Inhibition of smooth muscle cell proliferation by ezetimibe via the cyclin D1-MAPK pathway.

Proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of atherosclerosis. Ezetimibe is a new lipid lowering agent that inhibits cholesterol absorption. In the present study we attempted to investigate whether ezetimibe has any effect on VSMC proliferation and the potential mechanisms involved. Our data showed ezetimibe abrogated the proliferation and migration of primary rat VSMCs induced by Chol:MßCD. Mechanically, we found that ezetimibe was capable of abolishing cyclin D1, CDK2, phospho-Rb (p-Rb), and E2F protein expressions that were upregulated by Chol:MßCD treatment. In addition, Ezetimibe was able to reverse cell cycle progression induced by Chol:MßCD, which was further supported by its down-regulation of cyclin D1 promoter activity in the presence of Chol:MßCD. Furthermore, ezetimibe abrogated the increment of phospho-ERK1/2 (p-ERK1/2) and nuclear accumulation of ERK1/2 in VSMCs induced by Chol:MßCD. Inhibition of the MAPK pathway by using ERK1/2 inhibitor PD98059 attenuated the reduction effect of ezetimibe on the expressions of phosphor-MEK1 (p-MEK1), p-ERK1/2, and cyclin D1. Taken together our data suggest that ezetimibe inhibits Chol:MßCD-induced VSMCs proliferation and leads to cell cycle arrest at the G0/G1 phase by suppressing cyclin D1 expression via the MAPK signaling pathway. These novel findings support the potential pleiotropic effect of ezetimibe in cardiovascular disease.

Tumor lymphangiogenesis index reveals the immune landscape and immunotherapy response in lung adenocarcinoma.

Background: Lymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients. Methods: The Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy. Results: We screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm. Conclusion: Overall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.

Physicochemical Properties and Skin Protection Activities of Polysaccharides from Usnea longissima by Graded Ethanol Precipitation.

Four Usnea longissima polysaccharides (ULPs; ULP15, ULP30, ULP50, and ULP70) were obtained from the lichen U. longissima via water extraction and graded ethanol precipitation. The obtained ULPs were all heteropolysaccharides with a few proteins, with which glucose was the major monosaccharide composition. With the increase in the precipitated ethanol concentrations, the content of galactose, xylose, and mannose increased, whereas that of glucose decreased. Moreover, the antioxidant activity test demonstrated that ULP15 exhibited better reducing power and stronger scavenging ability on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl free radicals. Importantly, ULP15 also had a better proliferative effect on human HaCaT keratinocytes and dermal fibroblasts. Meanwhile, ULP15 protected HaCaT keratinocytes from UVB-induced proliferation inhibition and exhibited tyrosinase inhibition activity. Therefore, this work provides interesting insight into the preparation of cosmetic ingredients using the polysaccharide ULP15.