSK-3 pathway and associated molecular markers. Methods: Male Wistar rats were treated for 14 days with oral N-Cur (80 mg/kg) and with a single intraperitoneal dose of CDDP (7 mg/kg) administered on day 7. Hepatic integrity was assessed through liver injury markers, histopathological examination, and biochemical analysis of oxidative stress (SOD, GSH, and MDA), inflammation (IL-10, TNF-α, CRP, and NF-κB p65), and signaling protein expression (β-catenin, Nrf2, and GSK-3). Results: CDDP administration resulted in significant hepatic damage, characterized by elevated injury markers and distorted tissue architecture. It induced severe oxidative stress (increased MDA; decreased GSH and SOD) and a robust inflammatory response. At the molecular level, CDDP suppressed the cytoprotective β-catenin and Nrf2 pathways while increasing GSK-3. Conversely, N-Cur treatment effectively reversed these pathological shifts by restoring antioxidant defenses, inhibiting pro-inflammatory mediators, and normalizing the Wnt/β-catenin/GSK-3 signaling axis. Conclusions: Liposomal N-Cur demonstrates significant potential as a hepatoprotective agent when administered concomitantly with CDDP chemotherapy. N-Cur mitigates oxidative damage and inflammation, thereby preserving hepatic function during CDDP-based chemotherapy. In addition, these favorable effects were associated with modulation of the Wnt/β-catenin/GSK-3 and Nrf2 pathways.

Enhanced hepatoprotective effects of fisetin-loaded liposomal nanoparticles against DEHP-induced liver injury in rats: modulation of oxidative stress, inflammation, apoptosis, and ferroptosis pathways.