KIF4A promotes epithelial-mesenchymal transition by activating the TGF-ß/SMAD signaling pathway in glioma cells.

Gliomas are the most prevalent type of primary brain tumor, with poor prognosis reported in patients with high-grade glioma. Kinesin family member 4 A (KIF4A) stimulates the proliferation, migration, and invasion of tumor cells. However, its function in gliomas has not been clearly established. Therefore, this study aimed to investigate the effects of KIF4A on the epithelial-mesenchymal transition and invasion of glioma cells. We searched The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases to identify KIF4A-related signaling pathways and downstream genes. We further validated them using western blotting, transwell migration and invasion, wound-healing scratch, and dual-luciferase reporter assays in U251 and U87 human glioblastoma cells. Our analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas data showed elevated KIF4A expression in patients with gliomas and was associated with clinical grade. Here, KIF4A overexpression promoted the migration, invasion, and proliferation of glioma cells, whereas KIF4A knockdown showed contrasting results. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) analyses demonstrated that KIF4A positively controls TGF-ß/SMAD signaling in glioma cells. Additionally, genetic correlation analysis revealed that KIF4A transcriptionally controls benzimidazoles-1 expression in glioma cells. KIF4A promotes the epithelial-mesenchymal transition by regulating the TGF-ß/SMAD signaling pathway via benzimidazoles-1 in glioma cells.

Relationship between serum CHIP levels with cardiovascular disease in maintenance haemodialysis patients.

Many preclinical studies reported that the carboxyl terminus of Hsp70-interacting protein (CHIP) has cardiovascular protective effects. This study was designed to explore whether CHIP is related with cardiovascular disease (CVD) in maintanence haemodialysis (MHD) patients. 217 MHD patients and 150 healthy controls were recruited, serum CHIP concentration and clinical characteristics were measured. MHD patients were followed-up for 36 months and their cardiovascular events (CVEs) and survival conditions were recorded. Here, the data shows that serum CHIP concentrations in MHD patients were lower than those in healthy controls (31.69 ± 18.2 pg/mL vs 84.53 ± 22.1 pg/mL, p < 0.05). CHIP negatively correlated with age, C-reactive protein, B-type brain natriuretic peptide, phosphorus, parathyroid hormone, carotid intima-media thickness (CIMT) and left ventricular septal thickness (LVSTd), whereas it positively associated with albumin, haemoglobin, creatinine, Kt/V and ejection fraction (p < 0.05, respectively). Partial correlation and multiple linear regression analysis verified the negative relationship between CHIP with CIMT or LVSTd (p < 0.05, respectively). Using quartile method and Kaplan-Meier survival function, it indetified that the lower serum CHIP concentration predicted risk of CVEs, CVD and all-cause death (p < 0.001). Cox regression analysis manifested CHIP was negatively associated with CVEs (HR = 0.914, 95%CI 0.880-0.950, p < 0.001), CVD mortality (HR = 0.747, 95%CI 0.651-0.857, p < 0.001) and all-cause death (HR = 0.769, 95%CI 0.696-0.850, p < 0.001). In conclusion, the data of this study revealed that serum CHIP level is significantly correlated with multiple risk factors of CVD and may be one of the predictors of CVD risk and death in MHD patients.

Correlation of Serum Adropin Levels with Risk Factors of Cardiovascular Disease in Hemodialysis Patients.

Background: Many preclinical studies have shown that adropin has physiological effects such as regulating glucose, lipid, and energy metabolism, protecting endothelial cells and antiatherosclerosis. Our aim is to explore whether adropin is correlated with risk factors of cardiovascular disease (CVD) in hemodialysis (HD) patients. Methods: We recruited 170 HD patients and 120 healthy controls. The serum adropin concentration and clinical characteristics were measured. Results: The serum adropin concentration in HD patients was significantly lower than that in healthy controls and which in HD patients with CVD or diabetes mellitus (DM) was significantly lower than that in patients without CVD or DM. The correlation analysis showed that serum adropin levels were correlated negatively with Age, CVD history, DM history, C-reactive protein, type B natriuretic peptide, phosphorus, intact parathyroid hormone, carotid artery plaque amount and carotid intima-media thickness (CIMT), left ventricular septal thickness (LVSTd), and left ventricular posterior wall thickness, whereas it was correlated positively with albumin, hemoglobin, serum creatinine and Kt/V, and ejection fraction value. Partial correlation analysis verified that serum adropin levels were correlated negatively with CIMT, and multiple linear regression analysis revealed that low serum adropin levels may be one independent predictors of CIMT. However, the partial correlation analysis and multiple linear regression analysis did not identify the significant correlation between serum adropin levels and LVSTd. Conclusions: Our study revealed that serum adropin level is significantly correlated with risk factors of CVD and low serum adropin levels may be a potential predictor of CVD in HD patients.

Blockade of enhancer of zeste homolog 2 alleviates renal injury associated with hyperuricemia.

Hyperuricemia has been identified as an independent risk factor for chronic kidney disease (CKD) and is associated with the progression of kidney diseases. It remains unknown whether enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, can regulate metabolism of serum uric acid and progression of renal injury induced by hyperuricemia. In this study, we demonstrated that blockade of EZH2 with 3-DZNeP, a selective EZH2 inhibitor, or silencing of EZH2 with siRNA inhibited uric acid-induced renal fibroblast activation and phosphorylation of Smad3, epidermal growth factor receptor (EGFR), and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured renal fibroblasts. Inhibition of EZH2 also suppressed proliferation of renal fibroblasts and epithelial-mesenchymal transition of tubular cells. In a mouse model of renal injury induced by hyperuricemia, EZH2 and trimethylation of histone H3 at lysine27 expression levels were enhanced, which was coincident with renal damage and increased expression of lipocalin-2 and cleaved caspase-3. Inhibition of EZH2 with 3-DZNeP blocked all these responses. Furthermore, 3-DZNeP treatment decreased the level of serum uric acid and xanthine oxidase activity, alleviated renal interstitial fibrosis, inhibited activation of transforming growth factor-ß/Smad3, EGFR/ERK1/2, and nuclear factor-κB signaling pathways, as well as reduced expression of multiple chemokines/cytokines. Collectively, EZH2 inhibition can reduce the level of serum uric acid and alleviate renal injury and fibrosis through a mechanism associated with inhibition of multiple signaling pathways. Targeting EZH2 may be a novel strategy for the treatment of hyperuricemia-induced CKD.

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis.

The role of histone deacetylase 6 (HDAC6) in peritoneal fibrosis remains unknown. In this study, we examined the effect of HDAC6 inhibition on the epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and development of peritoneal fibrosis. Treatment with tubastatin A, a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA inhibited transforming growth factor ß1-induced EMT, as evidenced by decreased expression of α-smooth muscle actin, collagen I and preserved expression of E-cadherin in cultured human peritoneal mesothelial cells. In a mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of TA prevented thickening of the submesothelial region and decreased expression of collagen I and α-SMA. Mechanistically, tubastatin A treatment inhibited expression of TGF-ß1 and phosphorylation of Smad-3, epidermal growth factor receptor, STAT3, and NF-κBp65. HDAC6 inhibition also suppressed production of multiple inflammatory cytokines/chemokines and reduced the infiltration of macrophages to the injured peritoneum. Moreover, tubastatin A was effective in inhibiting peritoneal increase of CD31(+) blood vessels and expression of vascular endothelial growth factor in the injured peritoneum. Collectively, these results suggest that HDAC6 inhibition can attenuate peritoneal fibrosis by inhibiting multiple pro-fibrotic signaling pathways, EMT, inflammation and blood vessel formation.

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury.

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.