Water-Soluble Pristine C60 Fullerenes Inhibit Liver Fibrotic Alteration and Prevent Liver Cirrhosis in Rats.

Halyna Kuznietsova,Iryna Chereschuk,Yuriy Prylutskyy,Vasyl Hurmach,Olexandr Motuziuk,Olexandr Ogloblya,Natalia Dziubenko

doi:10.1155/2020/8061246

Halyna Kuznietsova, Iryna Chereschuk + Show 5 more

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https://doi.org/10.1155/2020/8061246

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Abstract

Liver cirrhosis is an outcome of a wide range of liver chronic diseases. It is attributed to oxidative stress; therefore, antioxidant usage could be a promising treatment of that. So, exploring the impact of effective free radical scavenger pristine C60 fullerenes on liver fibrosis and cirrhosis and their ability to interact with main growth factor receptors involved in liver fibrogenesis was aimed to be discovered. We used N-diethylnitrosamine/carbon tetrachloride-induced simulations of rat liver fibrosis (10 weeks) and cirrhosis (15 weeks). Pristine C60 fullerene aqueous colloid solution (C60FAS) was injected daily at a dose of 0.25 mg/kg throughout the experiment. Liver morphology and functional and redox states were assessed. C60 fullerenes' ability to interact with epidermal, vasoendothelial, platelet-derived, and fibroblast growth factor receptors (EGFR, VEGFR, PDGFR, and FGFR, respectively) was estimated by computational modeling. We observed that C60FAS reduced the severity of fibrosis in fibrotic rats (0.75 vs. 3.0 points according to Ishak score), attenuated the hepatocyte injury, normalized elevated blood serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and mitigated oxidative stress manifestation in liver tissue restoring its redox balance. When applied to cirrhotic animals, C60FAS reduced connective tissue deposition as well (2.4 vs. 5.4 points according to Ishak score), diminished ALP and LDH (by 16% and 61%), and normalized conjugated and nonconjugated bilirubin, restoring the liver function. Altered liver lipid and protein peroxides and glutathione peroxidase activity were also leveled. Within a computer simulation, it was shown that C60 fullerenes can block hinge prohibiting ATP binding for EGFR and FGFR and thus blocking associated signal pathways. This ability in addition to their antioxidant properties may contribute to C60 fullerene's antifibrotic action. Thus, C60FAS may have a substantial therapeutic potential as an inhibitor of liver fibrosis and cirrhosis.

Highlights

Liver cirrhosis is the end-stage condition of a wide variety of chronic liver diseases and an increasing cause of morbidity and mortality worldwide
We observed that C60FAS reduced the severity of fibrosis in fibrotic rats (0.75 vs. 3.0 points according to Ishak score), attenuated the hepatocyte injury, normalized elevated blood serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and mitigated oxidative stress manifestation in liver tissue restoring its redox balance
The prepared C60FAS was characterized by atomic force microscopy (AFM) and dynamic light scattering (DLS) techniques

Summary

Introduction

Liver cirrhosis is the end-stage condition of a wide variety of chronic liver diseases and an increasing cause of morbidity and mortality worldwide. The cirrhosis develops during fibrosis progress: the liver lobes become replaced with connective tissue with the formation of cirrhotic nodes. This leads to a significant decrease in the liver functional activity and the development of liver failure. Liver fibrosis and cirrhosis are considered as main risk factors of nonviral etiology of hepatocellular carcinoma (HCC) development. HCC arises from chronic liver inflammation, fibrosis, and eventually cirrhosis in 70-80% of cases [2]

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