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Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway., Graphical abstract S-Allylmercaptocysteine, a water-soluble component extracted from aged garlic, is an effective and safe hepato-protective complimentary agent against alcoholic liver disease partly through a direct modulation of insulin receptor signaling.Image 1

Highlights • D5D is an independent prognostic factor in cancer. • D5D aggravates cancer progression via mediating AA/PGE2 production from DGLA. • AA/PGE2 promotes cancer progression via regulating the tumor microenvironment. • Inhibition of D5D redirects COX-2 catalyzed DGLA peroxidation, producing 8-HOA. • 8-HOA suppress cancer by regulating proliferation, apoptosis, and metastasis., Delta-5 desaturase (D5D) is a rate-limiting enzyme that introduces double-bonds to the delta-5 position of the n-3 and n-6 polyunsaturated fatty acid chain. Since fatty acid metabolism is a vital factor in cancer development, several recent studies have revealed that D5D activity and expression could be an independent prognostic factor in cancers. However, the mechanistic basis of D5D in cancer progression is still controversial. The classical concept believes that D5D could aggravate cancer progression via mediating arachidonic acid (AA)/prostaglandin E2 production from dihomo-γ-linolenic acid (DGLA), resulting in activation of EP receptors, inflammatory pathways, and immunosuppression. On the contrary, D5D may prevent cancer progression through activating ferroptosis, which is iron-dependent cell death. Suppression of D5D by RNA interference and small-molecule inhibitor has been identified as a promising anti-cancer strategy. Inhibition of D5D could shift DGLA peroxidation pattern from generating AA to a distinct anti-cancer free radical byproduct, 8-hydroxyoctanoic acid, resulting in activation of apoptosis pathway and simultaneously suppression of cancer cell survival, proliferation, migration, and invasion. Hence, understanding the molecular mechanisms of D5D on cancer may therefore facilitate the development of novel therapeutical applications. Given that D5D may serve as a promising target in cancer, in this review, we provide an updated summary of current knowledge on the role of D5D in cancer development and potentially useful therapeutic strategies., Graphical abstract Image, graphical abstract

Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver., Graphical abstract fx1

Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases., Graphical abstract The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, authors discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases.

Elimination of excess cholesteryl esters from macrophage-derived foam cells is known to be a key process in limiting plaque stability and progression of atherosclerotic lesions. We have recently demonstrated that regulation of retinoid mediated cholesterol efflux is influenced by liver X receptor (LXR) signaling in mouse macrophages (Manna, P.R. et al., 2015, Biochem. Biophys. Res. Commun., 464:312-317). The data presented in this article evaluate the importance of the steroidogenic acute regulatory protein (StAR) in retinoid mediated macrophage cholesterol efflux. Overexpression of StAR in mouse RAW 264.7 macrophages increased the effects of both all-trans retinoic acid (atRA) and 9-cis RA on cholesterol efflux, suggesting StAR enhances the efficacy of retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) ligands. Additional data revealed that atRA enhances (Bu)2cAMP induced StAR and ATP-binding cassette transporter A1 protein levels. Treatment of macrophages transfected with an LXRE reporter plasmid (pLXREx3-Luc) was found to induce the effects of RAR and RXR analogs on LXR activity. Keywords: Macrophages, Retinoids, StAR, Cholesterol efflux, RAR, RXR, ABCA1