Articles

Early-onset neurodegenerative diseases (EO-NDs), such as early-onset Alzheimer’s disease (EOAD), Parkinson’s disease (EOPD), and familial amyotrophic lateral sclerosis (fALS), often stem from monogenic causes and manifest before typical age thresholds. These disorders frequently feature disrupted mitochondrial function and heightened oxidative stress, which together accelerate neuronal damage and degeneration. In this work, the author performs a comprehensive analysis of the literature and data related to mitochondrial dysfunction and redox imbalance in EO-NDs. Bibliometric trends were assessed using R-based tools on PubMed datasets, highlighting keyword networks and publication surges in recent years. Publicly available RNA-seq datasets from GEO and SRA were examined, with example DESeq2 analysis illustrating altered mitochondrial gene expression in EO-ND patient-derived samples. Network modeling of redox pathways using Python’s networkx demonstrates how oxidative stress can propagate through metabolic networks. Together, these computational approaches reinforce that mitochondrial DNA mutations, impaired electron transport chain (ETC) function, and reactive oxygen species (ROS) accumulation play central roles in EO-ND pathogenesis. The discussion further evaluates why antioxidant clinical trials have largely failed and how emerging therapies such as gene replacement, antisense oligonucleotides, and mitochondrial biogenesis modulators may provide more effective interventions.

The therapeutic effect of Cyclophosphamide (CPA) is thus attributed to phosphoramide mustard and acrolein leads to the formation of high levels of reactive oxygen species (ROS), which results in decreased antioxidant activity<b>.</b> Excessive production of ROS could also culminate in oxidative stress<b>.</b> <b>Objectives:</b> This study aims to evaluate the effect of sub-lethal dose of the cyclophosphamide, 5-FU, combination of 5-FU, and CPA on testicular antioxidant status, and oxidative stress in male albino rats.<b> </b><b>Materials and Method</b><b>s:</b> Twenty-eight male adult rats were grouped randomly into four groups (n=5 each group). Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood and testes tissue samples were taken and prepared for biochemical measurements. Biochemical parameters in rat serum and tissues were evaluated. <b>Results:</b> Individual injection of CPA and 5-FU to rats were reduced testes TAC, GSH concentration, GR, and CAT activities compared to control. However, the combination treatment of rats with 5-FU and CPA increased the levels of these non-enzymatic and enzymatic antioxidant compared with those treated with CPA alone. Also, results showed significantly increased TBARS and NO concentration in the testes of CPA treated rats when compared to normal ones, while 5-FU increased NO only compared with the control. <b>Conclusion: </b>It can be concluded that treatment of rats with CPA is associated with the production of free radicals that leads to hazardous alterations in certain non-enzymatic, and enzymatic functions. The increase in lipid peroxidation probably leads to the intracellular accumulation of ROS with the subsequent development of testes tissue injury. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to combat oxidative stress mediated non target organs injury even if it was not a complete protection. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism.