Background/Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a promising therapeutic avenue against mammary cancer. Thus, we investigated whether the EGFR inhibitor Nano-Gefitinib bilosome decreases Ehrlich tumor cells in a murine model, given that EGFR has been linked to carcinoma–macrophage crosstalk. Methods: Forty female mice were divided into control, Nano-Gefitinib, Ehrlich tumor and combination groups; the latter received Nano-Gefitinib treatment after tumor induction and lasted for 18 days. Results: Our results showed that Nano-Gefitinib ameliorated Ehrlich-induced hepatic injury, oxidative stress, and apoptosis in mice, as indicated by a significant reduction in serum level of hepatic enzymes, oxidative biomarkers (malondialdehyde and oxidized glutathione), total cholesterol, triglycerides, LDL, and BAX, along with an increase in antioxidant biomarkers, serum total protein, albumin, HDL, and hepatic antiapoptotic Bcl-2. A substantial reduction in tumor volume and size was noted in the combination group and was evidenced histopathologically by a reduction in tumor cell progression, mitotic activity, and giant cell formation. In addition, Nano-Gefitinib significantly inhibited EGFR/p-AKT/ERK1/2/RIPK2/NF-κB with subsequent suppression of TGF-triggered M2 macrophage reprogramming, evidenced by the lowered protein expression of the M2 surface markers CD163 and decreased M2 protein expression (Fizz1, MMPs, and VEGF). Additionally, Nano-Gefitinib significantly increased M1 macrophage phenotype, evidenced by the upregulation in the immunoexpression of the CD68, in addition to increasing CD8 and caspase-3 and decreasing CD4, with VEGF immunoreactivity in the combination group. Conclusions: Gefitinib biosomes encouraged macrophage polarization, apoptosis, and reduced inflammation, with a subsequent decrease in tumor volume.

Fipronil (FIP), as a broad-spectrum pesticide, contributes to adverse reproductive effects. Thus, our study aimed to investigate the effect of telmisartan (TEL) as a selective angiotensin 1 receptor (AT1R) blocker on mitochondrial damage induced by FIP intoxication in male rats. Forty healthy male albino rats were allocated into 4 groups (10/ group): the control group, the TEL group received TEL (10 mg/kg b.wt.), the FIP group received FIP (1/10 of the LD50 of 97 mg/kg b.wt.), and the FIP + TEL cotreated group. All treatments were taken orally for 60 days. Before the experiment, in-silico assessments of FIP and TEL were done. FIP administration diminished relative testicular weight, sperm count, and motility, besides significantly increasing sperm abnormalities ( p < 0.05). Biochemically, FIP treatment reduced considerably ( p < 0.05 ) serum testosterone, luteinizing hormone (LH), and follicular-stimulating hormone (FSH) levels related to control animals. Furthermore, FIP administration significantly increased testicular malondialdehyde (MDA), pro-inflammatory markers as tumor necrosis factor- α (TNF- α ), and interleukin-1 β (IL-1 β ) levels. Also, downregulated the activities of antioxidant markers, Nrf2, HO-1, and PCNA immunostaining. Furthermore, FIP significantly upregulated ( p < 0.05) DRP1 and downregulated PGC-1 α , MNF2, TFAM, and mtDNA mRNA transcripts. Histopathologically, FIP induced deterioration in seminiferous tubules' histoarchitecture with upregulation in Cosentino's score and downregulation in Johnson's score. On the contrary, TEL effectively restored the testicular function hormones, testicular and epididymal histoarchitecture, antioxidant indices, PGC-1 α , and TFAM, with downregulation in MDA levels and DRP1 mRNA transcript. In conclusion, TEL protects the testicular mitochondria against damage from FIP toxicosis by modulating the Nrf2/HO-1/PGC-1α/MNF2/DRP1 expressions. Graphical Abstract

Background: This study investigated the renoprotective potential of Nano-Cilostazol against cisplatin (CIS)-induced renal injury in male rats and explored its molecular mechanisms. Our results showed that Nano-Cilostazol has a favorable physicochemical characteristic, including a mean particle size of approximately 101 nm, narrow polydispersity, and high stability. FTIR analysis indicated successful drug entrapment, preserving functional groups and enhancing hydrogen bonding. Docking analysis showed that cilostazol had stronger binding affinities than disulfiram against seven acute kidney injury-related targets. Interaction profiling confirmed stable binding through hydrogen bonding, hydrophobic, and π-interactions with BAX, ASC, GSDMD, KIM-1, JAK2, NLRP3, and miRNA-155. In vivo, CIS administration led to marked renal dysfunction, showing up as significant elevations in serum urea, creatinine, cystatin-C, CRP, and NGAL which indicated by severe histopathological damage. Co-treatment with Nano-Cilostazol significantly lessened renal functional impairment biochemically and histopatologically. Nano-Cilostazol markedly reduced lipid peroxidation and oxidized glutathione while also restoring antioxidant defenses like superoxide dismutase and catalase, with total and reduced glutathione. Additionally, Nano-Cilostazol attenuated renal inflammation, inhibiting NF-κB activation, lowering pro-inflammatory cytokines (TNF-α and IL-1β), and downregulating inflammatory and injury-related genes. CIS-triggered apoptotic signaling was also mitigated, shown by increased caspase-3 and BAX expression with downregulation of BCL-2. Nano-Cilostazol significantly inhibited apoptosis and pyroptosis (NLRP3, ASC, GSDMD)-related pathways, modulated JAK2/STAT3 signaling, and downregulated miRNA-155 expression. In conclusion, Nano-Cilostazol offers potent protection against cisplatin-induced nephrotoxicity.