No abstract

No abstract

Homocysteine (Hcy) is a sulfur‐containing amino acid that originated in methionine metabolism and the elevated level of Hcy in plasma is considered to be an independent risk factor for cardiovascular diseases (CVD). Endothelial dysfunction plays a major role in the development of CVD, while the potential mechanism of Hcy‐induced endothelial dysfunction is still unclear. Here, in Hcy‐treated endothelial cells, we observed the destruction of mitochondrial morphology and the decline of mitochondrial membrane potential. Meanwhile, the level of ATP was reduced and the reactive oxygen species was increased. The expressions of dynamin‐related protein 1 (Drp1) and phosphate‐Drp1 (Ser616) were upregulated, whereas the expression of mitofusin 2 was inhibited by Hcy treatment. These findings suggested that Hcy not only triggered mitochondrial dysfunction but also incurred an imbalance of mitochondrial dynamics in endothelial cells. The expression of mitochondrial calcium uniporter (MCU) was activated by Hcy, contributing to calcium transferring into mitochondria. Interestingly, the formation of mitochondria‐associated membranes (MAMs) was increased in endothelial cells after Hcy administration. The inositol 1,4,5‐triphosphate receptor (IP3R)–glucose‐regulated protein 75 (Grp75)–voltage‐dependent anion channel (VDAC) complex, which was enriched in MAMs, was also increased. The accumulation of mitochondrial calcium could be blocked by inhibiting with the IP3R inhibitor Xestospongin C (XeC) in Hcy‐treated cells. Then, we confirmed that the mitochondrial dysfunction and the increased mitochondrial fission induced by Hcy could be attenuated after Hcy and XeC co‐treatment. In conclusion, Hcy‐induced mitochondrial dysfunction and dynamics disorder in endothelial cells were mainly related to the increase of calcium as a result of the upregulated expressions of the MCU and the IP3R–Grp75–VDAC complex in MAMs.

Introduction: FK506 binding proteins (FKBPs) function as oncogenes or tumor suppressors by interacting with steroid hormone receptors, kinases, or other cellular factors in addition to intracellular ligands FK506 and rapamycin. In this study, we aimed at evaluating the expression and function of FKBPs in renal cell carcinoma (RCC). Materials and Methods: Thirty-four RCC specimens were analyzed by whole transcriptome sequencing. Small interfere RNA was employed to knockdown FKBP10 in 786-O and A-704 cells, and cell proliferation, cell cycle progression, invasion and migration were evaluated. Results: FKBP10 was different from other members of FKBPs with most significant upregulation in almost all RCC specimens, compared to normal mucosa. FKBP10 expression was high in additional 38 RCC specimens and RCC cell lines compared to paired non-tumor tissues and normal renal tubule cells. FKBP10 knockdown led to cell cycle arrest at G0/G1 phase, and reduced cell proliferation, invasion, and migration in 786-O and A-704 cells. In addition, heat shock protein 90 was significantly downregulated after FKBP10 knockdown. Conclusions: FKBP10 is overexpressed and promotes RCC and is a new promising biomarker and therapy target for RCC.

No abstract