Function of Adipose-Derived Mesenchymal Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension through miR-191 via Regulation of BMPR2.

Pulmonary arterial hypertension (PAH) is a serious condition. However, prevailing therapeutic strategies are not effective enough to treat PAH. Therefore, finding an effective therapy is clearly warranted. Adipose-derived mesenchymal stem cells (ASCs) and ASCs-derived exosomes (ASCs-Exos) exert protective effects in PAH, but the underlying mechanism remains unclear. Using a coculture of ASCs and monocrotaline pyrrole (MCTP)-treated human pulmonary artery endothelial cells (HPAECs), we demonstrated that ASCs increased cell proliferation in MCTP-treated HPAECs. Results showed that ASCs-Exos improved proliferation of both control HPAECs and MCTP-treated HPAECs. In addition, by transfecting ASCs with antagomir we observed that low exosomal miR-191 expression inhibited HPAECs proliferation whereas the agomir improved. Similar results were observed in vivo using a monocrotaline (MCT)-induced PAH rat model following ASCs transplantation. And ASCs transplantation attenuated MCT-induced PAH albeit less than the antagomir treated group. Finally, we found that miR-191 repressed the expression of bone morphogenetic protein receptor 2 (BMPR2) in HPAECs and PAH rats. Thus, we conjectured that miR-191, in ASCs and ASCs-Exos, plays an important role in PAH via regulation of BMPR2. These findings are expected to contribute to promising therapeutic strategies for treating PAH in the future.

Inhibition of cell proliferation and migration in non­small cell lung cancer cells through the suppression of LYPLA1.

Lysophospholipase1 (LYPLA1) also known as acyl­protein thioesterase1 (APT1) belongs to the superfamily of α/ß hydrolase. It has been found to have the properties of a homodimer by manifesting depalmitoylation as well as lysophospholipase activity. LYPLAs are under the control of both microRNAs, miR­138 and miR­424. They were observed to be significantly overexpressed in chronic lymphocytic leukemia cells. To date, LYPLAs are the sole enzymes recognized to activate depalmitoylation. In this study, we provide the expression pattern of LYPLA1 in non­small cell lung cancer (NSCLC) using four different NSCLC cell lines. Western blot analysis and RT­PCR were performed to detect the protein expression and mRNA expression of LYPLA1 in NSCLC cell lines. We detected the highest LYPLA1 protein expression level in SPC­A­1 cells followed by A549 cells, and the highest LYPLA1 mRNA expression level was detected in the SPC­A­1 cells followed by the H1299 cell line. We found that suppression of LYPLA1 expression using small­interfering RNA significantly inhibited proliferation, migration and invasion of the LYPLA1­transfected NSCLC cells. Furthermore, we explored the involvement of LYPLA1 in the regulation of epithelial­mesenchymal transition (EMT). The epithelial marker E­cadherin was significantly increased, while mesenchymal markers N­cadherin, vimentin and SNAIL were markedly decreased in the LYPLA1­silenced cells. Collectively the results of the present study suggest that the LYPLA1 gene plays a tumor­promotor role in NSCLC cells in vitro.

Efficacy and Safety of Gabapentin in the Treatment of Chronic Cough: A Systematic Review.

Despite recent clinical guidelines, the optimal therapeutic strategy for the management of refractory chronic cough is still a challenge. The present systematic review was designed to assess the evidence for efficacy and safety of gabapentin in the treatment of chronic cough. A systematic search of PubMed, Embase, Cochrane Library databases, and publications cited in bibliographies was performed. Articles were searched by two reviewers with a priori criteria for study selection. Seven relevant articles were identified, including two randomized controlled trials, one prospective case-series designed with consecutive patients, one retrospective case series of consecutive patients, one retrospective case series with unknown consecutive status, and two case reports comprising six and two patients, respectively. Improvements were detected in cough-specific quality of life (Leicester Cough Questionnaire score) and cough severity (visual analogue scale score) following gabapentin treatment in randomized controlled trials. The results of prospective case-series showed that the rate of overall improvement of cough and sensory neuropathy with gabapentin was 68%. Gabapentin treatment of patients with chronic cough showed superior efficacy and a good safety record compared with placebo or standard medications. Additional randomized and controlled trials are needed.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a predictor of poor prognosis in non-small cell lung cancer, and its dynamic pattern following treatment with SGK1 inhibitor and γ-ray irradiation was elucidated.

The tumor suppressor gene p53 and its dynamic patterns have caused widespread attention in the field of cancer research. Serum and glucocorticoid-regulated kinase 1 (SGK1) with features of serine/threonine kinase activity, which also contributes to the structural and functional similarities with the AKT family of kinases, is a key enzyme in the regulation of immune responses in tumor cells, and SGK1 was noted to be expressed in close relation to p53 protein levels, and there exists a negative feedback pathway between intracellular SGK1 and p53. Noteworthy, SGK1 was detected to play a role in the development of resistance to cancer chemotherapy. In this study, we demonstrated that high SGK1 expression had strong prognostic value for reduced overall survival in NSCLC patients. Detection of SGK1 collectively was helpful to predict the prognosis of NSCLC. We also identified the expression level of SGK1 and the p53 pathway including downstream apoptotic proteins under the stimulation of γ-radiation and SGK1 inhibitor GSK650394, which presented a series of dynamic fluctuations. Our results suggest that SGK1 dynamics could play an important role in cell signaling, which is capable of directly influencing NSCLC cellular fate decisions.

Rosuvastatin improves myocardial hypertrophy after hemodynamic pressure overload via regulating the crosstalk of Nrf2/ARE and TGF-ß/ smads pathways in rat heart.

Left ventricular hypertrophy is more commonly associated with hemodynamic overload imposed by hypertension or volume overload. Transforming growth factor ß (TGF-ß) is involved in the cardiac hypertrophy and fibrosis of the left ventricle. The fact that TGF-ß1 and the nuclear factor erythroid 2-related factor 2 (Nrf2) both become up-regulated upon persistent vessel overload suggests that these two factors may virtually impact on their signaling pathways. In this research, 40 rats were divided into sham group, model group, rosuvastatin low and high dose group. Rat models were established by incomplete constriction of abdominal aorta. After five weeks treatment, blood pressure, heart mass index (HMI), hemodynamic parameters and the average diameter of myocardium cell and collagen volume fraction (CVF) improved significantly in rosuvastatin groups, compared with the model group. Both rosuvastatin groups, increased in expression of Smad7, Nrf2, NAD (P) H dehydrogenase [quinone] 1 (Nqo1) and heme oxygenase 1(Ho1),and decreased in expression of TGF-ßl、Smad3 compared with the model group. Results from co-immunoprecipitation and GST pull down showed that Nrf2 interacts with Smad7. Our results revealed the crosstalk between TGF-ß1/Smads and Nrf2/ antioxidant response elements (ARE) pathways in myocardial remodeling through the interaction between Smad7 and Nrf2. Rosuvastatin can improve cardiac function and hypertrophy by regulating the crosstalk of the two signaling pathways.

Panax notoginseng saponins reduce high-risk factors for thrombosis through peroxisome proliferator-activated receptor -γ pathway.

The classic Virchow theory suggests that blood stasis, hypercoagulability and endothelial dysfunction are three major factors that cause venous thrombosis (VT). It is a complicated biological process involved multi-factors. Platelet plays a central role and participates in multiple links of this process. Panax notoginseng saponins (PNS), the principal constituents derived from panax notoginseng, has been widely described for its anti-platelet activity. However, its potential mechanism against platelet aggregation has not been clarified. In this present study, we evaluated the anti-platelet effects of PNS on thrombin-induced platelet activation and its possible molecular mechanism of action, and further explored the therapeutic action of PNS on thrombin induced hypercoagulability in rat. Our results showed that PNS treatment inhibited platelet aggregation induced by thrombin, which was accompanied with over-expression of Peroxisome proliferator-activated receptor γ (PPAR-γ) protein, mRNA and upregulation of phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) pathway in platelet, and this effect could be reversed by PPAR-γ inhibitor T0070907. In vivo, PNS significantly reversed thrombin-induced hypercoagulable state in rat which was accompanied by PPAR-γ protein and mRNA upregulation in rat lung. In conclusion, these data suggested that PNS could suppress thrombin-induced platelet aggregation in vitro and effectively improve hypercoagulable state in vivo and PNS-induced activation of PPAR-γ and its downstream PI3K/Akt/eNOS pathway played the central role.