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Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1β and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Background: the nephrotoxicity of methotrexate (MTX) is observed in high-dose therapy. Moreover, low-dose MTX therapy for rheumatic diseases is debatable and claimed to cause renal impairment. This study aimed at studying the effect of methotrexate in repeated low doses on rat kidneys and assessing the efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and platelet rich plasma (PRP) for attenuating this effect. Methods: Forty-two male Wistar rats were used, 10 rats were donors of AD-MSCs and PRP, 8 rats served as control, and the remaining rats were subjected to induction of nephrotoxicity by MTX intraperitoneal injection once weekly for successive 8 weeks and then assigned into 3 groups of 8 animals each: Group II: received MTX only. Group III: received MTX + PRP. Group IV: received MTX + AD-MSCs. After one month, rats were anaesthetized, serum-sampled, and renal tissue removed for biochemical, histological, and ultrastructural evaluation. Results: there was significant tubular degeneration, glomerulosclerosis, fibrosis, decreased renal index, along with increased levels of urea and creatinine in the MTX group compared to the control group. Immunohistochemical expression of caspase-3 and iNOS in the renal tissue was significantly increased in group II compared to groups III and IV. Biochemical results revealed higher tissue malondialdehyde (MDA) concentration in the MTX-injected group which decreased significantly in co-treatment with either AD-MSC or PRP + MTX. MSC promoted the activation of the Nrf2/PPARγ/HO-1 and NF-κB/Keap1/caspase-3 pathways, increased antioxidant enzyme activities, reduced lipid peroxidation levels, and alleviated oxidative damage and apoptosis. PRP showed therapeutic effects and molecular mechanisms similar to MSC. Furthermore, MSC and PRP treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NF-κB, interleukin-1ß, and TNF-α), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (iNOS) markers in the kidney. Conclusion: repeated administration of low-dose MTX resulted in massive renal tissue toxicity and deterioration of renal function in rats which proved to be attenuated by PRP and AD-MSCs through their anti-inflammatory, anti-apoptotic and anti-fibrotic properties.

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