Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both “classical” and “non-classical” pathways and the former pathway is better understood. The “classical” activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of “classic” inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the “non-classical” activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1β, IL-18 and IL-33 in the fibrogenesis.

Mangostin, which has the function of anti-inflammatory, antioxidant, and anticancer, etc, is one of the main active ingredients of the hull of the mangosteen. The main objective of the study was to elucidate its anti-cancer function and possible mechanism. α-Mangostin was separated and structurally confirmed. MTT method was used to check the effect of mangostin on breast cancer cell proliferation. Then the effect of α-Mangostin on the transcriptional activity of RXRα was tested by dual-luciferase reporter gene assay. And Western blot (WB) was used to detect the expression of apoptosis-related proteins or cell cycle-associated proteins after treatment. Also, this study was to observe the effects of α-Mangostin on the invasion of breast cancer cell line MDA-MB-231. α-Mangostin regulates the downstream effectors of the PI3K/AKT signaling pathway by degrading RXRα/tRXRα. α-Mangostin can trigger PARP cleavage and induce apoptosis, which may be related to the induction of upregulated BAX expression and downregulation of BAD and cleaved caspase-3 expression in MDA-MB-231 cells through blockade of AKT signaling. The experiments verify that α-Mangostin have evident inhibition effects of invasion and metastasis of MDA-MB-231 cells. Cyclin D1 was involved in the anticancer effects of α-Mangostin on the cell cycle in MDA-MB-231 cells. α-Mangostin induces apoptosis, suppresses the migration and invasion of breast cancer cells through the PI3K/AKT signaling pathway by targeting RXRα, and cyclin D1 has involved in this process.

Kirenol possesses anti-inflammatory, antifibrotic and anti-arthritic effects. However, its reno-protective effects against diabetic nephropathy (DN) have not been evaluated.This study explores the ...

Glomerular matrix accumulation is a hallmark of diabetic renal disease. Serine/threonine kinase PKC-β1 mediates glucose-induced Akt S473 phosphorylation, RhoA activation, and transforming growth factor (TGF)-β1 upregulation and finally leads to matrix upregulation in mesangial cells (MCs). It has been reported that glucose-induced PKC-β1 activation is dependent on caveolin-1 and the presence of intact caveolae in MCs; however, whether activated PKC-β1 regulates caveolin-1 expression and phosphorylation are unknown. Here, we showed that, although the caveolin-1 protein level had no significant change, the PKC-β-specific inhibitor LY-333531 blocked caveolin-1 Y14 phosphorylation in high glucose (HG)-treated MCs and in the renal cortex of diabetic rats. The Src-specific inhibitor SU-6656 prevented the HG-induced association between PKC-β1 and caveolin-1 and PKC-β1 membrane translocation, whereas PKC-β1 small interfering RNA failed to block Src activation, indicating that Src kinase is upstream of PKC-β1 activation. Although LY-333531 blocked PKC-β1 membrane translocation, it had no effect on the PKC-β1/caveolin-1 association, suggesting that PKC-β1 activation requires the interaction of caveolin-1 and PKC-β1. PKC-β1-mediated Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation in response to HG were prevented by SU-6656 and nonphosphorylatable mutant caveolin-1 Y14A. In conclusion, Src activation by HG mediates the PKC-β1/caveolin-1 association and PKC-β1 activation, which assists in caveolin-1 Y14 phosphorylation by Src kinase. The downstream effects, including Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation, require caveolin-1 Y14 phosphorylation. Caveolin-1 is thus an important mediator of the profibrogenic process in diabetic renal disease.