Gamma-Glutamyl Transpeptidase to Platelet Ratio: A New Inflammatory Marker Associated with Outcomes after Cardiac Arrest.

INTRODUCTION: In recent years, gamma-glutamyl transpeptidase to platelet ratio (GPR) has been proposed as a new inflammatory marker. We aimed to evaluate the association between GPR and outcomes after cardiac arrest (CA). METHODS: A total of 354 consecutive patients with CA were included in this retrospective study. Patients were divided into three groups according to tertiles of GPR (low, n = 119; middle, n = 117; and high, n = 118). To determine the relationship between GPR and prognosis, a logistic regression analysis was performed. The ability of GPR to predict the outcomes was evaluated by receiver operating characteristic (ROC) curve analysis. Two prediction models were established, and the likelihood ratio test (LRT) and the Akaike Information Criterion (AIC) were utilized for model comparison. RESULTS: Among the 354 patients (age 62 [52, 74], 254/354 male) who were finally included in the analysis, those in the high GPR group had poor outcomes. Multivariate logistic regression analysis revealed that GPR was independently associated with the three outcomes, for ICU mortality (odds ratios (OR) = 1.738, 95% confidence interval (CI): 1.221-2.474, P = 0.002), hospital mortality (OR = 1.676[1.164 - 2.413], P = 0.005), and unfavorable neurologic outcomes (OR = 1.623[1.121 - 2.351], P = 0.010). The area under the ROC curve was 0.611 (95% Cl: 0.558-0.662) for ICU mortality, 0.600 (95% CI: 0.547-0.651) for hospital mortality, and 0.602 (95% CI: 0.549-0.653) for unfavorable neurologic outcomes. Further, the LRT analysis showed that compared with the model without GPR, the GPR-combined model had a higher likelihood ratio χ 2 score and smaller AIC. CONCLUSION: GPR, as an inflammatory indicator, was independently associated with outcomes after CA. GPR is helpful in estimating the clinical outcomes of patients with CA.

The combined utilization of Chlorhexidine and Voriconazole or Natamycin to combat Fusarium infections.

BACKGROUND: Fusarium species are the fungal pathogens most commonly responsible for the mycotic keratitis, which are resistant to the majority of currently available antifungal agents. The present study was designed to assess the efficacy of a combination of low doses chlorhexidine with two other commonly used drugs (voriconazole and natamycin) to treat Fusarium infections. RESULTS: We utilized combinations of chlorhexidine and natamycin or voriconazole against 20 clinical Fusarium strains in vitro using a checkerboard-based microdilution strategy. In order to more fully understand the synergistic interactions between voriconazole and chlorhexidine, we utilized a Galleria mellonella model to confirm the combined antifungal efficacy of chlorhexidine and voriconazole in vivo. We found that for voriconazole, natamycin, and chlorhexidine as single agents, the minimum inhibitory concentration (MIC) ranges were 2-8, 4-16, and > 16 µg/ml, respectively. In contrast, the MIC values for voriconazole and chlorhexidine were reduced to 0.25-1 and 1-2 µg/ml, respectively, when these agents were administered in combination, with synergy being observed for 90% of tested Fusarium strains. Combined chlorhexidine and natamycin treatment, in contrast, exhibited synergistic activity for only 10% of tested Fusarium strains. We observed no evidence of antagonism. Our in vivo model results further confirmed the synergistic antifungal activity of chlorhexidine and voriconazole. CONCLUSIONS: Our results offer novel evidence that voriconazole and chlorhexidine exhibit synergistic activity when used to suppress the growth of Fusarium spp., and these agents may thus offer value as a combination topical antifungal treatment strategy.

NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN.

BACKGROUND/AIMS: Neural precursor cell-expressed developmentally down-regulated gene 4 (NEDD4) plays an important role in tumor cell growth, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study is to establish NEDD4 as a prognostic biomarker by which the survival of HCC patients can be predicted and to reveal the role of NEDD4 in hepatocellular carcinoma cell growth. METHODS: The expression of NEDD4 in 219 HCC specimens was assessed by immunohistochemistry. Postoperative overall survival and time to recurrence were evaluated by univariate and multivariate analyses. The roles of NEDD4 in hepatocellular carcinoma cell proliferation and invasion were determined. RESULTS: The patients with low NEDD4 expression tumors had an average cumulative survival of 64.9 ± 6.5 months during follow-up while the patients with high NEDD4 expression tumors had an average cumulative survival of 20.3 ± 15.8 months. NEDD4 silencing inhibited Huh7 cell proliferation and altered cell cytoskeletal assembly, and NEDD4 depletion furthermore seemed to suppress cell migration and invasion. A possible molecular mechanism for the observed effects might be that NEDD4 silence led to an increase in PTEN (phosphatase and tensin homologue) expression, which in turn resulted in the inactivation of STAT3, AKT, and ERK1/2. CONCLUSION: Our findings indicate that NEDD4 may participate in the HCC progression and may therefore be a potential target for HCC therapy.

Low expression of DCXR protein indicates a poor prognosis for hepatocellular carcinoma patients.

The aim of this study was to investigate the prognostic value of dicarbonyl/L-xylulose reductase (DCXR) in human hepatocellular carcinoma (HCC). Immunohistochemistry and tissue microarrays were used to evaluate DCXR protein expression levels. Image-Pro Plus was used to calculate the integral optic density (IOD) in each tissue sample, which represented the expression level of DCXR. DCXR proteins were found to be significantly lower in HCC tumor tissues (P < 0.0001) according to immunohistochemical analysis of DCXR protein levels in 74 paired HCC tissue and peritumoral non-cancer tissues. The prognostic value of DCXR in HCC was assessed in 290 cases of the training cohort and 74 cases of the validation cohort. Shorter overall survival (OS) time and shorter time to recurrence (TTR) in both the training and validation set were found to be associated with lower expression levels of DCXR. In the training set, the expression level of DCXR in HCC was an independent prognostic factor for OS according to univariate and multivariate analyses. In conclusion, DCXR expression is an independent prognostic factor for OS and TTR of post-operative HCC patients, and low expression levels of DCXR in HCC may indicate poor outcome of HCC patients after surgical resection.

miR-9 enhances the transactivation of nuclear factor of activated T cells by targeting KPNB1 and DYRK1B.

The fast response to stimuli and subsequent activation of the nuclear factor of activated T cells (NFAT) signaling pathway play an essential role in human T cell functions. MicroRNAs (miRNAs) are increasingly implicated in regulation of numerous biological and pathological processes. In this study we demonstrate a novel function of miRNA-9 (miR-9) in regulation of the NFAT signaling pathway. Upon PMA-ionomycin stimulation, miR-9 was markedly increased, consistent with NFAT activation. Overexpression of miR-9 significantly enhanced NFAT activity and accelerated NFAT dephosphorylation and its nuclear translocation in response to PMA-ionomycin. Karyopherin-ß1 (KPNB1, a nucleocytoplasmic transporter) and dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) were identified as direct targets of miR-9. Functionally, miR-9 promoted IL-2 production in stimulated human lymphocyte Jurkat T cells. Collectively, our data reveal a novel role for miR-9 in regulation of the NFAT pathway by targeting KPNB1 and DYRK1B.

Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats.

In hypertensive animals and patients, oxidative stress represents the primary risk factor for progression of renal disease. Recently, it has been demonstrated that hydrogen, as a novel antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite anion to exert therapeutic antioxidant activity. Herein, we investigated the protective effect of hydrogen-rich water (HW) against renal injury in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into HW-treated (1.3 ± 0.2 mg/l for 3 months, drinking) and vehicle-treated group. Although treatment with HW had no significant effect on blood pressure, it significantly ameliorated renal injury in SHR. Treatment with HW lowered reactive oxygen species formation, upregulated the activities of superoxide dismutase, glutathione peroxidase, glutathione-S-epoxide transferase, and catalase, and suppressed NADPH oxidase activity. Treatment with HW in SHR depressed pro-inflammatory cytokines expression including TNF-α, IL-6, IL-1ß, and macrophage chemoattractant protein 1, which might be mediated by suppressing nuclear factor-κB activation. In addition, treatment with HW had protective effect on mitochondrial function including adenosine triphosphate formation and membrane integrity in SHR. In conclusion, consumption of HW is a promising strategy to alleviate renal injury as a supplement for anti-hypertensive therapy.

Dosimetric benefits of IMRT and VMAT in the treatment of middle thoracic esophageal cancer: is the conformal radiotherapy still an alternative option?

The purpose of this study is to investigate the dosimetric differences among conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated radiotherapy (VMAT) in the treatment of middle thoracic esophageal cancer, and determine the most appropriate treatment modality. IMRT and one-arc VMAT plans were generated for eight middle thoracic esophageal cancer patients treated previous with CRT. The planning target volume (PTV) coverage and protections on organs at risk of three planning schemes were compared. All plans have sufficient PTV coverage and no significant differences were observed, except for the conformity and homogeneity. The lung V5, V10, and V13 in CRT were 47.9% ± 6.1%, 36.5% ± 4.6%, and 33.2% ± 4.2%, respectively, which were greatly increased to 78.2% ± 13.7% (p < 0.01), 80.8% ± 14.9% (p < 0.01), 48.4% ± 8.2% (p = 0.05) in IMRT and 58.6% ± 10.5% (p = 0.03), 67.7% ± 14.0% (p < 0.01), and 53.0% ± 10.1% (p < 0.01) in VMAT, respectively. The lung V20 (p = 0.03) in VMAT and the V30 (p = 0.04) in IMRT were lower than those in CRT. Both IMRT and VMAT achieved a better protection on heart. However, the volumes of the healthy tissue outside of PTV irradiated by a low dose were higher for IMRT and VMAT. IMRT and VMAT also had a higher MU, optimization time, and delivery time compared to CRT. In conclusion, all CRT, IMRT, and VMAT plans are able to meet the prescription and there is no clear distinction on PTV coverage. IMRT and VMAT can only decrease the volume of lung and heart receiving a high dose, but at a cost of delivering low dose to more volume of lung and normal tissues. CRT is still a feasible option for middle thoracic esophageal cancer radiotherapy, especially for the cost-effective consideration.

Emodin protects against diabetic cardiomyopathy by regulating the AKT/GSK-3ß signaling pathway in the rat model.

Diabetes mellitus (DM) has been recognized as a major health problem. Emodin (Emo) has been reported to exhibit protective effects against diabetic nephropathy. However, little has been known about the effect of Emo on diabetic cardiomyopathy (DCM). A type 2 DM model was induced in rats by low dose streptozotocin (STZ) combined with high energy intake. We found that Emo-treated groups displayed significantly higher body weight (BW) and lower heart weight (HW)/BW. Furthermore, Emo could significantly decrease blood glucose, total cholesterol (TG) levels, and triglyceride (TC) levels in diabetic rats. Moreover, the Emo-treated group showed a marked increase in heart rate (HR) and showed lower left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular posterior wall thickness (LWPWT), and interventricular septal diastolic wall thickness (IVSD). Emo induced a significant increase in phosphorylation of Akt and GSK-3ß in myocardium. These results suggest that Emo may have great therapeutic potential in the treatment of DCM by Akt/GSK-3ß signaling pathway.

[Effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction].

OBJECTIVE: To investigate the effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction (MI). METHODS: Adult male SD rats were divided into six groups (n = 20 each group): control, diabetes mellitus (DM), MI, DM+MI, DM+MI+ghrelin, DM+MI+ghrelin+D-Lys3-GHRP-6 (GHSR1a inhibitor). DM was induced by streptozotocin (STZ, 60 mg/kg), 3 months later, MI was induced by left anterior descending artery ligation in DM rats. DM+MI+ghrelin group received ghrelin 200 µg×kg(-1)×d(-1) and DM+MI+ghrelin+D-Lys3-GHRP-6 group received ghrelin 200 µg×kg(-1)×d(-1) and D-Lys3-GHRP-6 50 mg×kg(-1)×d(-1) for 4 weeks. Then, cardiac function was measured by echocardiography, microvascular density (MVD) was measured by CD34 immunohistochemistry, myocardial infarct size was determined by Masson staining, the mRNA and protein expressions of vascular endothelial growth factor (VEGF) and receptors Flk-1, Flt-1 were detected by real-time PCR and Western-blot, respectively. RESULTS: Compared with MI group, MVD (15.3 ± 1.0 vs.20.7 ± 1.6, P < 0.05), left ventricular ejection fraction (LVEF) ((64.2 ± 3.4)% vs. (81.3 ± 3.8)%, P < 0.01), left ventricular fractional shortening (LVFS) ((31.7 ± 1.1)% vs. (48.8 ± 3.3)%, P < 0.01) and the mRNA and protein expression of VEGF, Flk-1 and Flt-1 (P < 0.01) were reduced, while myocardial infarct size ((55.8 ± 3.1)% vs. (35.7 ± 2.5)%, P < 0.01) was increased in DM+MI group. These effects were partly reversed in DM+MI+ghrelin group and the beneficial effects of ghrelin were partly abolished by D-Lys3-GHRP-6 (all P < 0.05). CONCLUSIONS: Our results demonstrate that ghrelin could improve microvascular density, cardiac function, and reduce myocardial infarct size of diabetic rats with myocardial infarction via modulating GHSR1a-mediated expressions of VEGF, Flk-1 and Flt-1.

[Effects end mechanisms of curcumol beta-cyclodextrin compound on the proliferation and apoptosls of esophageal carcinoma cell line TE-1].

OBJECTIVE: To investigate the effects and mechanisms of Curcumol beta-cyclodextrin Compound (CbetaC) on the proliferation and apoptosis of esophageal carcinoma cell line TE-1. METHODS: The CbetaC was prepared by saturated solution and confirmed by infrared absorption spectroscopy. The effects of CbetaC (at 25, 50, 100 mg/L) on the proliferation of human esophageal carcinoma cell line TE-1 in vitro was analyzed by MTT assay. The cell cycles and apoptosis were detected by flow cytometer. The relative expression of survivin mRNA was detected by real-time fluorescent quantitative PCR and calculated by the 2(-deltaCt) method. The protein expression of survivin was measured by Western blot. RESULTS: Compared with the control group, results of MTT showed that CbetaC at each dose significantly inhibited the proliferation of TE-1 cells in a dose-dependent manner (P < 0.05). The results of flow cytometry showed that CbetaC resulted in the cell cycle arrest at G0/G1 and G2/M phase, and promoted the cell apoptosis. Besides, when compared with the control group, the protein and mRNA expressions of survivin obviously decreased in each CbetaC group (P < 0.05). CONCLUSIONS: CbetaC could inhibit the proliferation of esophageal carcinoma cell TE-1 and promote the apoptosis. Its inhibition on the survivin expression was correlated with its inhibition on the malignant phenotypes of esophageal carcinoma cells.

[Comparison of ArcCheck and film verification for VMAT in the treatment of nasopharyngeal carcinoma].

To compare the performance of ArcCheck and film verification for volumetric intensity modulated arc therapy (VMAT) in the treatment of nasopharyngeal carcinoma, and to study the feasibility of ArcCheck in VMAT dosimetric verification. Five patients of nasopharyngeal carcinoma treated with VMAT were enrolled in this study. Dose verification was carried out by ArcCheck and film respectively. The result showed that there were no significant differences between ArcCheck and film verification. ArcCheck software can obtain three dimensional dose distribution directly with simple operation. It is convenient for ArcCheck to be used for VMAT dosimetric verification.

Structural characterization and immunomodulatory activity of a polysaccharide from finger citron extracted by continuous phase-transition extraction.

FCP-2-1, a water-soluble polysaccharide rich in galacturonic acid was isolated by continuous phase-transition extraction and purified with DEAE-52 cellulose and Sephadex G-100 column chromatography from finger citron with essential oil and flavonoids removed. The structural characterization and immunomodulatory activity of FCP-2-1 were further investigated in this work. FCP-2-1 with a Mw and Mn of 1.503 × 104 g/mol and 1.125 × 104 g/mol, respectively, was predominantly composed of galacturonic acid, galactose, and arabinose in a molar ratio of 0.685: 0.032: 0.283. The main linkage types of FCP-2-1 were proved to be →5)-α-L-Araf-(1→ and →4)-α-D-GalpA-(1→ based on methylation and NMR analysis. Moreover, FCP-2-1 was demonstrated to have significant immunomodulatory effects on macrophages in vitro by improving the cell viability, and enhancing phagocytic activity and secretion of NO and cytokines (IL-1ß, IL-6, IL-10 and TNF-α), indicating that FCP-2-1 could be used as a natural agent in immunoregulation functional foods.

Suppression of NHE1 by small interfering RNA inhibits HIF-1α-induced angiogenesis in vitro via modulation of calpain activity.

Hypoxia-inducible factor-1 (HIF-1) orchestrates angiogenesis under hypoxic conditions mainly due to increased expression of such target genes as vascular endothelial growth factor (VEGF). Na+/H+exchanger-1 (NHE1), a potential HIF target gene product, plays a pivotal role in proliferation, survival, migration, adhesion and so on. However, it is unknown whether NHE1 is involved in HIF-1α-induced angiogenesis. This present study demonstrated that the expression of NHE1 was much higher in human umbilical vein endothelial cells (HUVECs) infected with adenovirus encoding HIF-1α (rAd-HIF) than with vacuum adenovirus (vAd). HIF-1α also increased the expression of VEGF, the expression and activity of calpains, and the intracellular pH. Moreover, small interfering RNA targeting NHE1 (NHE1 siRNA) dramatically decreased the expression of NHE1 and thus lowered the intracellular pH, and it also attenuated the protein expression of calpain-2 but not calpain-1, resulting in the lower calpain activity. Furthermore, HIF-1α enhanced the proliferation, migration and Matrigel tube formation, which were inhibited by NHE1 siRNA. Finally, the inhibitory effect of NHE1 siRNA was reversed by VEGF and the reversibility of the later was abrogated by the calpain inhibitor ALLM. In conclusion, the findings have revealed that NHE1 might participate in HIF-1-induced angiogenesis due, at least in part, to the alteration of the calpain activity, suggesting that NHE1 as well as calpains might represent a potential target of controlling angiogenesis in response to the hypoxic stress under various pathological conditions.

[Clinical analysis of treatment and postoperative efficacy in neonatal congenital pyriform sinus fistula].

Objective:To discuss the diagnosis and treatment of congenital pyriform sinus fistula（CPSF） in newborn. Methods:Clinical data of 5 patients with CPSF innewborn were reviewed and the clinical symptoms, auxiliary examinations, surgical methods were analyzed after the operation, patients were followed up closely at different stages. Results:All the 5 neonates successfully completed the surgery without pharyngeal fistula, dysphagia, perifistula and distal fistula infection. Follow-up survey ranged from 3 months to 2 years and no one recurred. Conclusion:Neonatal CPSF is a rare disease with a short course of disease and rapid progression. In severe cases, it may threaten life and should be treated in time.

Investigation of the structural and physical properties, antioxidant and antimicrobial activity of konjac glucomannan/cellulose nanocrystal bionanocomposite films incorporated with phlorotannin from Sargassum.

In this study, environmentally friendly bionanocomposite films were prepared by incorporating phlorotannins from Sargassum (PS) into konjac glucomannan (KGM)/cotton cellulose nanocrystals (CNC) composites. The effects of different concentrations of PS (5%, 9%, 13%, and 17%, w/w) on the microstructure, physical properties, antioxidant and antibacterial activities of the resultant bionanocomposite films were evaluated. The results of scanning electron microscopy, X-ray diffraction, and Fourier-transform infrared spectra showed that PS was well compatible with the KGM/CNC composites matrix, which led to form a compact and uniform structure of the films. Thermogravimetric analysis and differential scanning calorimetry demonstrated that incorporating PS improved the heat stability of KGM/CNC bionanocomposite films. And addition of the appropriate amount of PS improved the mechanical and water-vapor barrier-related properties of the bionanocomposite film. For instance, with 9% PS, the tensile strength of the KGM/CNC/PS bionanocomposite film increased by 33.9%, and the water-vapor transmittance decreased by 41.67% compared to that of the KGM/CNC films. Moreover, the addition of PS endowed the KGM/CNC film with excellent antioxidant and antibacterial properties. Therefore, KGM/CNC/PS bionanocomposite films have great potential to be applicated as active packaging in the food packaging industry.

The long noncoding RNA EMBP1 inhibits the tumor suppressor miR-9-5p and promotes renal cell carcinoma tumorigenesis.

INTRODUCTION AND OBJECTIVES: Long non-coding RNAs (lncRNAs) have garnered interest because of their roles in cancer progression. We aimed to explore the role of the lncRNA embigin pseudogene 1 (EMBP1)-miR-9-5p axis in renal cell carcinoma (RCC). MATERIALS AND METHODS: Expression profiling of miR-9-5p and EMBP1 were performed in RCC cell lines and tumor samples. To evaluate miR-9-5p and EMBP1's role in proliferation, invasion, migration, and colony formation, we performed in vitro assays along with studies in a xenograft tumor model. In silico binding site analysis using the RNA22 algorithm, RNA-immunoprecipitation (RIP), and luciferase reporter assays were used to validate a direct interaction between EMBP1 and miR-9-5p. Changes in key proteins were also analyzed. RESULTS: miR-9-5p was significantly down-regulated, and EMBP1 was significantly up-regulated, in RCC cell lines and tumor tissue. The clinicopathological characteristics of RCC patients significantly correlated with their expression. Overexpression of miR-9-5p or EMBP1 suppression in RCC cell lines significantly retarded their proliferative, migratory, and invasive behavior, in addition to promoting apoptosis and cell-cycle arrest. EMBP1 directly binds to and negatively regulates miR-9-5p. The EMBP1-miR-9-5p axis dysregulated the expression of the epithelial-to-mesenchymal transition (EMT) markers E-cadherin, claudin, and vimentin, the stemness markers KLF4 and Nanog, and the cell cycle checkpoint gene cyclin E2 (CCNE2) and its downstream mediator E2F1. miR-9-5p overexpression or EMBP1 suppression inhibited xenograft tumor growth in vivo, effects that were abrogated by CCNE2 overexpression. CONCLUSIONS: Our findings suggest an important role of the EMBP1/miR-9-5p axis dysregulation in RCC tumor progression.

Effect of carboxylation cellulose nanocrystal and grape peel extracts on the physical, mechanical and antioxidant properties of konjac glucomannan films.

Active bionanocomposite films were prepared by incorporating konjac glucomannan (KGM) as a matrix, with carboxylation cellulose nanocrystal (C-CNC) as a reinforcement agent and grape peel extracts (GPE) as a natural antioxidation agent. The effects of C-CNC and/or GPE addition on the structural, morphological, barrier, thermal, mechanical and antioxidant properties of the bionanocomposite films were investigated. The rheological results of film forming solutions revealed that C-CNC and GPE were well dispersed in the KGM matrix. Scanning electron micrographs observed the addition of C-CNC had little effect on the microstructure, while more roughness and unevenness were observed on the film surface and cross-section with the C-CNC and GPE. Furthermore, the water vapor barrier property and transparency of the films improved by the addition of the C-CNC and GPE. Notably, the incorporating of C-CNC or GPE significantly alter the mechanical of the KGM/C-CNC/GPE bionanocomposite films. The highest tensile strength was achieved for the KGM/GPE bionanocomposite film with 10 wt% C-CNC, indicating C-CNC and GPE had synergistic effect on enhancing the TS of KGM film. Moreover, the KGM/C-CNC/GPE films exhibited strong antioxidant activity. These results suggested that KGM/C-CNC/GPE bionanocomposite films can be used as an active food packaging for increasing shelf life of packaged foods.

Effectiveness of Ivabradine in Treating Stable Angina Pectoris.

Many studies show that ivabradine is effective for stable angina.This meta-analysis was performed to determine the effect of treatment duration and control group type on ivabradine efficacy in stable angina pectoris.Relevant articles in the English language in the PUBMED and EMBASE databases and related websites were identified by using the search terms "ivabradine," "angina," "randomized controlled trials," and "Iva." The final search date was November 2, 2015.Articles were included if they were published randomized controlled trials that related to ivabradine treatment of stable angina pectoris.Patients with stable angina pectoris were included.The patients were classified according to treatment duration (<3 vs ≥3 months) or type of control group (placebo vs beta-receptor blocker). Angina outcomes were heart rate at rest or peak, exercise duration, and time to angina onset.Seven articles were selected. There were 3747 patients: 2100 and 1647 were in the ivabradine and control groups, respectively. The ivabradine group had significantly longer exercise duration when they had been treated for at least 3 months, but not when treatment time was less than 3 months. Ivabradine significantly improved time to angina onset regardless of treatment duration. Control group type did not influence the effect of exercise duration (significant) or time to angina onset (significant).Compared with beta-blocker and placebo, ivabradine improved exercise duration and time to onset of angina in patients with stable angina. However, its ability to improve exercise duration only became significant after at least 3 months of treatment.

A novel cyclic dipeptide from deep marine-derived fungus Aspergillus sp. SCSIOW2.

A novel cyclic dipeptide, 14-hydroxy-cyclopeptine (1), was purified from a deep sea derived fungal isolate identified as an Aspergillus sp. The structure was elucidated by detailed spectroscopic analyses using 1D and 2D NMR experiments and high resolution mass spectrometry. The absolute configuration of the amino acid was determined by Marfey's method. Two conformational isomers of 1 were established by ROE analyses. 1 inhibited nitric oxide production with IC50 values at 40.3 µg/mL in a lipopolysaccharide and recombinant mouse interferon-γ -activated macrophage-like cell line, RAW 264.7 and showed no cytotoxic effect in the tested dose range up to 100 µg/mL.

MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells.

There is growing evidence that microRNAs are implicated in pulmonary arterial hypertension (PAH), but underlying mechanisms remain elusive. Here, we identified that miR-223 was significantly downregulated in chronically hypoxic mouse and rat lungs, as well as in pulmonary artery and pulmonary artery smooth muscle cells (PASMC) exposed to hypoxia. Knockdown of miR-223 increased PASMC proliferation. In contrast, miR-223 overexpression abrogated cell proliferation, migration and stress fiber formation. Administering miR-223 agomir in vivo antagonized hypoxia-induced increase in pulmonary artery pressure and distal arteriole muscularization. RhoB, which was increased by hypoxia, was identified as one of the targets of miR-223. Overexpressed miR-223 suppressed RhoB and inhibited the consequent phosphorylation of myosin phosphatase target subunit (MYPT1) and the expression of myosin light chain of myosin II (MLC2), which was identified as another target of miR-223. Furthermore, serum miR-223 levels were decreased in female patients with PAH associated with congenital heart disease. Our study provides the first evidence that miR-223 can regulate PASMC proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of PAH. It also highlights miR-223 as a potential circulating biomarker and a small molecule drug for diagnosis and treatment of PAH.