Upregulation of SLAMF8 aggravates ischemia/reperfusion-induced ferroptosis and injury in cardiomyocyte.

BACKGROUND: Myocardial infarction (MI) is a cardiovascular diseases, that seriously threatens human life. Signaling lymphocytic activation molecule family member 8 (SLAMF8) has been discovered to regulate the development and function of many immune cells. However, there are limited reports on SLAMF8 in the field of cardiopathy, and its regulatory role also remains unclear. METHODS: The mRNA and protein expressions of genes were examined through RT-qPCR and western blot. The infarct size in heart was assessed through TTC staining. The pathological section of heart tissue was evaluated through HE staining. The iron, Fe2+, MDA and SOD levels were assessed through the corresponding commercial kits. The ROS level was detected through Immunofluorescence (IF) staining. The cell viability and cell apoptosis were assessed through MTT assay and flow cytometry. RESULTS: Through GEO (GSE84796) database, SLAMF8 exhibited higher expression in heart failure patients. Furthermore, the ischemia/reperfusion SD rat (ischemia/reperfusion, I/R treatment) and H9C2 cell (hypoxia/reoxygenation, H/R treatment) models were set up. The mRNA and protein levels of SLAMF8 were upregulated in ischemia/reperfusion SD rat and H9C2 cell models. In addition, SLAMF8 inhibition alleviated ischemia/reperfusion-induced myocardial injury in SD rats. Moreover, SLAMF8 suppression inhibited ischemia/reperfusion-induced ferroptosis and oxidative stress. Further experiments were performed in H/R stimulated H9C2 cells, and the results showed that SLAMF8 knockdown alleviated H/R-induced cardiomyocyte death, ferroptosis and oxidative stress in H/R-induced cardiomyocyte. Lastly, SLAMF8 activated the TLR4/NOX4 pathway in I/R treated-SD rats or H/R treated-H9C2 cells. CONCLUSION: SLAMF8 aggravated ischemia/reperfusion-induced ferroptosis and injury in cardiomyocyte. This discovery may provide a useful bio-target for MI treatment.

Association between estimated pulse wave velocity and all-cause mortality in patients with coronary artery disease: a cohort study from NHANES 2005-2008.

BACKGROUND: Arterial stiffness has been shown to be an independent risk factor for adverse events and all-cause mortality in patients. Although PWV is the gold standard for pulse wave velocity, its application in clinical practice is limited by the high cost and complexity. ePwv is a new, simple, non-invasive indicator of arterial stiffness. The aim of this study was to assess the relationship between ePwv and all-cause mortality in patients with coronary artery disease. METHODS: This is a cohort study, selected from NHANES 2005 to 2008, 402 patients with coronary artery disease were included. The ePWV was divided into two groups and KM survival curves were used to calculate cumulative mortality in patients with coronary artery disease. Restricted cubic spline were used to represent the relationship between ePWV and all-cause mortality in patients with coronary artery disease. Cox regression was used to diagnose the relationship between ePwv and all-cause mortality. RESULTS: The mean age of the study subjects was 68.5 ± 11.8 years, of which 282 (70.1%) were men and 120 (29.9%) were women. During 180 months of follow-up, 160 all-cause mortality occurred. KM survival curves indicated that all-cause mortality increased with increasing ePWV. The relationship between ePWV and all-cause mortality in patients with coronary artery disease was verified by cox models. Patients in higher ePWV tertile tended to have higher all-cause mortality. After complete multivariate adjustment, an increase in ePWV was positively associated with all-cause mortality (HR = 1.180, 95% confidence interval (CI): 1.056-1.320). The multivariate-adjusted HR and 95% CI for the highest ePWV tertile was 1.582 (95% CI: 0.968-2.587) compared to the lowest tertile. In addition, the association between ePWV and mortality was visualized employing restricted spline curves, in which we found curves indicating a possible threshold for the effect of ePWV on all-cause mortality, with HR less than 1 when ePWV was less than 11.15 m/s; thereafter, there was a tendency for HR to increase with enhanced ePWV. Subgroup analysis showed that the correlation between ePWV and mortality persisted in population subgroups. CONCLUSION: Our findings suggest that higher ePWV is associated with increased all-cause mortality in patients with coronary artery disease, particularly when ePWV exceeds 11.15 m/s.

Prevalence and Risk Factors for Hypertension in Adolescents Aged 12 to 17 Years: A School-Based Study in China.

[Figure: see text].

Isoliquiritigenin (ISL) and its Formulations: Potential Antitumor Agents.

Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL) is one of the most important chalcone compounds which is mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti-diabetic activities, etc. Numerous research teams have demonstrated that ISL posseses the ability to carry out antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL that inhibit cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limit its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinics over the past 20 years.

The effects and possible mechanism of ß2AR gene expression in cardiocytes of canines with heart failure.

The objective of the present study was to observe the changes of ß2-adrenergic receptor (ß2AR) protein expression in a canine model of heart failure (HF), and the function of cardiocytes after transfection with Adv-ß2AR. The canine model of chronic HF was induced by rapid right ventricular pacing and cardiocytes were isolated with collagenase II. Cardiocytes were transfected with Adv-ß2AR to observe contractile function with a motion edge-detection system of single cells. Expression of ß2AR protein in cardiocytes was measured by immunoblotting and the levels of intracellular cAMP were measured by ELISA. Compared with the control group (the sham group), the expression of ß2AR protein in HF cardiocytes did not change, but the basal (1 mM Ca2+) contraction amplitude percentage (1.809±0.922 vs. 1.120±0.432%, P<0.05), the maximum contraction amplitude percentage (14.855±2.377 vs. 10.784±2.675%, P<0.01) and the basal levels of intracellular cAMP (9.39±2.54 vs. 5.26±0.95 pmol/ml, n=6, P<0.05) of HF cardiocytes were significantly decreased. However, when HF cardiocytes were transfected with Adv-ß2AR and cultured for 48 h, compared with the non-transfected group, the basal contraction amplitude percentage (0.851±0.324 vs. 1.629±0.522%, P<0.05), the maximum contraction amplitude percentage (9.260±2.208% vs. 12.205±1.437%, P<0.01) and the basal levels of intracellular cAMP (5.26±0.95 vs. 9.03±1.03 pmol/ml, n=6, P<0.05) of cardiocytes in the transfected group were significantly increased. In conclusion, the expression of ß2AR protein in HF cardiocytes did not change, but contraction function was impaired. The moderate overexpression of ß2AR gene in the HF cardiocytes increased the levels of intracellular cAMP and improved contraction function.

Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte-like cells of BMSCs induced by IGF-1.

Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte­like cells (CLCs) if an appropriate cardiac environment is provided. Insulin­like growth factor­1 (IGF­1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF­1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF­1 and IGF­1 receptor (IGF­1R) kinase inhibitor I­OMe AG538 were added to detect if IGF­1 could induce BMSCs to transdifferentiate into CLCs and if I­OMe AG538 could inhibit IGF­1­mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF­1 revealed positivity for cardiac troponin­T and cardiac troponin­I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I­OMe AG538 and completely inhibited by 10 µmol/l I­OMe AG538. Western blotting showed that the level of IGF­1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I­OMe AG538 selectively inhibited IGF­1­mediated growth and signal transduction and the inhibitory effect of I­OMe AG538 were not reverted in the presence of exogenous IGF­1. In addition, when a time course analysis of the effects of I­OMe AG538 on mitogen­activated protein kinase kinase and phosphatidylinositol 3­kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I­OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent.

Modulatory effects of hydrochlorothiazide and triamterene on resistant hypertension patients.

The present study explored the modulatory potential of hydrochlorothiazide and triamterene on resistant hypertension patients. The mechanistic information for resistant hypertension was explored by studying the pressure-natriuresis curves between the salt sensitive population and non-salt sensitive population. A cohort of 23 patients with non-hypertension (NH) (13 males and 10 females; aged from 23 to 62 years), 26 patients with controlled hypertension (CH) (14 males and 12 females; aged from 19 to 72 years) and 23 patients with resistant hypertension (RH) (13 males and 10 females; aged from 19 to 76 years) were selected. The patients were divided into two main groups on the basis of salt sensitivity viz. salt sensitive (SS) and non-SS (NSS) groups. These two groups were further classified into four subgroups based on the diuretic drug used. Hydrochlorothiazide-treated subgroups were named as salt sensitive hydrochlorothiazide (SSHy) and non-SSHy (NSSHy) groups. Similarly, triamterene-treated subgroups were named as salt sensitive triamterene (SSTr) and non-SSTr (NSSTr) groups. Treatment continued for 2 weeks and the pressure-natriuresis curves were recorded. Additionally, the plasma aldosterone and renin activity was monitored by radioimmunoassay. The pressure-natriuresis curves of the SS group were shifted towards the right relative to NSS group. On the other hand, hydrochlorothiazide and triamterene treatments reversed the changes of pressure-natriuresis curves. Moreover, significant differences were observed among various important indices including plasma aldosterone, renin activity, office blood pressure as evaluated by the chronic salt load test and diuretic intervention tests. The study concludes that hydrochlorothiazide and triamterene hold good potential as an efficient modulator of resistive hypertension.

Morphological and functional changes in bone marrow mesenchymal stem cells in rats with heart failure.

The changes in bone marrow-derived mesenchymal stem cells (BMSCs), in terms of cell morphology and protein expression in rats with heart failure, were studied. Pressure overload chronic heart failure rat model was induced with partial constriction of the abdominal aorta. BMSCs from the model and the sham operation groups were isolated and cultured (cell density, 108 cells/l), and supernatant was collected after 72 h. Enzyme-linked immunosorbent assay was used to measure HGF, IGF-1, PDGF, SCF, FGF and VEGF levels in the supernatant. Results showed that in the model group, the minimum cell diameter, the average cell area and the protein expression in single BMSCs were significantly less than those in the sham operation group. In the model group, SCF and PDGF levels were significantly lower than those in the sham operation group. VEGF concentration in the model group was significantly higher than that in the sham operation group. Compared with normal rats, the morphology of BMSCs in rats with heart failure changed considerably, the protein expression of a single cell and the ability to secrete cytokines decreased in a meaningful way.

Effect of adenovirus mediated ß2-AR overexpression on IL-10 level secreted by cardiomyocytes of heart failure rats.

The effect of ß2-adrenergic receptor (AR) overexpression on interleukin (IL)-10 content secreted by cardiomyocytes of heart failure (HF) rats was investigated. A rat model of chronic HF was established by partially banding abdominal aorta and the cardiomyocytes were isolated with collagenase II. The cardiomyocytes were then transfected with adenovirus type 5-ADRß2-enhanced green fluorescent protein (EGFP) for 48 h to observe the changes of ß2-AR protein expression using western blot analysis. The IL-10 level was detected by ELISA. The experiment was divided into seven groups: Control, HF, HF+EGFP, HF+ß2, sham, sham+EGFP and sham+ß2 groups. Compared with the sham-operated group, left ventricular diastolic dimension, and left ventricular systolic dimension were increased (P<0.05), whereas ejection fraction and fractional shortening were decreased (P<0.05) in the HF group. Compared with the sham group, the cardiomyocyte survival rate of the HF group was significantly reduced (P<0.05). Compared with the control or sham group, the ß2-AR protein level of the HF group showed no significant differences (P>0.05). Compared with the HF and HF+EGFP groups, the expression of ß2-AR protein of cardiomyocytes was increased in the HF+ß2 group (P<0.05). Compared with the sham group, IL-10 content secreted by cardiomyocytes in the HF group was increased (P<0.05). Compared with the HF and HF+EGFP groups, IL-10 content in the HF+ß2 group was increased significantly (P<0.05). In conclusion, the concentration of IL-10 secreted by cardiomyocytes of HF rats was increased. The overexpression of ß2-AR in the cardiomyocytes of HF rats was able to enhance the secretion of IL-10.

Short-term effects of ß2-AR blocker ICI 118,551 on sarcoplasmic reticulum SERCA2a and cardiac function of rats with heart failure.

The study was conducted to examine the effects of ICI 118,551 on the systolic function of cardiac muscle cells of rats in heart failure and determine the molecular mechanism of selective ß2-adrenergic receptor (ß2-AR) antagonist on these cells. The chronic heart failure model for rats was prepared through abdominal aortic constriction and separate cardiac muscle cells using the collagenase digestion method. The rats were then divided into Sham, HF and HF+ICI 50 nM goups and cultivated for 48 h. ß2-AR, Gi/Gs and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) protein expression levels in the cardiac muscle cells were evaluated by western blotting and changes in the systolic function of cardiac muscle cells based on the boundary detection system of contraction dynamics for individual cells was measured. The results showed that compared with the Sham group, the survival rate, percentage of basic contraction and maximum contraction amplitude percentage of cardiac muscle cells with heart failure decreased, Gi protein expression increased while Gs and SERCA2a protein expression decreased. Compared with the HF group, the maximum contraction amplitude percentage of cardiac muscle cells in group HF+ICI 50 nM decreased, the Gi protein expression level increased while the SERCA2a protein expression level decreased. Following the stimulation of Ca2+ and ISO, the maximum contraction amplitude percentage of cardiac muscle cells in the HF+ICI 50 nM group was lower than that in group HF. This indicated that ICI 118,551 has negative inotropic effects on cardiac muscle cells with heart failure, which may be related to Gi protein. Systolic function of cardiac muscle cells with heart failure can therefore be reduced by increasing Gi protein expression and lowering SERCA2a protein expression.

Synthesis, Biological Evaluation, and Docking of Dihydropyrazole Sulfonamide Containing 2-hydroxyphenyl Moiety: A Series of Novel MMP-2 Inhibitors.

In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2-hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase-2 (MMP-2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP-2 along with potent anticancer activity against four tumor cell lines. Structure-activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V-FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent.

Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors.

4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.

[Insulin-like growth factor 1 induces bone mesenchymal stem cells differentiation into cardiomyocyte-like cells].

OBJECTIVE: To explore the ability and mechanism of insulin-like growth factor 1 (IGF-1) induced bone mesenchymal stem cells (BMSCs) differentiation into cardiomyocyte-like cells (CLCs). METHODS: BMSCs were isolated and purified in vitro. BMSCs were treated with control medium and 15 ng/ml IGF-1 for 3, 7, 14 and 21 d, respectively. The expression of Troponin-T (TNT), Troponin-I (TNI) and pIGF-1R were detected by immunocytochemistry and Western blot. In another experimental setting, BMSCs were treated with control medium and 15 ng/ml IGF-1, IGF-1 antagonist I-OMe AG538 (300 nmol/L) and 300 nmol/L I-OMe AG538 + 15 ng/ml IGF-1 for 3 to 48 h, respectively. Phosphorylation status of ERK1/2 and AKT, the two downstream mediators of mitogen-activated protein kinase (MAPK) kinase and phosphatidylinositol 3-kinase (PI3K) pathways, were detected by immunocytochemistry and Western blot. RESULTS: After 3 to 21 d exposure to IGF-1, the expression of pIGF-1R, TNT and TNI were significantly higher in IGF-1 group than those in control group, pIGF-1R peaked 14 d (all P < 0.05). After 3 and 6 h treatment, the ratio of pAKT/AKT (0.17 ± 0.03) and pERK1/2/ERK1/2 (0.06 ± 0.03) were significantly downregulated in I-OMe AG538 group compared to control group (1.00 ± 0.05) (all P < 0.05). The ratio of pAKT/AKT (1.00 ± 0.07) and pERK1/2/ERK1/2 (1.00 ± 0.09) were significantly upregulated in IGF-1 group compared to control group (0.72 ± 0.05) (all P < 0.05), but the ratio of pAKT/AKT (0.31 ± 0.10) and pERK1/2/ERK1/2 (0.39 ± 0.04) were significantly downregulated in I-OMe AG538 group compared to control group (0.63 ± 0.05) (all P < 0.05), the value of gray scale of TNT (195.06 ± 5.98) and TNI (198.32 ± 3.46) in I-OMe AG538 + IGF-1 group were significantly upregulated than that in IGF-1 group for TNT (188.70 ± 5.35) and TNI (176.10 ± 4.96) (all P < 0.05). CONCLUSIONS: IGF-1 could induce BMSCs differentiation into CLCs in vitro by activating MAPK and PI3K signaling pathways.

Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents.

A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 µM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 µM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 µg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.

Novel Schiff-base-derived FabH inhibitors with dioxygenated rings as antibiotic agents.

Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, ß-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad-spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine (10) showed the most potent antibacterial activity with a MIC value of 3.89-7.81 µM(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 µM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.

Synthesis, biological evaluation and molecular modeling of dihydro-pyrazolyl-thiazolinone derivatives as potential COX-2 inhibitors.

A series of dihydro-pyrazolyl-thiazolinone derivatives (5a-5t) have been synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 2-(3-(3,4-dimethylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (5a) displayed the most potent COX-2 inhibitory activity with IC(50) of 0.5µM, but weak to COX-1. Docking simulation was performed to position compound 5a into the COX-2 active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity and low toxicity would be a potential and selective anti-cyclooxygenase-2 agent.

Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors.

A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 µM for MCF-7 and IC(50) = 0.45 µM for WM266.5, IC(50) = 0.22 µM for BRAF(V600E), 3m: IC(50) = 0.97 µM for MCF-7 and IC(50) = 0.72 µM for WM266.5, IC(50) = 0.46 µM for BRAF(V600E), which were comparable with the positive control Erlotinib.

Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors.

It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.

High levels of circulating epinephrine trigger apical cardiodepression in a ß2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic ß(2)-adrenergic receptor (ß(2)AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways. METHODS AND RESULTS: We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G(i) inactivation by pertussis toxin pretreatment. ß(2)AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a ß(2)AR-Gi-dependent manner. Preventing epinephrine-G(i) effects increased mortality in the Takotsubo model, whereas ß-blockers that activate ß(2)AR-G(i) exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality. CONCLUSIONS: We suggest that biased agonism of epinephrine for ß(2)AR-G(s) at low concentrations and for G(i) at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in ß(2)ARs explaining the differential regional responses. We suggest this epinephrine-specific ß(2)AR-G(i) signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress.

Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors.

Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 µg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 µg/mL were most potent inhibitors of Escherichia coli FabH.