Administration of Steamed and Freeze-Dried Mature Silkworm Larval Powder Prevents Hepatic Fibrosis and Hepatocellular Carcinogenesis by Blocking TGF-β/STAT3 Signaling Cascades in Rats

Abstract

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide and the majority of HCC patients occur with a background of hepatic fibrosis and cirrhosis. We have previously reported the hepatoprotective effects of steamed and freeze-dried mature silkworm larval powder (SMSP) in a chronic ethanol-treated rat model. Here, we assessed the anti-fibrotic and anti-carcinogenic effects of SMSP on diethylnitrosamine (DEN)-treated rats. Wistar rats were intraperitoneally injected with DEN once a week for 12 or 16 weeks with or without SMSP administration (0.1 and 1 g/kg). SMSP administration significantly attenuated tumor foci formation and proliferation in the livers of the rats treated with DEN for 16 weeks. SMSP administration also inhibited hepatic fibrosis by decreasing the levels of collagen fiber and the expression of pro-collagen I and alpha-smooth muscle actin (α-SMA). Moreover, SMSP supplementation improved the major parameters of fibrosis such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and collagen type I (Col1A1) in the livers from the rats treated with DEN for 16 weeks. As s possible mechanisms, we investigated the effects of SMSP on the TGF-β and signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascades, which are known to promote hepatic fibrosis. We found that SMSP treatment inhibited the activation of TGF-β and the phosphorylation of STAT3 pathway in DEN-treated rats. Moreover, SMSP administration suppressed the expressions of the target genes of TGF-β and STAT3 induced by DEN treatment. Our findings provide experimental evidences that SMSP administration has inhibitory effects of hepatic fibrosis and HCC induced by DEN In Vivo and could be a promising strategy for the prevention or treatment of hepatic fibrosis and hepatocellular carcinogenesis.

Hepatoprotective Effects of Steamed and Freeze-Dried Mature Silkworm Larval Powder against Ethanol-Induced Fatty Liver Disease in Rats

“…We did not show any side effects such as weight change or decreased dietary intake in rats treated with SMSP. In addition, the previous study with DEN-induced hepatocellular carcinoma rat model have shown that the administration of 1 g/kg of SMSP for 16 weeks does not induce any toxicity compared to the normal group [29]. These results demonstrate that the supplementation of 1-10 g/kg rat body weight of SMSP for 4-16 weeks would be safe.…”

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

“…IL-6 and TGF-β1 also operate as positive stimulators of the cytoplasmic transcription factor STAT3 in HSCs, promoting fibrosis by stimulating the synthesis of fibrotic marker proteins. Cirrhosis and carcinogenesis are the results of long-term fibrosis 109 . Upregulation of TGF-β1 has been identified as a wound healing process that protects against the spread of hepatocyte proliferation associated with genetic abnormalities following injury 51 , 52 .…”

Survival Fate of Hepatic Stem/Progenitor and Immune Cells in a Liver Fibrosis/Cirrhosis Animal Model and Clinical Implications

“…It is known that inflammation is involved in pathological features during regenerative fibrotic nodule formation, which replaces normal functional liver parenchyma to remodel the vasculature in the liver and ultimately compromises liver function [39][40][41][42]. Histologically, the inflammatory responses to toxic signals of DEN and influence fibrotic load have been characterized by our [18] and other studies [43]. These…”