Genotypes and allele frequencies of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism among Bahraini population with type 2 diabetes mellitus and related diseases

Insertion/deletion (I/D) polymorphism, of a 287-bp Alu repetitive sequence in intron 16 of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with different types of diseases and has been widely investigated in different populations with different ethnic origins. Various reports were published suggesting inter-ethnic variations in the frequency of allelic forms of the ACE gene. The goal of this study was to test the distribution of alleles and the different genotypes of ACE (I/D) polymorphism in Bahraini subjects and compare the results with those obtained from other population studies. The Bahraini population is an Arabic peninsula population with a high prevalence of T2DM and hypertension. A total of 560 unrelated Bahraini individuals were recruited in this study and the presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was done by PCR-based assays and the presence or absence of the genotypes were analyzed by the gel electrophoresis. The distribution of II, ID, and DD genotypes showed differences among Bahraini subjects, and the frequency of the D allele was significantly (P < 0.05) higher in the studied group. The results obtained for the D allele are consistent with those obtained from previous studies among Arabs, Africans, and Caucasians, but differs significantly (P < 0.05) from those in Japanese and Chinese, thus proving the ethnic variation in the distribution of the ACE alleles in different populations.     

Immediate and one-year outcome of patients presenting with Acute Coronary Syndrome complicated by stroke: Findings from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2)

ABSTRACT: BACKGROUND: Stroke is a potential complication of acute coronary syndrome (ACS). The aim of this study was to identify the prevalence, risk factors predisposing to stroke, in-hospital and 1-year mortality among patients presenting with ACS in the Middle East. METHODS: For a period of 9 months in 2008 to 2009, 7,930 consecutive ACS patients were enrolled from 65 hospitals in 6 Middle East countries. RESULTS: The prevalence of in-hospital stroke following ACS was 0.70%. Most cases were ST segment elevation MI-related (STEMI) and ischemic stroke in nature. Patients with in-hospital stroke were 5 years older than patients without stroke and were more likely to have hypertension (66% vs. 47.6%, P = 0.001). There were no differences between the two groups in regards to gender, other cardiovascular risk factors, or prior cardiovascular disease. Patients with stroke were more likely to present with atypical symptoms, advanced Killip class and less likely to be treated with evidence-based therapies. Independent predictors of stroke were hypertension, advanced killip class, ACS type --STEMI and cardiogenic shock. Stroke was associated with increased risk of in-hospital (39.3% vs. 4.3%) and one-year mortality (52% vs. 12.3%). CONCLUSION: There is low incidence of in-hospital stroke in Middle-Eastern patients presenting with ACS but with very high in-hospital and one-year mortality rates. Stroke patients were less likely to be appropriately treated with evidence-based therapy. Future work should be focused on reducing the risk and improving the outcome of this devastating complication.     

16.1% Efficient Hysteresis‐Free Mesostructured Perovskite Solar Cells Based on Synergistically Improved ZnO Nanorod Arrays

Significant efficiency improvements are reported in mesoscopic perovskite solar cells based on the development of a low‐temperature solution‐processed ZnO nanorod (NR) array exhibiting higher NR aspect ratio, enhanced electron density, and substantially reduced work function than conventional ZnO NRs. These features synergistically result in hysteresis‐free, scan‐independent, and stabilized devices with an efficiency of 16.1%. Electron‐rich, nitrogen‐doped ZnO (N:ZnO) NR‐based electron transporting materials (ETMs) with enhanced electron mobility produced using ammonium acetate show consistently higher efficiencies by one to three power points than undoped ZnO NRs. Additionally, the preferential electrostatic interaction between the ­nonpolar facets of N:ZnO and the conjugated polyelectrolyte polyethylenimine (PEI) has been relied on to promote the hydrothermal growth of high aspect ratio NR arrays and substantially improve the infiltration of the perovskite light absorber into the ETM. Using the same interactions, a conformal PEI coating on the electron‐rich high aspect ratio N:ZnO NR arrays is ­successfully applied, resulting in a favorable work function shift and altogether leading to the significant boost in efficiency from <10% up to >16%. These results largely surpass the state‐of‐the‐art PCE of ZnO‐based perovskite solar cells and highlight the benefits of synergistically combining mesoscale control with doping and surface modification.     

Loss of Prolyl Carboxypeptidase in Two-Kidney,One-Clip Goldblatt Hypertensive Mice

It is well documented that angiotensin (Ang) II contributes to kidney disease progression. The protease prolyl carboxypeptidase (PRCP) is highly expressed in the kidney and may be renoprotective by degrading Ang II to Ang-(1-7). The aim of the study was to investigate whether renal PRCP protein expression and activity are altered in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice. Left renal artery was constricted by using 0.12 mm silver clips. Blood pressure was measured using telemetry over the eleven weeks of study period and revealed an immediate increase in 2K1C animals during the first week of clip placement which was followed by a gradual decrease to baseline blood pressure. Similarly, urinary albumin excretion was significantly increased one week after 2K1C and returned to baseline levels during the following weeks. At 2 weeks and at the end of the study, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion and renal fibrosis. Renal PRCP expression and activity were significantly reduced in clipped kidneys. Immunofluorescence revealed the loss of renal tubular PRCP but not glomerular PRCP. In contrast, expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected, while angiotensin converting enzyme was elevated in unclipped kidneys and renin was increased in clipped kidneys. Results suggest that PRCP is suppressed in 2K1C and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PRCP.     

CCTeta, a novel soluble guanylyl cyclase-interacting protein

Nitric oxide (NO) transduces most of its biological effects through activation of the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC results in the production of cGMP from GTP. In this paper, we demonstrate a novel protein interaction between CCT (chaperonin containing t-complex polypeptide) subunit eta and the alpha1beta1 isoform of sGC. CCTeta was found to interact with the beta1 subunit of sGC via a yeast-two-hybrid screen. This interaction was then confirmed in vitro with a co-immunoprecipitation from mouse brain. The interaction between these two proteins was further supported by a co-localization of the proteins within rat brain. Using the yeast two-hybrid system, CCTeta was found to bind to the N-terminal portion of sGC. In vitro assays with purified CCTeta and Sf9 lysate expressing sGC resulted in a 30-50% inhibition of diethylamine diazeniumdiolate-NO-stimulated sGC activity. The same assays were then performed using BAY41-2272, an NO-independent allosteric sGC activator, and CCTeta had no effect on this activity. Furthermore, CCTeta had no effect on basal or sodium nitroprusside-stimulated alphabeta(Cys-105) sGC, a constitutively active mutant that only lacks the heme group. The N-terminal 94 amino acids of CCTeta seem to be critical for the mediation of this inhibition. Lastly, a 45% inhibition of sGC activity by CCTeta was seen in vivo in BE2 cells stably transfected with CCTeta and treated with sodium nitroprusside. These data suggest that CCTeta binds to sGC and, in cooperation with some other factor, inhibits its activity by modifying the binding of NO to the heme group or the subsequent conformational changes.     

Antibacterial and Antifugal Mono- and Di-substituted Symmetrical and Unsymmetrical Triazine-derived Schiff-bases and their Transition Metal Complexes

A new series of antibacterial and antifungal triazine-derived mono- and di-substituted (symmetrical and unsymmetrical) Schiff-bases and their cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes have been synthesized and characterized by their elemental analyses, molar conductances, magnetic moments and IR and electronic spectral measurements. IR spectra indicated the ligands to act as tridentate towards divalent metal ions via a trazine-N, the azomethine-N and, indole-NH and deprotonated-O of salicylaldehyde. The magnetic moments and electronic spectral data suggest octahedral geometry for the Co(II), Ni(II) and Zn(II)complexes and square-pyramid for Cu(II) complexes. NMR spectral data of the ligands and their diamagnetic zinc(II) complexes well-define their proposed structures/geometries. Elemental analyses data of the ligands and metal complexes agree with their proposed structures/geometries. The synthesized ligands, along with their metal complexes were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Shigella flexneri, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. The results of these studies show the metal complexes to be more antibacterial/antifungal against two or more species as compared to the uncomplexed Schiff-base ligands.     

PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners

Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.     

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

During this study, one new coumarin; 7-O-beta-D-glucopyranoside-2H-1-benzopyran-2-one (1) and three quinoline alkaloids; 3-hydroxy, 2, 2, 6-trimethyl-3, 4, 5, 6-tetrahydro-2H-pyrano[3,2-c] quinoline 5-one (2), ribalinine (3) and methyl isoplatydesmine (4) were isolated from the aerial parts of Skimmia laureola and their structures established by spectroscopic studies. Compounds 2-4 were found to be linear mixed type inhibitors of acetylcholinesterase (K(i) = 110.0, 30.0 and 30.0 microM, respectively). Compounds 2 and 3 were also found to be linear mixed type inhibitors of butyrylcholinesterase, while compound 4 was a noncompetitive inhibitor of the enzyme (K(i) = 90.0, 70.0 and 19.0 microM, respectively). The inhibition of acetyl- and butyryl-cholinesterase enzymes persists as the most promising therapeutic strategy for activating the impaired cholinergic functions in Alzheimer's disease and related dementias. Compound 4 also showed dose-dependent spasmolytic activity in the isolated rabbit jejunum intestinal preparation by relaxing the spontaneous (EC50 = 0.1 mg/mL) and K(+)-induced contractions (EC50 = 0.4 mg/mL), suggesting that the spasmolytic effect of compound 4 is mediated through the blockade of voltage-dependent Ca2+ channels.