Therapeutic Effect of Dithiophenolato Chitosan Nanocomposites Against Carbon Tetrachloride-induced Hepatotoxicity in Rats

Abstract Our previous study showed that dithiophenolate (DTP) and its chitosan nanoparticles (DTP-CSNPs) have abilities to bind with DNA helixes. So in this study, their lethal doses (LD50) and therapeutic roles against rat liver injuries induced by carbon tetrachloride (CCl4) were evaluated. The study focused on the determination of the markers of oxidative stress (OS) and apoptosis and compare the results with those of cisplatin treatment. The results revealed that LD50 values of DTP and DTP-CSNPs are 2187.5 and 1462.5 mg/kg, respectively. Treatment with DPT and DPT-CSNPs after CCl4 administration reduced liver injuries, induced by CCl4, and improved liver functions and architecture through the reduction of OS and apoptosis. Where the oxidant marker was decreased with elevations of antioxidant markers. Also, there was an elevation in Bcl 2 value, with decreases in caspase-8, Bax, and Bax/Bcl 2 ratio. DPT-CSNPs treatment gave preferable results than that treated with DPT. Moreover, DTP and DPT-CSNPs treatment gave better results than Cisplatine treatment. The administration of healthy rats with low doses of DTP and DTP-CSNPs for 14 days had no effect. Otherwise, the study on HepG2 cell line showed that DTP and DPT-CSNPs inhibited cell growth by arresting cells in the G2/M phase and inducing cell death. In conclusion: DTP and DTP-CSNPs have anti-apoptotic and anti-oxidative stress towards hepatotoxicity induced by CCl4. Moreover, DTP and DTP-CSNPs have anticancer activity against the HepG2 cell line. Generally, DTP-CSNPs are more effective than DTP. So, they can be used in the pharmacological fields, especially DTP-CSNPS.

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Curative Role of Dithiophenolato Titanium (IV)-Chitosan Nanocomposite Complex Against Carbon Tetrachloride-Induced Liver Injuries

10.21203/rs.3.rs-320823/v1 ◽

2021 ◽

Author(s):

Nadia Z Shaban ◽

Salah A Yehiaa ◽

Doaa Awad ◽

Shaban Y Shaban ◽

Samar R Saleh

Keyword(s):

Oxidative Stress ◽

Carbon Tetrachloride ◽

Lipid Profile ◽

Hepg2 Cell ◽

Chitosan Nanoparticles ◽

Antibacterial Activities ◽

Therapeutic Effects ◽

Liver Histopathology ◽

Liver Injuries ◽

Kidney Functions

Abstract Background Titanium-based compounds have been incorporated as promising antineoplastic metals. In our previous studies, dithiophenolato titanium (IV) Complex "DBT" and its chitosan nanocomposite "DBT-CSNPs" were prepared and we showed that these compounds have antibacterial activities, cytotoxic, and have abilities to bind with DNA helixes. Therefore, in this study, we evaluated the LD50 values of dithiophenolato titanium (IV)-complex (DBT) and its high thermal stable chitosan nanoparticles (DBT-CSNPs). Then their therapeutic effects against liver injuries induced by carbon tetrachloride (CCl4) were assessed and compared with cisplatin treatment. Additionally, the anti-proliferative activity of DBT and DBT-CSNPs against human liver cancer (HepG2) cell lines through the analysis of the cell cycle was evaluated. Methods Nine groups of rats were prepared: normal, DBT, DBT-CSNPs, CSNPs, CCl4, CCl4-DBT, CCl4-DBT-CSNPs, CCl4-CSNPs and CCl4-cisplatin. Liver histopathology and the biochemical markers involving oxidative stress, apoptosis, liver and kidney functions, and lipid profile were determined. Results The results revealed that the treatment with DBT-CSNPs and DBT after CCl4 administration abolished liver damage since it reduced the apoptosis induced by CCl4 via the reduction of DNA fragmentation, Bax and caspase- 8 with an elevation of Bcl2 and Bcl2/Bax ratio. Also, these treatments caused nonsignificant changes in the markers of oxidative stress. Therefore, liver histopathology and functions, lipid profile, and kidney functions were improved. Cisplatin treatment reduced liver injury with a degree less than DBT-CSNPs and DBT, but it induced nephrotoxicity. Administration of DBT-CSNPs and DBT to healthy rats for 14 days has no adverse effect. Also, the results showed that DBT-CSNPs and DBT inhibited the proliferation of HepG2 cells by arresting cells in the G2/M phase and inducing cell death. Conclusion DBT-CSNPs and DBT have a therapeutic effect against CCl4-induced liver injuries via the reduction of apoptosis induced by CCl4. Moreover, both compounds have antineoplastic activities against the HepG2 cell line. In all cases, DBT-CSNPs have a greater effect due to their nanostructure. Therefore, both compounds can be used in the pharmacological fields, particularly DBT-CSNPs.

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