No abstract

Tamoxifen inhibits estrogen receptor (ER)-positive breast cancer growth while CD36 potentiates cancer metastasis. The effects of CD36 on proliferation/migration of breast cancer cells and tamoxifen-inhibited ER-positive cell growth are unknown. In this study, we correlated the mortality of breast cancer patients to tumor CD36 expression levels. We also found CD36 was higher in ER-rich (MCF-7>T-47D~ZR-75-30) than ER-negative (MDA-MB-231) cells. CD36 siRNA decreased viability and migration of MCF-7 and MDA-MB-231 cells with more potent effects on MCF-7 cells. Inversely, high expressing CD36 enhanced cell growth/migration. Mechanistically, CD36 increased expression of genes responsible for cell proliferation, migration and anti-apoptosis. CD36 also activated ERα and ER-targeted genes for cell cycles, and phosphorylated ERK1/2 (p-ERK1/2). Tamoxifen inhibited CD36 and p-ERK1/2 in ERα-positive but not ERα-negative cells. Reciprocally, inhibition of MCF-7 cell growth by tamoxifen was attenuated by high expressing CD36. CD36, ERα and p-ERK1/2 expression was higher in tamoxifen-resistant MCF-7 (MCF-7/TAMR) cells than normal MCF-7 cells. However, CD36 siRNA restored the capacity of tamoxifen inhibiting MCF-7/TAMR cell growth. CD36 antibody inhibited cell growth and expression of ERα, p-ERK1/2 and CCND1. Therefore, our study unveils a pro-tumorigenic role of CD36 in breast cancer by enhancing proliferation/migration of breast cancer cells while attenuating tamoxifen-inhibited ER-positive cell growth.

Cholesterol 25-hydroxylase (CH25H) catalyzes the production of , an oxysterol which can play an important role in different biological processes.However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high expressing LXR or LXR activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXR/ expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon  expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC.

Both myocardial infarction (MI) and the follow-up reperfusion will lead to an inevitable injury to myocardial tissues, such as cardiac dysfunctions, fibrosis, and reduction of intercellular cell-to-cell interactions. Recently, exosomes (Exo) derived from stem cells have demonstrated a robust capability to promote angiogenesis and tissue repair. However, the short half-life of Exo and rapid clearance lead to insufficient therapeutic doses in the lesion area. Herein, an injectable conductive hydrogel is constructed to bind Exo derived from human umbilical cord mesenchymal stem cells to treat myocardial injuries after myocardial infarction–ischemia/reperfusion (MI-I/R). To this end, a hyperbranched epoxy macromer (EHBPE) grafted by an aniline tetramer (AT) was synthesized to cross-link thiolated hyaluronic acid (HA-SH) and thiolated Exo anchoring a CP05 peptide via an epoxy/thiol “click” reaction. The resulting Gel@Exo composite system possesses multiple features, such as controllable gelation kinetics, shear-thinning injectability, conductivity matching the native myocardium, soft and dynamic stability adapting to heartbeats, and excellent cytocompatibility. After being injected into injured hearts of rats, the hydrogel effectively prolongs the retention of Exo in the ischemic myocardium. The cardiac functions have been considerably improved by Gel@Exo administration, as indicated by the enhancing ejection fraction and fractional shortening, and reducing fibrosis area. Immunofluorescence staining and reverse transcription-polymerase chain reaction (RT-PCR) results demonstrate that the expression of cardiac-related proteins (Cx43, Ki67, CD31, and α-SMA) and genes (VEGF-A, VEGF-B, vWF, TGF-β1, MMP-9, and Serca2a) are remarkably upregulated. The conductive Gel@Exo system can significantly improve cell-to-cell interactions, promote cell proliferation and angiogenesis, and result in a prominent therapeutic effect on MI-I/R, providing a promising therapeutic method for injured myocardial tissues.

Co-treatment with T317 and metformin inhibited the development of atherosclerosis without activation of lipogenesis, suggesting that combined treatment with T317 and metformin may be a novel approach to inhibition of atherosclerosis.