الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
The prevalence of hepatic C viral infection in Egypt is the highest worldwide. World Health Organization, records around 3-4 million new cases of infection annually. The Egyptian national plan has been proposed by the Health Ministry to governor the HCV epidemic with a great fund, and aided from the WHO as well as other institutes. This scheme was called ―The Plan of Action for the Prevention, Care and Treatment of HCV infection 2014–2018‖ and recommended Sofosbuvir as its primary therapy. Sofosbuvir acts like a nucleotide analogue that specifically inhibits the replication of HCV virus.
Nucleoside or nucleotide inhibitors as Sofosbuvir are shown to affect mitochondrial biogenesis, contributing to mitochondrial stress. Mitochondrial stress mechanisms have been associated with mitochondrial dysfunction symptoms. Several lines of evidence indicate that mitochondrial dysfunction produces uncontrollable ROS that eventually lead to organ failure.
The study aimed to explore the possible side effect of the therapeutic dose of Sofosbuvir on the mitochondrial biogenesis and functions of the ovary, liver, and muscle tissues of young females using rats as the animal model. The study was conducted on 20 female albino rats 2 months old that was classified into 2 groups. group I (control group): 10 healthy female rats maintained under normal diet and received placebo for three months. group II (exposed group):10 female rats supplemented with 4 mg/kg of Sofosbuvir for 3 months. At the end of the treatment period, rats were sacrificed and dissected out to obtain blood, ovary, liver and muscles. Serum samples were used for the analysis of FBS, insulin, lipid profile, liver and kidney function tests. The obtained tissues were used for the assessment of MDA, ND5 content, mtDNA-CN, gene expressions of PGC-1α, Tfam, Nrf2, NF-κB and POLG.
The results showed a significant decrease in FBG level (caused hypoglycemia) in the rats treated for 3 months with the therapeutic dose of Sofosbuvir compared to control rats. This hypoglycemic effect was not related to significant changes in the serum insulin level or HOMA-IR. Rats exposed to therapeutic dose of Sofosbuvir have significantly higher TC and LDL-C levels than the control rats with no significant changes in the levels of both TAG and HDL-cholesterol. The treatment of rats with Sofosbuvir for three months caused significant elevation in serum activity of SGPT compared with control rats. On the other hand, Sofosbuvir treatment showed no significant effect on the serum markers of kidney functions: urea, and creatinine.
Summary and Conclusions
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The present work demonstrates the Sofosbuvir-toxicity on different tissues of young females exposed to the therapeutic dose of Sofosbuvir for three months (to mimic human regimen). The reported toxicity was mediated through suppression of PGC-1α and Tfam which impair mitochondrial biogenesis and exhibited a decline in mtDNA-CN. Also, Sofosbuvir suppresses the expression of POLG and declines the mitochondrial content of ND5 which impair the mitochondrial functions; it also causes inflammation and oxidative stress in all tissues as shown by the induced expression of NF-κB, increase in the MDA content, and the decrease in the Nrf2 expression.
from the previous discussion we can concluded that:
1. Ovarian tissue is the most affected organ followed by the liver tissue, while muscle tissue appears to resist Sofosbuvir-induced mitochondrial toxicity.
2. The effects of Sofosbuvir on the ovarian mitochondrial biogenesis and functions not just affect the exposed females but unfortunately may have long-lasting consequences by impairing the embryonic development and transfer these mitochondrial abnormalities to the next generations.
3. Further studies are required to examine the exact mechanism(s) of Sofosbuvir-induced mitochondrial toxicity and to explore the possible transgenerational effects of this toxicity. Also, the possible intervention by co-supplementation with natural antioxidant needs to be investigated.