Bin Geng

HMDD v2.0: a database for experimentally supported human microRNA and disease associations

The Human microRNA Disease Database (HMDD; available via the Web site at http://cmbi.bjmu.edu.cn/hmdd and http://202.38.126.151/hmdd/tools/hmdd2.html) is a collection of experimentally supported human microRNA (miRNA) and disease associations. Here, we describe the HMDD v2.0 update that presented several novel options for users to facilitate exploration of the data in the database. In the updated database, miRNA–disease association data were annotated in more details. For example, miRNA–disease association data from genetics, epigenetics, circulating miRNAs and miRNA–target interactions were integrated into the database. In addition, HMDD v2.0 presented more data that were generated based on concepts derived from the miRNA–disease association data, including disease spectrum width of miRNAs and miRNA spectrum width of human diseases. Moreover, we provided users a link to download all the data in the HMDD v2.0 and a link to submit novel data into the database. Meanwhile, we also maintained the old version of HMDD. By keeping data sets up-to-date, HMDD should continue to serve as a valuable resource for investigating the roles of miRNAs in human disease.

Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been reported to have beneficial effects on cardiac function. The authors used the Langendorff model of ischemia/reperfusion (I/R) injury in isolated rat heart to determine whether ghrelin exerts direct cardioprotective effects. Also, the capacity of ghrelin to bind to sarcolemmal membrane fractions before and after ischemia and reperfusion was examined. Compared with vehicle administration, administration of ghrelin (100–10,000 p M) during the reperfusion period resulted in improvement in coronary flow, heart rate, left ventricular systolic pressure, and left ventricular end-diastolic pressure. Ghrelin also enhanced the rates of left ventricular contraction and relaxation after ischemia following reperfusion. Administration of ghrelin during reperfusion reduced myocardial release of lactate dehydrogenase and myoglobin, indicating protection against cardiomyocyte injury. In addition, ghrelin attenuated the depletion of myocardial ATP resulting from ischemia and reperfusion. A receptor-binding assay demonstrated that maximum binding capacity of ghrelin to sarcolemmal membranes was significantly increased after ischemia and was further increased after I/R. However, Scatchard analysis showed that the affinity of ghrelin for its receptor was not altered. The authors have concluded that administration of ghrelin during reperfusion protects against myocardial I/R injury. The cardioprotective effects are independent of growth hormone release and likely involve binding to cardiovascular receptors, a process that is upregulated during I/R.

Hydrogen sulfide protects rat lung from ischemia–reperfusion injury

Recent studies have indicated that hydrogen sulfide (H(2)S) is capable of modulating many physiological processes, which prompted us to investigate the potential of H(2)S as a lung protective agent. To explore changes in the generation of endogenous H(2)S and the role of H(2)S in the pathogenesis of pulmonary ischemia-reperfusion (I/R) injury in rats, we built an isolated rat lung I/R model. Lungs were subjected to 45 min ischemia followed by reperfusion (45 min) and were pretreated with H(2)S (50 micromol/l or 100 micromol/l) or an irreversible inhibitor of cystathionine-gamma-lyase (CSE), propargylglycine (PPG; 2 mmol/l). We examined indices of lung injury: lung histological change, perfusion flow rate, ratio of lung wet weight to dry weight (w/d), and lung compliance. H(2)S content and CSE protein expression in lung tissues were measured. Malondialdehyde (MDA) content, activities of superoxide dismutase (SOD) and catalase (CAT), and restraint of superoxide anion (O(2)(-)) production in lung tissues were measured to reflect oxidative stress. In the current study, we demonstrated that H(2)S content and CSE activity in lungs after I/R were significantly higher than those in the control group. Preperfusion with H(2)S attenuated the lung I/R injury while preperfusion with PPG aggravated the lung I/R injury. H(2)S preperfusion reduced I/R-induced MDA production and potentiated SOD and CAT activities and the restraint of O(2)(-) production in the lungs under I/R, which attenuated lung oxidative injury. These findings suggest that endogenous CSE/H(2)S pathway might be involved in the pathogenesis of lung I/R injury and that administration of H(2)S might be of clinical benefit in lung I/R injury.

Endogenous hydrogen sulfide reduces airway inflammation and remodeling in a rat model of asthma

Endogenous hydrogen sulfide (H(2)S) is hypothesized to have an important role in systemic inflammation. We investigated if endogenous H(2)S may be a crucial mediator in airway inflammation and airway remodeling in a rat model of asthma and if endogenous H(2)S may exert its anti-inflammatory effect by inhibiting inducible nitric oxide synthase (iNOS)/NO pathway. Cystathionine-gamma-lyase (CSE; a H(2)S-synthesizing enzyme) was mainly expressed in airway and vascular smooth muscle cells in rat lung tissue. Levels of endogenous H(2)S was decreased in pulmonary tissue in ovalbumin (OVA)-treated rats. Exogenous administration of NaHS alleviated airway inflammation and airway remodeling: peak expiratory flow (PEF) increased, goblet cell hyperplasia and collagen deposition score decreased, with decreased total cells recovered from bronchoalveolar fluid (BALF) and influx of eosinophils and neutrophils. The H(2)S levels of serum and lung tissue were positively correlated with PEF and negatively correlated with the level of eosinophils and neutrophils in BALF, score of lung pathology. NaHS treatment significantly attenuated pulmonary iNOS activation in OVA-treated rats. These results suggest that the CSE/H(2)S pathway plays an anti-inflammatory and anti-remodeling part in asthma pathogenesis and could be a novel target in prevention and treatment of asthma.

Hydrogen sulfide derived from periadventitial adipose tissue is a vasodilator

Background Recently, periadventitial adipose tissue (PAT) was found to secrete bioactive factors playing an important role in the regulation of vascular tension. Hydrogen sulfide (H2S), a novel cardiovascular gasotransmitter, relaxes vessels through the KATP channel in a calcium-dependent and endothelial-independent manner. Methods We first identified the endogenous H2S-generated key enzyme cystathionase (CSE) expressed in adipocytes of PAT and H2S released from PAT in rats. Results The CSE inhibitors DL-propargylglycine and/or beta-cyano-L-alanine largely blocked the vasorelaxing effects on aorta rings (removed adventitia), induced by PAT, the culture medium of PAT or isolated adipocytes from PAT. Phenylephrine, serotonin and angiotensin II inhibited endogenous H2S production from the aortic medium but increased its release from PAT. Endogenous H2S generated in the aorta and PAT was decreased but the level of CSE protein was increased with the aging of rats. In rats with hypertension induced by abdominal aortic banding, H2S generation and CSE protein expression were significantly increased in PAT but not aortic tissues. Transplanting PAT into periadventitia of stenotic aortas ameliorated the elevated arterial blood pressure and decreased angiotensin II level in aorta. Conclusion These results suggested PAT could endogenously generate H2S, which might act as an adipocyte-derived relaxing factor and contribute to the pathogenesis of hypertension.

Apelin protects myocardial injury induced by isoproterenol in rats

We aimed to explore the change in level of apelin and its receptor APJ during myocardial injury and the therapeutic effects of apelin in myocardial injury. Rat myocardial injury was induced by subcutaneous injection of a high dose of isoproterenol (ISO); apelin and APJ mRNA levels were determined by RT-PCR; APJ protein was determined by Western blot; EIA and RIA were used to measure the apelin content and receptor binding, respectively. Plasma lactate dehydrogenase (LDH) activity and myocardial and plasma malondialdehyde (MDA) contents were higher in ISO-treated hearts than that in controls. ISO-treated rats showed lower +/-LV dp/dt(max) values and higher LVEDP value (all P<0.01), which suggested severe heart failure. As well, the apelin content in plasma, atrial and ventricular myocardium was decreased by 27%, 30% and 25% (P<0.01), respectively. The mRNA levels of apelin and APJ in myocardia were also markedly reduced; but the APJ protein level in myocardia was increased. However, administration of apelin significantly ameliorated myocardial injury and ISO-induced heart failure. Compared with the ISO-alone group, the group given low-dosage apelin (5 nmol/kg/day) had 39% and 66% higher +LV dp/dt(max) and -LV dp/dt(max) values, and 40.7% lower LVEDP value (P<0.01), and the leakage of myocardial LDH and increased MDA content were attenuated (all P<0.01). Interestingly, bolus injections of apelin (10 nmol/kg/day) resulted in potent inotropic effects in ISO-treated rats. ISO-induced myocardial injury resulted in hypoexpression of apelin and its receptor APJ, and the administration of exogenous apelin ameliorated heart failure and myocardial injury. Apelin could have a cardioprotective effect, and the apelin-APJ system may be a new therapeutic target in myocardial injury and heart failure.

Endogenously generated sulfur dioxide and its vasorelaxant effect in rats

AbstractAim:The present study was designed to explore the endogenous production and localization of the sulfur dioxide (SO2)/aspartate aminotransferase pathway in vascular tissues of rats and to examine its vasorelaxant effect on isolated aortic rings, as well as the possible mechanisms.Methods:The content of SO2 in the samples was determined by using high performance liquid chromatography with fluorescence detection. Aspartate aminotransferase activity and its gene expression were measured by an enzymatic method and quantitative RT–PCR, respectively. Aspartate aminotransferase mRNA location in aorta was detected by in situ hybridization. The vasorelaxant effect of SO2 on isolated aortic rings of the rats was investigated in vitro. L-type calcium channel blocker, nicardipine, and L-type calcium channel agonist, Bay K8644, were used to explore the mechanisms by which SO2 relaxed the aortic rings.Results:Aorta had the highest SO2 content among the vascular tissues tested (P<0.01). The aortic aspartate aminotransferase mRNA located in endothelia and vascular smooth muscle cells beneath the endothelial layer. Furthermore, a physiological dose of the SO2 derivatives (Na2SO3/NaHSO3) relaxed isolated artery rings slightly, whereas higher doses (1–12 mmol/L) relaxed rings in a concentration-dependent manner. Pretreatment with nicardipine eliminated the vasorelaxant response of the norepinephrine-contracted rings to SO2 completely. Incubation with nicardipine or SO2 derivatives successfully prevented vasoconstriction induced by Bay K8644.Conclusion:Endogenous SO2 and its derivatives have a vasorelaxant function, the mechanisms of which might involve the inhibition of the L-type calcium channel.

Hydrogen sulfide from adipose tissue is a novel insulin resistance regulator

Recent data suggested that endogenous hydrogen sulfide (H(2)S) contributes to the pathogenesis of diabetes. Here, we identified that cystathionine gamma lyase (CSE) was expressed in adipose tissue in rats and endogenously generated H(2)S. The CSE/H(2)S system exists in both rat adipocytes and pre-adipocytes. This system was up-regulated with aging, although a high level of glucose down-regulated the system in a concentration- and time-dependent manner. H(2)S inhibited the basal and insulin-stimulated glucose uptake of mature adipocytes, whereas administration of CSE inhibitors enhanced the glucose uptake of adipocytes. The PI3K but not K(ATP) channel pathway is involved in the inhibitory effect of H(2)S on glucose uptake. Finally, in fructose-induced diabetes in rats, we confirmed the up-regulated CSE/H(2)S system in adipose tissue, which was negatively correlated with glucose uptake in this tissue. Our findings suggest that H(2)S might be a novel insulin resistance regulator.

Transcriptome Analysis Reveals Distinct Patterns of Long Noncoding RNAs in Heart and Plasma of Mice with Heart Failure

Objective To assess the global changes in and characteristics of the transcriptome of long noncoding RNAs (LncRNAs) in heart tissue, whole blood and plasma during heart failure (HF) and association with expression of paired coding genes. Methods Here we used microarray assay to examine the transcriptome of LncRNAs deregulated in the heart, whole blood, and plasma during HF in mice. We confirmed the changes in LncRNAs by quantitative PCR. Results We revealed and confirmed a number of LncRNAs that were deregulated during HF, which suggests a potential role of LncRNAs in HF. Strikingly, the patterns of expression of LncRNA differed between plasma and other tissue during HF. LncRNA expression was associated with LncRNA length in all samples but not in plasma during HF, which suggests that the global association of LncRNA expression and LncRNA length in plasma could be biomarkers for HF. In total, 32 LncRNAs all expressed in the heart, whole blood and plasma showed changed expression with HF, so they may be biomarkers in HF. In addition, sense-overlapped LncRNAs tended to show consistent expression with their paired coding genes, whereas antisense-overlapped LncRNAs tended to show the opposite expression in plasma; so different types of LncRNAs may have different characteristics in HF. Interestingly, we revealed an inverse correlation between changes in expression of LncRNAs in plasma and in heart, so circulating levels of LncRNAs may not represent just passive leakage from the HF heart but also active regulation or release of circulatory cells or other cells during HF. Conclusions We reveal stable expression of LncRNAs in plasma during HF, which suggests a newly described component in plasma. The distinct expression patterns of circulatory LncRNAs during HF indicate that LncRNAs may actively respond to stress and thus serve as biomarkers of HF diagnosis and treatment.

Effect of relaxin on myocardial ischemia injury induced by isoproterenol

The omnipresent 6-kDa polypeptide relaxin (RLX) is emerging as a multifunctional endocrine and paracrine factor in a broad range of target tissues including cardiovascular tissues. To explore the pathophysiological roles of RLX in ischemic cardiovascular diseases, we studied the changes in RLX mRNA level in the myocardium and the effect of RLX supplements in rats with isoproterenol (ISO)-induced myocardial injury. In ISO-treated rats, RLX levels in myocardia and plasma increased 3.7- and 6.9-fold, respectively (P<0.01), the mRNA level increased significantly in myocardia compared with controls. Co-administration of RLX (0.2 and 2.0 microg/kg/d) and ISO increased left-ventricular pressure development and decreased left ventricular end-diastolic pressure (LVDEP) (all P<0.01). Malondialdehyde content in myocardia and lactate dehydrogenase and creatine phosphokinase activities in plasma in RLX-treated rats decreased markedly compared with that in ISO-treated alone rats (P<0.01 or P<0.05). In the high-dose RLX group, fibroblastic hyperplasia was relieved in myocardia, hydroxyproline level was lower, by 33% (P<0.05), and endothelin content in plasma was lower, by 31% (P<0.01) than in the ISO-alone group. Compared with control group, any indexes in sham rats treated with high-dose RLX were unaltered (all P>0.05). These results showed an up-regulation of myocardial RLX during ISO-induced myocardial ischemia injury and the protective effect of RLX on ISO-induced cardiac inhibition and fibrosis, which suggests that RLX could be an endogenous cardioprotective factor in ischemic heart diseases.