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

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.

Water-Soluble Pristine C60 Fullerene Inhibits Liver Alterations Associated with Hepatocellular Carcinoma in Rat

“…Herein, we could suggest the multiplicity of the mechanisms of C 60 fullerene action, which could contribute (in our opinion) to its substantial anti-inflammatory and anti-fibrotic effect because of multiplicity of cellular targets and, therefore, ways of action. Furthermore, obtained results of the anti-inflammatory, anti-fibrotic, and hepatoprotective effects of C 60 FAS correspond to our previous studies [ 8 , 9 , 20 , 21 , 77 ]. It is important to note that C 60 FAS is a relatively safe substance: we did not observe any alterations of vital organs (liver, kidney, spleen, pancreas) or other signs of acute or subacute toxicity in animals receiving C 60 FAS for 7 weeks.…”

“…C 60 FAS was administered daily intraperitoneally in a volume corresponded to the dose of C 60 fullerene 0.25 mg/kg (0.3–0.6 mL per rat depending on body weight), which is considered as safe and effective as evidenced by our previous studies [ 8 , 9 , 20 ]. Administrations were started at 16th week of the experiment (the stage of cirrhosis and malignant cell degeneration, which is confirmed by our previous research [ 21 ]) and followed for 7 weeks to explore C 60 FAS effect on the development of liver tumors and metastasis. We use the common antitumor drug 5-fluorouracil (5FU, Ebewe Pharma, Austria) as a reference.…”

“…Moreover, taken into consideration that C 60 fullerene inhibits the progression of liver fibrosis, we could assume that it unlikely contributes to activation of hepatic stellate cells but might inhibit their viability instead. Furthermore, the ability of C 60 fullerene to inhibit liver fibrosis and cirrhosis was demonstrated in our previous results [ 20 , 21 ]. Meanwhile, the obtained in vitro results are controversial and require further investigation.…”

“…Indeed, C 60 fullerene having been shown to possess potent antioxidant activity because of free radical scavenging [ 74 , 75 ], also could modulate p53 expression and G6PD activity and induce apoptosis if applied in relatively high doses. Moreover, it was shown that C 60 fullerene is able to interact with epithelial growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) [ 21 ], to affect the expression of extracellular matrix proteins pan-cytokeratins [ 20 ] and to modulate the immune response [ 75 , 76 ]. Herein, we could suggest the multiplicity of the mechanisms of C 60 fullerene action, which could contribute (in our opinion) to its substantial anti-inflammatory and anti-fibrotic effect because of multiplicity of cellular targets and, therefore, ways of action.…”

Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment

“…A powerful free radical scavenger carbon-based nanoparticle C60 fullerene could be considered as another unusual RTK inhibitor. It explores wide range of biological activities including antifibrotic and anticirrhotic ones [71][72][73][74][75] probably realized by its antioxidant capacity. However, we also demonstrated its ability to bind to ATP-binding pockets of EGFR and FGFR and to avoid interaction of those with ATP [75], which could be an alternative mechanism of this nanoparticle's antifibrotic action.…”