Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activating Axl/Rac1 Signaling in Subarachnoid Hemorrhage Mice.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is characterized by rapid development of neuron apoptosis and dysregulated inflammatory response. Microglia efferocytosis plays a critical role in the clearance of apoptotic cells, attenuation of inflammation, and minimizing brain injury in various pathological conditions. Here, using a mouse SAH model, we aim to investigate whether microglia efferocytosis is involved in post-SAH inflammation and to determine the underlying signaling pathway. We hypothesized that TAM receptors and their ligands regulate this process. To prove our hypothesis, the expression and cellular location of TAM (Tyro3, Axl, and Mertk) receptors and their ligands growth arrest-specific 6 (Gas6) and Protein S (ProS1) were examined by PCR, western blots, and fluorescence immunostaining. Thirty minutes after SAH, mice received an intraventricular injection of recombinant Gas6 (rGas6) or recombinant ProS1 (rPros1) and underwent evaluations of inflammatory mediator expression, neurological deficits, and blood-brain barrier integrity at 24 h. Microglia efferocytosis of apoptotic neurons was analyzed in vivo and in vitro. The potential mechanism was determined by inhibiting or knocking down TAM receptors and Rac1 by specific inhibitors or siRNA. SAH induced upregulation of Axl and its ligand Gas6. The administration of rGas6 but not rPros1 promoted microglia efferocytosis, alleviated inflammation, and ameliorated SAH-induced BBB breakdown and neurological deficits. The beneficial effects of rGas6 were arrogated by inhibiting or knocking down Axl and Rac1. We concluded that rGas6 attenuated the development of early brain injury in mice after SAH by facilitating microglia efferocytosis and preventing inflammatory response, which is partly dependent on activation of Axl and Rac1.

Heart failure and left ventricular dysfunction in older patients with chronic kidney disease: the China Hypertension Survey (2012-2015).

BACKGROUND: Heart failure (HF) is a leading cause of hospitalization and mortality for older chronic kidney disease (CKD) patients. However, the epidemiological data is scarce. We aimed to determine the prevalence of left ventricular (LV) dysfunction and HF, and to explore the risk factors for HF among those patients. METHODS: This is a cross-sectional analysis of the China Hypertension Survey conducted between October 2012 and December 2015. A total of 5, 808 participants aged ≥ 65 years were included in the analysis. Self-reported history of HF and any other cardiovascular diseases was acquired. 2-D and Doppler echocardiography were used to assess LV dysfunction. CKD was defined as either estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2 or urinary albumin to creatinine ratio (ACR) ≥ 30 mg/g. RESULTS: Among CKD patients aged ≥ 65 years, the weighted prevalence of HF, heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF) was 4.8%, 2.5%, 0.8%, and 1.7%, respectively. The weighted prevalence of HF was 5.0% in patients with eGFR < 60 mL/min per 1.73 m2, and was 5.9% in patients with ACR ≥ 30 mg/g. The prevalence of LV systolic dysfunction was 3.1%, and while it was 8.9% for moderate/severe diastolic dysfunction. Multivariate analysis showed that smoking was significantly associated with the risk of HF. Furthermore, age, smoking, and residents in rural areas were significantly associated with a risk of LV diastolic dysfunction. CONCLUSIONS: The prevalence of HF and LV dysfunction was high in older patients with CKD, suggesting that particular strategies will be required.

The Long Non-coding RNA LINC01705 Regulates the Development of Breast Cancer by Sponging miR-186-5p to Mediate TPR Expression as a Competitive Endogenous RNA.

Long non-coding RNAs (lncRNAs) may be a regulatory factor of tumorigenesis. However, it is unclear what its biomechanisms are in breast cancer. In this study, different lncRNAs were detected in breast cancer through microarray analysis (GSE119233) and LINC01705 was selected for further study. qRT-PCR was then utilized for the detection of LINC01705 expression in breast cancer cells. A transwell assay, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), a cell counting Kit-8 (CCK-8), and a wound-healing assay were performed to determine cell migration, invasion, apoptosis, and proliferation in breast cancer, respectively. For the identification of potential targets of LINC01705, dual-luciferase reporter gene and bioinformatics assays were conducted. Moreover, for the clarification of their interaction and roles in the regulation of the occurrence of breast cancer, Western blotting and RIP assays were conducted. Our findings revealed high LINC01705 expression in breast cancer tissues relative to adjacent non-cancerous tissues (n = 40, P < 0.001). Overexpression of LINC01705 notably enhanced cell migration and proliferation in breast cancer. In addition, LINC01705 positively regulated the translocated promoter region, nuclear basket protein (TPR) through competition with miR-186-5p. In conclusion, our results suggest that LINC01705 is implicated in the progression of breast cancer via competitively binding to miR-186-5p as a competing endogenous RNA (ceRNA), thereby regulating TPR expression.

Characterization of a unique proline iminopeptidase from white-rot basidiomycetes Phanerochaete chrysosporium.

A putative gene encoding proline iminopeptidase (PchPiPA) was cloned from Phanerochaete chrysosporium BKM-F-1767 by RT-PCR and expressed successfully in Escherichia coli. The cDNA is 942 bp in length and encodes 313 amino acids. The recombinant enzyme was only able to hydrolyze Pro-pNA among the tested synthetic substrates. There is no activity detected toward Leu-pNA, Phe-pNA and Tyr-pNA, as well as GGG-pNA, SGR-pNA, AAV-pNA, AAPL-pNA, AAVA-pNA. And the recombinant enzyme could cleave the peptides derived from enzyme-hydrolytic natural proteins to release free lysine, which was confirmed using synthetic oligopeptides with lysine at N termini as substrate. The optimal pH and temperature for this enzyme were 8.0 and 45 degrees C, respectively. The catalytic activity was inhibited slightly by Mg(2+), Al(3+), Ca(2+), Fe(3+), Fe(2+) and Ba(2+); strongly by Ni(2+), Mn(2+) and Co(2+), and almost inactivated by Zn(2+), Cu(2+) and Hg(2+). In addition, the enzyme was not sensitive to EDTA-Na(2), as well as redoxes of DTT, beta-ME and H(2)O(2). The protease inhibitors of benzamidine hydrochloride and phenylmethyl sulfonyfluoride caused a moderate inhibition. The V(max), K(m) and k(cat) toward Pro-pNA were 347.86 mumol min(-1) mg(-1), 2.15 mM and 218.10 S(-1), respectively. The deduced catalytic triad of Ser(107), Asp(264) and His(292) was confirmed by site-directed mutagenesis because the individual replacement of Ser(107) to Asp, Asp(264) to Ala or His(292) to Leu led complete inactivation. Transcriptional analysis by RT-PCR showed that PchPiPA could be expressed under ligninolytic and non-ligninolytic conditions. Conclusively, it was suggested that the proline iminopeptidase may be a member of the proteolytic system in this fungus. The availability of recombinant protein may be potentially used in certain proteolytic processing.

[Hypertension Control in Communities (HCC): evaluation result of blood pressure management among hypertensive].

OBJECTIVE: To determine the effects related to community-based standardized blood pressure management programs on the control of hypertension. METHODS: A protocol of community-based standardized blood pressure management was developed based on the current Chinese guideline for prevention, treatment of hypertension. Grass-roots caretakers from community health service centers across China were trained using this protocol and required to manage hypertensive patients according to the protocol. Patients were treated on therapeutic life style change or/and medication, and followed up based on the criteria of risk stratification. The control rate of hypertension was evaluated after 1 year. Effect of intervention (EI) was estimated as '1 year rate (mean)' minus the number showed at the baseline. RESULTS: By the end of 2008, a total of 29 411 hypertensive patients (47.2% for male, mean age 61.4 +/- 10.9 years) with full information had been under management for one year according to the protocol. Among all patients, 8.9% were classified as under low risk, 50.8% as moderate risk and 40.3% as high and very high risk showed in baseline data. After standardized management, the EI of smoking, drinking and systolic/diastolic blood pressure were -7.1% (P < 0.05), -7.3% (P < 0.05), and -14.8-8.3 mm Hg (P < 0.05), respectively. However, EI of overweight/obesity was 0.3% (P > 0.05). For all patients, the control rate rose to 74.7%, with EI as 53.1%, and all of the sub-groups, including age, risk stratification, had significant increases. The longer the management was under, the higher the control rate was seen. Results from the multivariate logistic regression showed that older age, male and having higher blood level were adverse factors for the undertaking the control and management programs of hypertension. CONCLUSION: Results from our study showed that standardized management could significantly improve the program on the control of hypertension at the community level, in China.

[A cohort study on parental history and risk factors of stroke in Chinese population].

OBJECTIVE: To assess the relationship between parental history and the incidence of stroke in Chinese populations. METHODS: A total of 15,131 individuals (7015 men and 8116 women, aged from 35 to 59 years) in China were enrolled and followed up from 1992 to 2005. Information on the parental history of stroke of the participants was collected at baseline study under face to face interview. Individuals were divided into three groups according to their parental history of hypertension: those with no parental history of hypertension (Group 1), those with only one parent having the history of hypertension (Group 2) and those with both parents having the history of hypertension (Group 3). The hazard ratio and its 95% confidence interval were calculated using the Cox proportional hazard model. RESULTS: There were 370 stroke events during 163 858 person-years of observation. After adjusting for age and sex, the hazard ratioon stroke for group 1, group 2 and group 3 were 1.00, 1.74 (1.33-2.29), 3.61 (1.86-7.01), respectively. After adjusting for age, sex, smoking, drinking, serum total cholesterol (TC), high density lipid cholesterol (HDL-C), fasting glucose, body mass index (BMI) and systolic blood pressure (SBP) in the model, the hazard ratio for stroke of those three groups were 1.00, 1.34 (1.02-1.77), 2.50 (1.29-4.87), respectively. CONCLUSION: Individuals with parental history of stroke had a higher risk of stroke, and this was especially true for those with both parents having the history of stroke.

[A cohort study on parental history of hypertension and the risk of cardiovascular disease in Chinese population].

OBJECTIVE: To assess the relationship between parental history of hypertension and the incidence of cardiovascular disease in Chinese populations. METHODS: A total of 15 131 individuals (7015 men and 8116 women, aged from 35 to 59 years) in China were enrolled and followed up from 1992 to 2005. The information on the parental history of hypertension of the participants was collected. The individuals were divided into three groups according to their parental history of hypertension: those without parental history of hypertension (group 1), those with one parent history of hypertension (group 2) and those with both parents history of hypertension (group 3). The hazard ratio and its 95% confidence interval were calculated using the Cox proportional hazard model. RESULTS: There were 448 cardiovascular events (including 82 cardiac events and 370 stroke events and 4 with both cardiac and stroke events) during the 163 858 person-years of observation. After adjusting for age, smoking and drinking, the hazard ratio for cardiovascular disease for group 1, group 2 and group 3 were 1.00, 1.34 (1.01 - 1.78), 2.58 (1.62 - 4.11) in men respectively and 1.00, 1.77 (1.27 - 2.45), 2.55 (1.44 - 4.54) in women respectively. After further adjusting for serum total cholesterol (TC), high density lipid cholesterol (HDL-C), fasting glucose, body mass index (BMI) and systolic blood pressure (SBP) in the model, the hazard ratio for cardiovascular disease for those three groups were 1.00, 1.01 (0.76 - 1.35), 1.72 (1.07 - 2.75) in men respectively and 1.00, 1.31 (0.94 - 1.84), 1.76 (0.98 - 3.15) in women respectively. CONCLUSION: The individuals with parental history of hypertension have a higher risk of cardiovascular disease, especially for those with both parents history of hypertension.