The Preventive Effects and Mode of Actions of Ulva Fasciata Synthesized Silver Nanoparticles in Doxorubicin-Induced Hepatotoxicity in Wistar Rats

Background: Hepatotoxicity was one of the major side effects associated with doxorubicin treatment in cancer chemotherapy. The synthesized silver nanoparticles (AgNPs) from natural products such as algae especially green algae is one of the favorable means to minimize the deleterious effects of the chemotherapy. Thus, this study aimed to evaluate the preventive role of AgNPs synthesized by Ulva fasciata (U. fasciata) against doxorubicin-induced hepatotoxicity and oxidative stress in the liver of male Wistar rats.  Materials and Methods: In the present study, the green macroalga U. fasciata ethanolic extract was used as reducing agents to reduce Ag ions to Ag0. Doxorubicin-injected male Wistar rats were concomitantly treated with U. fasciata ethanolic extract and AgNPs synthesized by U. fasciata extract (AgNPs/U. fasciata) 3 times/week by oral gavage for 6 weeks. Results: The results showed that male Wistar rats injected with doxorubicin showed a significant increase in ALT, ALP and GGT activities and total bilirubin level as well as a reduction in the serum albumin level. The concurrent treatments of doxorubicin-injected rats with U. fasciata ethanolic extract and AgNPs/U. fasciata significantly abrogate these alterations. The altered levels of tumor biomarkers CA19.9 and AFP as well as pro-inflammatory cytokine, TNF-α, and anti-inflammatory cytokine, IL-4, in doxorubicin-injected animals were significantly ameliorated by concurrent treatment with U. fasciata and AgNPs/U. fasciata. Moreover, the elevated mRNA expression of p53 significantly decreased by treatment. In association, the doxorubicin-induced deleterious histological changes represented by severe hydropic degenerative changes, steatosis, inflammatory cell infiltration, Kupffer cell proliferation and apoptosis were remarkably improved by concurrent treatment with U. fasciata extract and AgNPs/U. fasciata which was more potent. Conclusion: Based on results of this study, it can be concluded that U. fasciata extract and AgNPs/U. fasciata counteracts doxorubicin-induced toxicity by suppression of inflammation, oxidative stress and apoptosis. AgNPs/U. fasciata was the most potent in improving hepatocyte integrity and liver histological architecture.  Graphical Abstract