Structure, function, and mechanism of the TNFAIP8 (TIPE) family of proteins in cancer and inflammation

The multiple roles of the tumor necrosis factor(TNF)-α-inducible protein 8(TNFAIP8),also named TIPE family of proteins have been shown in tumor and inflammation progression and regulation of cellular autophagy and apoptosis.In this review,we found that the TIPE family showed highly homologous sequences and conserved functional domains,such as the death effector domain(DED)-like domain but displayed different roles and mechanisms in different biological activities.For example,while TIPE is primarily associated with tumor progression and antitumor drug resistance,TIPE1 suppresses tumor progression in most instances.TIPE2 has multiple roles in tumor progression regulation,and antitumor drug resistance.Moreover,TIPE2 was also involved in inflammatory response regulation,tumor typing,and staging.A few studies reported that TIPE3 was engaged in tumor development by activating the phosphatidylinositol-3-kinase(PI3K)/protein kinase B(AKT)signaling pathway.The structure,function,and mechanism of the TIPE family in cancer and inflammation have been summarized in this review.This might serve as a reference for further research on the TIPE family and shed new light on the crosstalk among antitumor responses,inflammation,and immunology.

S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling

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/GSK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC(250 mmol/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/GSK3 b pathway.