Astragaloside-IV regulates endoplasmic reticulum stress-mediated neuronal apoptosis in a murine model of Parkinson's disease via the lincRNA-p21/CHOP pathway.

OBJECTIVES: Astragaloside-IV (AS-IV) protects the nerve cells of Parkinson's disease (PD) from damage. Long non-coding RNA (lincRNA) has been found to be important for many diseases. Lincnra-p21 is abnormally expressed in PD. The purpose of this study was to investigate whether Astragaloside-IV (AS-IV) affects endoplasmic reticulum stress (ERS)-induced neuronal apoptosis in PD, and its possible mechanisms. METHODS: The PD mouse model was established via injecting 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP) and the PD cell model was established via inducing the MN9D cell line with 1-methyl-4-pehnyl-pyridine (MPP+). The behavioral testing of PD model mice was tested after AS-IV treatment and PD-related lincRNAs expression were detected by qRT-PCR. After treatment of PD model cells with AS-IV, lincRNA-p21 expression was detected by qRT-PCR, and cell viability and apoptosis were detected by MTT assay and flow cytometry, respectively. The binding of lincRNA-p21 to C/EBP-homologous (CHOP) protein was investigated by RNA immunoprecipitation and RNA pull-down, and the effect of lincRNA-p21 on the ubiquitination of CHOP protein was examined by ubiquitination assay. The role of lincRNA-p21 in PD model was studied by cell transfection. RESULTS: In PD mice, AS-IV can improve the behavior of mice and significantly inhibit expression of lincRNA-p21. Similarly, AS-IV can obviously restrain the expression of lincRNA-p21 in PD cells, and obviously elevated cell viability and restrained apoptosis. LincRNA-p21 is able to bind to CHOP protein. Further studies showed that restraint of lincRNA-p21 expression can facilitate ubiquitination of CHOP and accelerate its protein degradation. In AS-IV-treated PD model cells, overexpression of lincRNA-p21 lessened cell viability and facilitated apoptosis, whereas low expression of CHOP reversed this result. CONCLUSION: In this study, we found that AS-IV can lessen the expression of CHOP protein by restraining the expression of lincRNA-p21 in the PD model, thereby inhibiting neuronal apoptosis.

Four-microRNA signature for detection of type 2 diabetes.

BACKGROUND: Sensitive, novel, and accurate biomarkers for the detection of physiological changes in type 2 diabetes (T2DM) at an early stage are urgently needed. AIM: To build a multi-parameter diagnostic model for the early detection of T2DM. METHODS: MiR-148b, miR-223, miR-130a, and miR-19a levels were detected by real-time polymerase chain reaction in serum of healthy controls, individuals with impaired glucose regulation, and T2DM patients. The diagnostic value of miR-148b, miR-223, miR-130a, and miR-19a, alone or in combination, was analyzed. RESULTS: The area under the curve (AUC) of miR-223, which had the best diagnostic value for discriminating the impaired glucose regulation and T2DM groups, was 0.84, and the sensitivity and specificity were 73.37% and 81.37%, respectively. The AUC of the four-miRNA signature was 0.90, and the sensitivity and specificity were 78.82% and 88.23%, respectively. In the validation set, the AUC was 0.88, and the sensitivity and specificity were 78.36% and 87.63%, respectively. CONCLUSION: In summary, we have built a multi-parameter diagnostic model consisting of miR-148b, miR-223, miR-130a, and miR-19a for the detection of T2DM. It may be a potential tool for the early detection of T2DM.

Overexpression of p58ipk protects neuroblastoma against paraquat-induced toxicity.

BACKGROUND: Paraquat (PQ) is a powerful pathologic pesticide that contribute to the neurotoxicity, however, the pathogenic mechanism between them was unclear. The aims of this study were to explore the underlying mechanism of PQ-induced toxicity and then make potential contribute to such neuronal diseases therapy. METHODS: Human cell line SH-SY5Y was pretreated with a set concentrations of PQ to detect the cell apoptosis and the expression of related genes and proteins. Next, pcDNA 3.1-p58ipk or si-p58ipk was transfected the PQ-induced cells to detect the cytotoxicity. RESULTS: PQ significantly increased the cell apoptosis as well as the expression of p58ipk and CHOP, but decreased the expression of pAKT. p58ipk suppression resulted in an increase of cell apoptosis and CHOP expression, but the expression of pAKT was significantly decreased in PQ-induced SH-SY5Y cells. However, overexpressed p58ipk led to an opposite result. CONCLUSION: The results indicated that the expression of p58ipk was related to the toxicity level of PQ-induced cells and the mechanism between them was that p58ipk regulated the toxicity might through regulating the endoplasmic reticulum stress (ER-stress) and then regulating cell apoptosis. Further studies take emphasize on the effect of ER-stress on neuron system and explore ER-stress-related therapy are important on the treatment of neurodegenerative disease.

Simvastatin attenuates the lipopolysaccharideinduced inflammatory response of rat pulmonary microvascular endothelial cells by downregulating toll-like receptor 4 expression.

OBJECTIVE: The therapeutic potential of simvastatin as an anti-inflammatory agent was explored by investigating its effect on the lipopolysaccharide (LPS)-induced inflammatory response in rat pulmonary microvascular endothelial cells (RPMVECs). METHODS: RPMVECs were isolated and the mRNA and protein levels of different toll-like receptors (TLR) were assessed by qRT-PCR and western blotting. The LPS-induced expressions of TLR4, TNF-α and iNOS were analyzed in RPMVECs treated with different concentrations of simvastatin for different times. NF-κB activation was examined by immuofluroscence, luciferase reporter assay and western blotting. RESULTS: TLR4 is abundantly expressed in RPMVECs, and its expression is induced by LPS stimulation. Simvastatin inhibited LPS-induced TLR4 expression at the mRNA and protein levels in a time-dependent manner (p<0.01), and alleviated inflammation in RPMVECs by inhibiting the release of inflammatory factors such as TNF-α and iNOS. Further study indicated that simvastatin significantly attenuated NF-κB activity by inhibiting the degradation of IκB-α. Pretreatment with pyrrolidine dithiocarbamate (PDTC) and knock-down of TLR4 expression by RNA interference down-regulated the LPS-induced inflammatory response in RPMVECs. CONCLUSION: Simvastatin inhibits the LPS-induced inflammatory response in RPMVECs by down-regulating TLR4 expression, suggesting its role as a potential inhibitor of LPS-induced inflammation.