Current status in the discovery of dual BET/HDAC inhibitors.

The development of desired multitarget agents may provide an attractive and cost-effective complement or alternative to drug combinations. Bromodomain and extraterminal domain (BET) and histone deacetylase (HDAC), as important epigenetic modulators, are attractive targets in drug discovery and development. Considering the fact that BET and HDAC inhibitors exert a synergistic effect on cellular processes in cancer cells, the design of dual BET/HDAC inhibitors may be a rational strategy to improve the efficacy of their single-target drugs for tumor treatment. In the current review, we depict the development of dual BET/HDAC inhibitors and particularly highlight their structure-activity relationships (SARs), binding modes, and biological functions with the aim to facilitate rational drug design and develop more dual BET/HDAC inhibitors.

Current status in the discovery of dual BET/HDAC inhibitors.

The development of desired multitarget agents may provide an attractive and cost-effective complement or alternative to drug combinations. BET and HDAC, as important epigenetic modulators, are both attractive targets in drug discovery and development. Considering the fact that BET and HDAC inhibitors exert a synergistic effect on cellular processes in cancer cells, the design of dual BET/HDAC inhibitors may be a rational strategy to improve the efficacy of their single-target drugs for tumor treatment. In current review, we depict the development of dual BET/HDAC inhibitors and particularly highlight their SARs, binding modes and biological functions with the aim to facilitate rational design and develop more dual BET/HDAC inhibitors.

MicroRNA transcriptome analysis in chicken kidneys in response to differing virulent infectious bronchitis virus infections.

Infectious bronchitis virus (IBV) can cause a highly contagious and acute respiratory disease in poultry. MicroRNAs (miRNAs) have emerged as a class of crucial regulators for gene expression and are involved in the regulation of virus defence and immunological processes. To understand miRNA regulation in chickens in response to IBV infection, high-throughput sequencing was performed to compare the small RNA libraries from the kidneys of chicken infected with SCK2, SCDY2 and LDT3-A. By comparing these data to healthy chickens, a total of 58 differentially expressed (DE) miRNAs were identified. The DE miRNAs were further classified into five miRNA expression patterns (up or down regulation compared to control). Using Gene Ontology (GO) enrichment prediction, the DE miRNAs were shown to be mostly associated with metabolic processes, catalytic activities, gene expression, binding activities and immune responses. Seven highly expressed miRNAs (gga-miR-30d, gga-miR-1454, gga-miR-7b, gga-miR-215-5p, gga-miR-1a-3p, gga-miR-3538 and gga-miR-2954) were selected for miRNA-mRNA conjoint analysis. Furthermore, the miRNAs inversely correlated with the corresponding target gene mRNAs. These seven miRNAs were considered to play an important role in IBV-host interactions and the differing virulence of IBV strains. This is the first demonstration that infection with different virulent IBVs elicits different expression of miRNAs in chicken kidneys; this expression also seems to be associated with the virulence of IBV. These results are significant for the study of immune responses to infection with different virulent IBVs mediated by miRNAs as well as the interaction between the chicken host and IBV.

Recombinant infectious bronchitis virus (IBV) H120 vaccine strain expressing the hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) protects chickens against IBV and NDV challenge.

Infectious bronchitis (IB) and Newcastle disease (ND) are common viral diseases of chickens, which are caused by infectious bronchitis virus (IBV) and Newcastle disease virus (NDV), respectively. Vaccination with live attenuated strains of IBV-H120 and NDV-LaSota are important for the control of IB and ND. However, conventional live attenuated vaccines are expensive and result in the inability to differentiate between infected and vaccinated chickens. Therefore, there is an urgent need to develop new efficacious vaccines. In this study, using a previously established reverse genetics system, we generated a recombinant IBV virus based on the IBV H120 vaccine strain expressing the haemagglutinin-neuraminidase (HN) protein of NDV. The recombinant virus, R-H120-HN/5a, exhibited growth dynamics, pathogenicity and viral titers that were similar to those of the parental IBV H120, but it had acquired hemagglutination activity from NDV. Vaccination of SPF chickens with the R-H120-HN/5a virus induced a humoral response at a level comparable to that of the LaSota/H120 commercial bivalent vaccine and provided significant protection against challenge with virulent IBV and NDV. In summary, the results of this study indicate that the IBV H120 strain could serve as an effective tool for designing vaccines against IB and other infectious diseases, and the generation of IBV R-H120-HN/5a provides a solid foundation for the development of an effective bivalent vaccine against IBV and NDV.

The difference between Asian and Western in the effect of LDL-C lowering therapy on coronary atherosclerotic plaque: a meta-analysis report.

BACKGROUND: The different effects of LDL-C levels and statins therapy on coronary atherosclerotic plaque between Western and Asian remain to be settled. METHODS: PubMed, EMBASE, and Cochrane databases were searched from Jan. 2000 to Sep. 2014 for randomized controlled or blinded end-points trials assessing the effects of LDL-C lowering therapy on regression of coronary atherosclerotic plaque (CAP) in patients with coronary heart disease by intravascular ultrasound. The significance of plaques regression was assessed by computing standardized mean difference (SMD) of the volume of CAP between the baseline and follow-up. RESULTS: Twenty trials (ten in the West and ten in Asia) were identified. For Westerns, Mean lowering LDL-C by 49.4% and/or to level 61.9 mg/dL in the group of patients with baseline mean LDL-C 123.2 mg/dL could significantly reduce the volume of CAP at follow up (SMD -0.156 mm(3), 95% CI -0.248 ~ -0.064, p = 0.001). LDL-C lowering by rosuvastatin (mean 40 mg daily) could significantly decrease the volumes of CAP at follow up. For Asians, Mean lowering LDL-C by 36.1% and/or to level 84.0 mg/dL with baseline mean LDL-C 134.2 mg/dL could significantly reduce the volume of CAP at follow up (SMD -0.211 mm(3), 95% CI -0.331 ~ -0.092, p = 0.001). LDL-C lowering by rosuvastatin (mean 14.1 mg daily) and atorvastatin (mean 18.9 mg daily) could significantly decrease the volumes of CAP at follow up. CONCLUSIONS: There was a different effect of LDL-C lowering on CAP between Westerns and Asians. For regressing CAP, Asians need lower dosage of statins or lower intensity LDL-C lowering therapy than Westerns.

Systematic study of the effects of lowering low-density lipoprotein-cholesterol on regression of coronary atherosclerotic plaques using intravascular ultrasound.

BACKGROUND: Conflicting results currently exist on the effects of LDL-C levels and statins therapy on coronary atherosclerotic plaque, and the target level of LDL-C resulting in the regression of the coronary atherosclerotic plaques has not been settled. METHODS: PubMed, EMBASE, and Cochrane databases were searched from Jan. 2000 to Jan. 2014 for randomized controlled or blinded end-points trials assessing the effects of LDL-C lowering therapy on regression of coronary atherosclerotic plaque (CAP) in patients with coronary heart disease by intravascular ultrasound. Data concerning the study design, patient characteristics, and outcomes were extracted. The significance of plaques regression was assessed by computing standardized mean difference (SMD) of the volume of CAP between the baseline and follow-up. SMD were calculated using fixed or random effects models. RESULTS: Twenty trials including 5910 patients with coronary heart disease were identified. Mean lowering LDL-C by 45.4% and to level 66.8 mg/dL in the group of patients with baseline mean LDL-C 123.7 mg/dL, mean lowering LDL-C by 48.8% and to level 60.6 mg/dL in the group of patients with baseline mean LDL-C 120 mg/dL, and mean lowering LDL-C by 40.4% and to level 77.8 mg/dL in the group of patients with baseline mean LDL-C 132.4 mg/dL could significantly reduce the volume of CAP at follow up (SMD -0.108 mm3, 95% CI -0.176 ~ -0.040, p = 0.002; SMD -0.156 mm3, 95% CI -0.235 ~ -0.078, p = 0.000; SMD -0.123 mm3, 95% CI -0.199 ~ -0.048, p = 0.001; respectively). LDL-C lowering by rosuvastatin (mean 33 mg daily) and atorvastatin (mean 60 mg daily) could significantly decrease the volumes of CAP at follow up (SMD -0.162 mm3, 95% CI: -0.234 ~ -0.081, p = 0.000; SMD -0.101, 95% CI: -0.184 ~ -0.019, p = 0.016; respectively). The mean duration of follow up was from 17 ~ 21 months. CONCLUSIONS: Intensive lowering LDL-C (rosuvastatin mean 33 mg daily and atorvastatin mean 60 mg daily) with >17 months of duration could lead to the regression of CAP, LDL-C level should be reduced by >40% or to a target level <78 mg/dL for regressing CAP.

An Ester-Functionalized Bidentate Titanium-based Metal-Organic Framework with Visible-Light Enhanced Activity for CO2 Photoreduction.

The limited visible light response is a critical drawback that hampers the photocatalytic efficacy of Ti-MOFs. However, study concerning the enhancement of the visible-light response of Ti-MOFs is still in its nascent stage. In this study, we employ the 'dual-ligand decrystallization strategy' to manipulate the electronic environment of Ti4+, leading to the synthesis of three ester-functionalized bidentate Ti-MOFs with enhanced visible light response. Our findings reveal that this approach not only reduces the bandgap of Ti-MOFs but also enhances their photocatalytic activity for carbon dioxide reduction. Specifically, compared to the bandgap of Ti-BPDC at 2.98 eV, the bandgap of Ti-BPDC-CA 1:2 has been reduced to 2.14 eV. Moreover, Ti-BPDC-CA 1:2 exhibits extraordinary photocatalytic activity with the formic acid (HCOOH) production rate of 617 µmol g-1 h-1 with over 99.5% selectivity, which is 3.47 times higher than that of Ti-BPDC. Besides providing a cost-effective strategy for enhancing the visible light response of Ti-MOFs, our study also serves as an illustrative example for establishing the correlation between electronic structure and optical properties.

Mechanism underlying the weakening effect of ß-glucan on the gluten system.

The high ß-glucan content in barley disrupts the gluten network in dough. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and solid-state nuclear magnetic resonance (NMR) techniques were used to clarify how ß-glucan affected the quality of the gluten network structure with ß-glucan contents of 0-2%. The results suggest that the physical hindrance of the ß-glucan gel destroyed the formation of the gluten network structure. When 1.0-2.0% ß-glucan was added, the percentage of α-helical structures increased significantly. When the added amount of ß-glucan reached 2.0%, the sulfhydryl group (SH) content increased from 8.06 to 10.27 µmol/g, and the disulfide bond (SS) content decreased from 240.09 to 217.38 µmol/g. The interaction between ß-glucan and gluten mainly resulted from the interaction of electron-withdrawing groups, such as carbonyl groups (CO) and double bond carbons (CC), and carbon atoms on the side chains of ß-glucan, which play an important role in the central structure of glutenin.

Infectious Bronchitis Virus Infection Induces Apoptosis during Replication in Chicken Macrophage HD11 Cells.

Avian infectious bronchitis has caused huge economic losses in the poultry industry. Previous studies have reported that infectious bronchitis virus (IBV) infection can produce cytopathic effects (CPE) and apoptosis in some mammalian cells and primary cells. However, there is little research on IBV-induced immune cell apoptosis. In this study, chicken macrophage HD11 cells were established as a cellular model that is permissive to IBV infection. Then, IBV-induced apoptosis was observed through a cell viability assay, morphological changes, and flow cytometry. The activity of caspases, the inhibitory efficacy of caspase-inhibitors and the expression of apoptotic genes further suggested the activation of apoptosis through both intrinsic and extrinsic pathways in IBV-infected HD11 cells. Additionally, ammonium chloride (NH4Cl) pretreated HD11 cells blocked IBV from entering cells and inhibited IBV-induced apoptosis. UV-inactivated IBV also lost the ability of apoptosis induction. IBV replication was increased by blocking caspase activation. This study presents a chicken macrophage cell line that will enable further analysis of IBV infection and offers novel insights into the mechanisms of IBV-induced apoptosis in immune cells.

Management of acute perioperative myocardial infarction: a case report of concomitant acute myocardial infarction and tumor bleeding in the transverse colon.

Acute myocardial infarction complicated by bleeding colon tumor is problematic with regard to management, and appropriate balance of antiplatelet or anticoagulation therapy and hemostasis or surgery is crucial for effective treatment. Here, we present a case of concomitant acute myocardial infarction and bleeding tumor in the transverse colon, and share our experience of successfully balancing anticoagulation therapy and hemostasis.

GRK 2 level in peripheral blood lymphocytes of elderly patients with acute myocardial infarction.

OBJECTIVE: To investigate the G protein-coupled receptor kinase 2 (GRK 2) level in peripheral blood lymphocytes with cardiac function in elderly patients with acute myocardial infarction. METHODS: This study enrolled 40 patients with acute ST-segment elevation myocardial infarction (STEMI) and 40 patients with unstable angina. All patients were 65 years or older. Cardiac function was evaluated by echocardiography, and the GRK 2 level in peripheral blood lymphocytes was measured. Patients with STEMI were followed up for 2 years. RESULTS: The GRK 2 level in peripheral blood lymphocytes was significantly higher in patients with STEMI than in patients with unstable angina, and was negatively correlated with left ventricular ejection fraction, cardiac output, stroke volume, and left ventricular fractional shortening. The GRK 2 level was significantly elevated in some patients with acute STEMI and poor cardiac function. CONCLUSIONS: Increased GRK 2 level in patients with acute STEMI may contribute to poor myocardial systolic function and myocardial remodeling. Measurement of the GRK 2 level in peripheral blood lymphocytes may assist in the evaluation of cardiac function and myocardial remodeling in elderly patients with acute STEMI.

[Lymphocyte GRK2 expression of the very elderly with chronic heart failure].

OBJECTIVE: To explore the correlation of lymphocyte G protein-coupled receptor kinases 2 (GRK2) expression of the very elderly with chronic heart failure (HF) and heart ejection fraction (EF). METHODS: 16 elderly patients with chronic heart failure were divided into 2 groups as following: EF < 45% (n=7), EF > or = 45% (n=9); and health elderly as control (n=8). Lymphocytes were obtained from blood, reverse transcription polymerase chain reaction were used to measure GRK2 mRNA levels. RESULTS: Lymphocyte GRK2 mRNA levels of EF < 45% group were higher than that of EF > 45% group, which were greater than that of control. CONCLUSION: Elevation of lymphocyte GRK2 levels in HF is associated with heart EF, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.

Antithrombotic therapy in very elderly patients with atrial fibrillation: is it enough to assess thromboembolic risk?

Although attention has been given to thromboprophylaxis for atrial fibrillation (AF) in present treatment guidelines, practical, clinical antithrombotic therapy is poorly developed for very elderly patients. We reviewed the records of 105 consecutive patients with AF of mean age 85 years, to determine how the greatest benefits from antithrombotic therapy could be obtained in this group. The mean CHADS2 score in these patients was 3.1 +/- 1.5. Before antithrombotic therapy, 21.0% of the patients had diseases with a risk of hemorrhage, 26.7% had diseases with a risk of thrombosis, and 8.6% had diseases with a risk of both hemorrhage and thrombosis. Moreover, 89 patients (84.8%) were receiving a single antiplatelet drug, 10 (9.5%) used aspirin plus clopidogrel, and six (5.7%) were taking an oral anticoagulant (OAC). Additionally, dual antiplatelet therapy was more commonly given to patients with permanent AF (paroxysmal and persistent versus permanent, 6.3% and 12.5% versus 30%, respectively, Chi-square = 8.4, P = 0.010). The incidence of adverse events was 25.7%, with thromboembolic events in 20.0% and hemorrhage in 5.7% of patients. There were no thromboembolic events in those patients taking OACs, but 33% of patients who took OACs had bleeding complications. It is difficult to choose appropriate antithrombotic strategies in very elderly patients. Both the thrombotic risk and the bleeding risk should be considered for helping such patients derive optimal benefit from thromboprophylaxis for AF.

[Effect of metoprolol on the expression of GRK2 in lymphocyte of advanced elderly patients with chronic heart failure].

OBJECTIVE: To investigate the effect of metoprolol on the expression of G protein-coupled receptor kinases 2 (GRK2) in lymphocyte of advanced elderly patients with chronic heart failure. METHODS: 32 elderly patients with chronic heart failure were divided into control group and metoprolol group, 16 each. Conventional therapy was used in the control group, conventional therapy plua metoprolol was used in metoprolol group. The treatment courses were 8 weeks in both groups. RESULTS: Left ventricular end-diastolic diameter and left ventricular ejection fraction were not different between the two groups. Lymphocyte GRK2 mRNA level in metoprolol group was lower than that in control group. CONCLUSION: Metoprolol can inhibit the expression of GRK2 in lymphocyte of advanced elderly patients with chronic heart failure.