Hepatocyte-generated 27-hydroxycholesterol promotes the growth of melanoma by activation of estrogen receptor alpha.

Cholesterol plays an important role in maintaining normal physiological function of human body. However, excessive intake will induce a series of diseases including cancer. For melanoma, the relationship between hypercholesterolemia and its incidence remains unknown. The cholesterol metabolite 27-hydroxy cholesterol (27-HC) catalyzed by CYP27A1 has been reported to activate estrogen receptor (ER). As studies have indicated that melanoma expresses ER, we designed experiments to explore whether 27-HC could link hypercholesterolemia and melanoma. In this study, hepatocyte-specific CYP27A1-/- mice were generated by CRISPR/Cas9 technology. The results revealed that high-cholesterol diet induced metabolism disorder and promoted the melanoma growth through 27-HC. Further study found that 27-HC promoted the growth of melanoma cells by activating ERα and eliciting the AKT and MAPK signaling pathway. This study puts forward the important role of 27-HC in the development of melanoma for the first time, links hypercholesterolemia with melanoma progression. The research also provides the rationale for the use of tamoxifen in melanoma therapy. The levels of 27-HC in blood could act as a novel biomarker for tamoxifen treatment in melanoma patients.

Hepatoprotective effect of methyl ferulic acid against carbon tetrachloride-induced acute liver injury in rats.

The present study aimed to investigate the hepatoprotective effects of methyl ferulic acid (MFA) against oxidative stress and apoptosis in acute liver injury induced by carbon tetrachloride (CCl4) in rats, as well as the underlying mechanisms. Sprague Dawley rats were treated with CCl4 after oral administration of MFA (25, 50, and 100 mg/kg) or dimethyl diphenyl bicarboxylate (200 mg/kg) for 7 days. The hepatoprotective effects of MFA were determined by analyzing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as changes of oxidant parameters. Histopathological analysis was performed to determine the degree of hepatic injury. The mechanisms were investigated by detecting the levels of NADPH oxidase (NOX) trans-membrane subunit NOX4, its ligand p22phox, as well as caspase3, cleaved caspase3, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), tumor necrosis factor (TNF)-α, interleukin (IL)-1, reactive oxygen species (ROS), thiobarbituric acid-reactive substances (TBARS), total anti-oxidant capacity (TAC), phosphorylated J-Jun N-terminal kinase (p-JNK) and p-p38 mitogen-activated protein kinase (MAPK) using semi-quantitative polymerase chain reaction, western blot analysis and colorimetric assays. MFA treatment significantly decreased serum enzymatic activities of ALT and AST. MFA markedly increased activities of liver superoxide dismutase, catalase and glutathione peroxidase, and reduced the malondialdehyde concentration. Histopathological examination demonstrated that MFA reduced lipid degeneration, cytoplasmic vacuolization, necrosis and inflammatory cell infiltration in the liversof CCl4-treated rats. MFA treatment markedly inhibited the expression of inflammatory factors TNF-α and IL-1ß. Mechanistic study revealed that MFA decreased the TAC and the levels of ROS and TBARS. Furthermore, MFA treatment led to a reduction of the mRNA and protein expression of NOX4 and p22phox, as well as the protein levels of caspase3, cleaved caspase-3 and Bax, and an upregulation of p-JNK, p-p38 MAPK and Bcl-2 proteins in the liver. The present study demonstrated that MFA has hepatoprotective effects against CCl4-induced acute liver damage. MFA has anti-oxidant, anti-inflammatory and anti-apoptotic activities and was able to modulate the NOX4/p22phox/ROS-JNK/p38 MAPK signaling pathway.