The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.

Accumulating data confirms that Methotrexate (MTX), a well-known immunosuppressive and anticancer drug, causes nephrotoxicity. Infliximab (INF), the inhibitor of tumor necrosis factor-alpha (TNF-α), was proven to have anti-inflammatory properties. Thus, it may have potential in preventing MTX-induced nephrotoxicity. Therefore, this study aimed to inspect the prospective nephroprotective effect of INF on MTX-induced rat nephrotoxicity through investigating the possible molecular mechanisms, including its interference with different death routes, oxidative stress as well as mitochondrial biogenesis. Rats received an INF intraperitoneal single dose of 7 mg/kg 72 h prior to a single 20 mg/kg MTX injection. MTX nephrotoxicity was demonstrated by significantly increased serum levels of the renal indicators urea and creatinine as well as renal inflammatory markers TNF-α and Interleukin-6 (IL-6) and the renal oxidative stress marker malondialdehyde (MDA), while renal antioxidant enzyme superoxide dismutase (SOD) was significantly decreased compared to control. INF injection prior to MTX markedly reversed these MTX-induced effects. Besides, MTX impaired mitochondrial biogenesis, while INF attenuated this impairment, as indicated by increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Finally, MTX triggered apoptotic and autophagic cascades in renal tissues as evidenced by reduced anti-apoptotic Bcl-2 protein expression as well as elevated expression of the pro-apoptotic protein Bax and both key regulators of autophagy; beclin-1 and LC-3, whereas INF pretreatment counteracted these apoptotic and autophagic effects of MTX. Summarily, these results suggest that INF provides protection against MTX-induced nephrotoxicity which could be elucidated by its antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagic effects as well as upregulating mitochondrial biogenesis.

Cognitive impairments are frequently observed in cancer survivors who received chemotherapy based on doxorubicin (DOX), attributable to oxidative stress, neuroinflammation, and the apoptotic effect of DOX. Dapagliflozin (DAPA) has gained significant attention attributable to its powerful anti-inflammatory, antioxidant, and anti-apoptotic characteristics. The present investigation seeks to assess the possible neuroprotective properties of DAPA in alleviating neurodegeneration and cognitive dysfunction caused by DOX. Chemobrain was induced by DOX (2 mg/kg, i.p.) once weekly for four weeks. Additionally, rats were treated with DAPA (2 mg/kg, p.o.) for 28 consecutive days. DAPA markedly mitigated behavioral deficits associated with cognitive impairment induced by DOX, as demonstrated by cognitive behavioral tests. Likewise, DAPA reversed histopathological abnormalities. Mechanistically, DAPA alleviated the oxidative stress induced by DOX by reducing tissue levels of NADPH oxidase 4 (NOX4) and malondialdehyde (MDA) while enhancing the activities of superoxide dismutase (SOD) and glutathione (GSH). Additionally, DAPA suppressed neuroinflammation by attenuating the production of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) in brain tissue, as well as the signaling pathways involved in apoptosis, including the Protein Kinase B (AKT)/Glycogen Synthase Kinase-3 beta (GSK-3β) pathway and the Wingless-related integration site (Wnt)/β-catenin pathway. Further evidence of DAPA’s anti-apoptotic effects was attributed to a decrease in the immunohistochemical expression of total caspase-3 and the p65 subunit of NF-κB (NF-κB-p65). DAPA induces neuroprotection against DOX-induced cognitive deterioration by providing antioxidant, anti-inflammatory, and anti-apoptotic effects. Graphical Abstract