MicroRNA 182 inhibits CD4+CD25+Foxp3+ Treg differentiation in experimental autoimmune encephalomyelitis.

MicroRNA 182 has been found to have a distinct contribution in the clonal expansion of activated- and functioning of specialized-helper T cells. In this study we knocked down microRNA 182 in vivo and induced experimental autoimmune encephalomyelitis (EAE) to determine the influences of microRNA 182 in the Treg cells functional specialization through Foxo1 dependent pathway in the peripheral lymphoid organs. Down-regulation of microRNA 182 significantly increased the proportions of Foxp3+ T cells in the peripheral lymph nodes and spleen. In vivo study verified a positive correlation between microRNA 182 levels and symptom severity of EAE, and a negative correlation between microRNA 182 and the transcriptional factor Foxp3. In vitro polarization study also confirmed the contribution of Foxo1 in microRNA 182 mediated down-regulation of Foxp3+ T cells. Together, our results provide evidence that during the development of EAE, microRNA 182 repressed Treg cells differentiation through the Foxo1 dependent pathway.

Renin-angiotensin system antagonists and mortality due to pneumonia, influenza, and chronic lower respiratory disease in patients with hypertension.

BACKGROUND: It is controversial whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) have a potentially beneficial role in the respiratory system. This study investigated the association between ACEI/ARB medications and respiratory-related mortality in hypertensive patients in a real-world nationally representative cohort. METHODS: This was a retrospective analysis based on a prospective cohort study. A total of 10,530 patients with hypertension aged ≥ 20 years were included. The data was extracted from the US National Health and Nutrition Examination Survey during 1988-1994 and 1999-2006. The study was approved by the Institutional Review Boards. Moreover, inform concent was taken form all the participants. RESULTS: Overall, 27.7% (n = 2920) patients took ACEI/ARB agents. During a median follow-up of 12.4 years, 278 individuals died of respiratory disease, including chronic lower respiratory disease (n = 155) and influenza or pneumonia (n = 123). Compared with the patients without ACEI/ARB use, those taking ACEI/ARB were not associated with respiratory-specific mortality in a multivariable-adjusted Cox model. After 1: 1 matching, taking ACEI/ARB was also not related to respiratory mortality (Hazard ratio (HR) = 1.07, 95% CI: 0.79-1.43), influenza- or pneumonia-related (HR = 1.00, 95% CI: 0.65-1.54) and chronic pulmonary mortality (HR = 1.13, 95% CI: 0.75-1.69). After separating ACEI and ARB from anti-hypertensive medications, those associations remained unchanged. CONCLUSIONS: We discovered no significant link between ACEI or ARB medication and pulmonary-related mortality in hypertensive patients. In hypertensive patients, standard ACEI/ARB administration may have little effect on the respiratory system.

Potassium variability during hospitalization and outcomes after discharge in patients with acute myocardial infarction.

BACKGROUND: The variability of metabolic biomarkers has been determined to provide incremental prognosis information, but the implications of electrolyte variability remained unclear. METHODS: We investigate the relationships between electrolyte fluctuation and outcomes in survivors of acute myocardial infarction (n = 4386). Ion variability was calculated as the coefficient of variation, standard deviation, variability independent of the mean (VIM) and range. Hazard ratios (HR) were estimated using the multivariable-adjusted Cox proportional regression method. RESULTS: During a median follow-up of 12 months, 161 (3.7%) patients died, and heart failure occurred in 550 (12.5%) participants after discharge, respectively. Compared with the bottom quartile, the highest quartile potassium VIM was associated with increased risks of all-cause mortality (HR = 2.35, 95% CI: 1.36-4.06) and heart failure (HR = 1.32, 95% CI: 1.01-1.72) independent of cardiac troponin I (cTnI), N terminal pro B type natriuretic peptide (NT-proBNP), infarction site, mean potassium and other traditional factors, while those associations across sodium VIM quartiles were insignificant. Similar trend remains across the strata of variability by other three indices. These associations were consistent after excluding patients with any extreme electrolyte value and diuretic use. CONCLUSIONS: Higher potassium variability but not sodium variability was associated with adverse outcomes post-infarction. Our findings highlight that potassium variability remains a robust risk factor for mortality regardless of clinical dysnatraemia and dyskalaemia.

Mesenchymal Stromal Cells from Patients with Cyanotic Congenital Heart Disease are Optimal Candidate for Cardiac Tissue Engineering.

Engineered heart tissues (EHTs) are regarded as being the most promising alternative to synthetic materials, and autologous mesenchymal stem cells (MSCs) are widely used as seeding cells. However, few studies have evaluated the feasibility of using MSCs from patients with cyanotic congenital heart disease (C-CHD) as seeding cells for EHTs, in comparison with cells from patients of acyanotic congenital heart disease (A-CHD). In the present study, we cultured MSCs from A-CHD and C-CHD patients in normoxia or hypoxia conditions, and compared their pro-angiogenic, anti-apoptotic and inflammation-modulatory potentials. In vivo, we seeded the cells into collagen patches conjugated with, or without, proangiogenic cytokines, which were used to repair the right ventricular outflow tract (RVOT) of rats. The in vitro results showed that C-CHD MSCs expressed higher levels of VEGFA and VEGFR2, and secreted more pro-angiogenic and anti-inflammatory cytokines under hypoxic conditions. On the other hand, apoptosis-related genes from C-CHD MSCs were modulated adaptably, converting these cells into an anti-apoptotic phenotype. In vivo studies demonstrated that in 4 weeks after RVOT reconstruction, cytokine-immobilized patches seeded with C-CHD MSCs exhibited preserved morphology, prolonged cell survival and enhanced angiogenesis compared to A-CHD MSCs. C-CHD MSCs that undergo "naturally hypoxic precondition" present a better cell source for EHTs, which would provide a promising individualized biomaterial for C-CHD patients.

Lower Senescence of Adipose-Derived Stem Cells than Donor-Matched Bone Marrow Stem Cells for Surgical Ventricular Restoration.

Surgical ventricular reconstruction (SVR) can restore cardiac function for left ventricular aneurysm to some extent. However, the patches used in this treatment have some limitations such as stiffness and calcification. Engineering heart tissues (EHTs) have emerged as a promising biomaterial to repair damaged heart. Nevertheless, selecting optimal candidate cells for EHTs has been controversial. Aging is a major consideration for seed cells derived from elderly patients. Hence, this study was aimed to assess the proliferation of, antiapoptosis potential of, and expression of senescence-associated factors (eg, SA-ß-Gal, cyclin-dependent kinase inhibitor 2A (P16), cyclin-dependent kinase inhibitor 1 (P21) in adipose-derived stem cells (ADSCs), and bone marrow stem cells (BMSCs) in vitro. In addition, cardiac function, cell survival, and angiogenesis of ADSCs and BMSCs after SVR were assessed in vivo. The in vitro results showed that old ADSCs (OAs) grew faster; expressed lower levels of SA-ß-Gal, P16, and P21; and possessed more pronounced antiapoptosis activity than old BMSCs (OBs). The in vivo results demonstrated that 28 days after patch implantation, animals that received OAs patches showed better restoration of cardiac function than animals that received OBs patches. Meanwhile, old ADSCs possessed more potential regarding cell survival and angiogenesis. These results suggest that ADSCs may be superior to BMSCs with regard to autologous cell transplantation in elderly patients.

Juglone induces apoptosis and autophagy via modulation of mitogen-activated protein kinase pathways in human hepatocellular carcinoma cells.

Juglone (JG), a naturally-occurring naphthoquinone of Manchurian walnut (Juglans mandshurica) was shown to inhibit proliferation in various tumor types. However, the molecular mechanisms of JG on the induction of apoptosis and autophagy in HepG2 cells have not been examined. Herein, we investigated that JG could inhibit cell proliferation by induction of G2/M phase arrest. Also, occurrence of apoptosis was closely related with loss of mitochondrial membrane potential, the changes of apoptosis-related proteins after treatment with JG. In addition, we found that JG caused autophagy, as evidenced by increased expressions of LC3-II and Beclin-1. Interestingly, inhibition of JG-induced autophagy by 3-methyladenine (3-MA) and wortmannin (WT) significantly decreased apoptosis, whereas the apoptosis inhibitor z-VAD-fmk slightly enhanced autophagy. Furthermore, the induction of autophagy and apoptosis was associated with activation of MAPK family members (p38 and JNK) and production of reactive oxygen species (ROS). Both JNK inhibitor (SP600125) and ROS scavenger (N-acetylcysteine, NAC) could attenuate JG-induced autophagy and apoptosis. However, the p38-specific inhibitor SB203580 enhanced autophagic and apoptotic death. Moreover, the ROS scavenger NAC prevented phosphorylation of both p38 and JNK. Collectively, our data revealed that JG induced G2/M phase arrest, apoptosis, and autophagy through the ROS-dependent signaling pathway.