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Saturated free fatty acids (FFAs) strongly correlate with metabolic syndromes and are well-known risk factors for cardiovascular diseases (CVDs). The mechanism of palmitic acid (PA)-induced vascular lipotoxicity under endoplasmic reticulum (ER) stress is unknown. In the present paper, we investigate the roles of spliced form of X-box-binding protein 1 (XBP1s) target gene oxidative stress-induced growth inhibitor 1 (OSGIN1) in PA-induced vascular dysfunction. PA inhibited the tube formation assay of primary human umbilical vein endothelial cells (HUVECs). Simultaneously, PA treatment induced the XBP1s expression in HUVECs. Attenuate the induction of XBP1s by silencing the XBP1s retarded cell migration and diminished endothelial nitric oxide synthase (eNOS) expression. OSGIN1 is a target gene of XBP1s under PA treatment. The silencing of OSGIN1 inhibits cell migration by decreasing phospho-eNOS expression. PA activated autophagy in endothelial cells, inhibiting autophagy by 3-methyladenine (3-MA) decreased endothelial cell migration. Silencing XBP1s and OSGIN1 would reduce the induction of LC3 II; therefore, OSGIN1 could maintain autophagy to preserve endothelial cell migration. In conclusion, PA treatment induced ER stress and activated the inositol-requiring enzyme 1 alpha–spliced XBP1 (IRE1α–XBP1s) pathway. OSGIN1, a target gene of XBP1s, could protect endothelial cells from vascular lipotoxicity by regulating autophagy.

In this study, we investigated the antitumor activity of a novel coumarin derivative, 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC), on colorectal carcinoma. DMAC treatment resulted in substantial proapoptotic activity against colon cancer HCT116 and LoVo cells. Induction of apoptotic characteristics, including cellular shrinkage, chromatin condensation, and Annexin V detection, was observed following DMAC treatment. Mechanistically, we observed that DMAC elicited induction of proteolytic cascade activation including cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) expression and loss of the antiapoptotic proteins, Mcl-1 and Bcl-XL, accompanied by an increase in expression of the proapoptotic protein, Bak. In addition, suppressing c-Jun N-terminal protein kinase (JNK), but not extracellular-regulated protein kinase (ERK) or p38, substantially diminished DMAC-induced cell death and caspase-3 and PARP cleavage. However, pretreatment with antioxidants, including N-acetyl-l-cysteine (NAC) and diphenylene iodonium (DPI), failed to protect against DMAC-elicited apoptosis. Pretreatment with the JNK inhibitor, SP600125, suppressed DMAC-induced JNK phosphorylation, which was accompanied by a reversal of Bcl-XL expression. Moreover, combining DMAC treatment with the conventional anticancer drugs, 5-FU and CPT-11, considerably enhanced their therapeutic efficacies. Structural-activity relationship analyses further revealed that an alkylation substitution at position 6 of the coumarin ring was critical for inducing apoptosis, and the phenyl group at position 4 might have enhanced its bioactivity. Our data showed that DMAC can be used as part of a promising strategy to enhance therapeutic efficacies, and could be used to develop an approach for structure-based drug design for cancer treatment. [ABSTRACT FROM AUTHOR]