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61.
Alaa Abdul-Ridha J. Robert Lane Shailesh N. Mistry Laura López Patrick M. Sexton Peter J. Scammells Arthur Christopoulos Meritxell Canals 《The Journal of biological chemistry》2014,289(48):33701-33711
Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug discovery efforts identified 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one (referred to herein as benzoquinazolinone 12) as a more potent M1 mAChR PAM with a structural ancestry originating from BQCA and related compounds. In the current study, we optimized the synthesis of and fully characterized the pharmacology of benzoquinazolinone 12, finding that its improved potency derived from a 50-fold increase in allosteric site affinity as compared with BQCA, while retaining a similar level of positive cooperativity with acetylcholine. We then utilized site-directed mutagenesis and molecular modeling to validate the allosteric binding pocket we previously described for BQCA as a shared site for benzoquinazolinone 12 and provide a molecular basis for its improved activity at the M1 mAChR. This includes a key role for hydrophobic and polar interactions with residues Tyr-179, in the second extracellular loop (ECL2) and Trp-4007.35 in transmembrane domain (TM) 7. Collectively, this study highlights how the properties of affinity and cooperativity can be differentially modified on a common structural scaffold and identifies molecular features that can be exploited to tailor the development of M1 mAChR-targeting PAMs. 相似文献
62.
Alaa Abdul-Ridha Laura López Peter Keov David M. Thal Shailesh N. Mistry Patrick M. Sexton J. Robert Lane Meritxell Canals Arthur Christopoulos 《The Journal of biological chemistry》2014,289(9):6067-6079
Benzylquinolone carboxylic acid (BQCA) is an unprecedented example of a selective positive allosteric modulator of acetylcholine at the M1 muscarinic acetylcholine receptor (mAChR). To probe the structural basis underlying its selectivity, we utilized site-directed mutagenesis, analytical modeling, and molecular dynamics to delineate regions of the M1 mAChR that govern modulator binding and transmission of cooperativity. We identified Tyr-852.64 in transmembrane domain 2 (TMII), Tyr-179 and Phe-182 in the second extracellular loop (ECL2), and Glu-3977.32 and Trp-4007.35 in TMVII as residues that contribute to the BQCA binding pocket at the M1 mAChR, as well as to the transmission of cooperativity with the orthosteric agonist carbachol. As such, the BQCA binding pocket partially overlaps with the previously described “common” allosteric site in the extracellular vestibule of the M1 mAChR, suggesting that its high subtype selectivity derives from either additional contacts outside this region or through a subtype-specific cooperativity mechanism. Mutation of amino acid residues that form the orthosteric binding pocket caused a loss of carbachol response that could be rescued by BQCA. Two of these residues (Leu-1023.29 and Asp-1053.32) were also identified as indirect contributors to the binding affinity of the modulator. This new insight into the structural basis of binding and function of BQCA can guide the design of new allosteric ligands with tailored pharmacological properties. 相似文献
63.
The aim of the study was to examine the stimulatory effect of the inflammatory agent lipopolysaccharide (LPS) on the capacity of human term placenta to secrete interleukin (IL)-15 and IL-18. Isolated placental cotyledons from normal human term deliveries were dually perfused for ten hours with perfusion medium alone (n=5) or with perfusion medium containing LPS (1 microg/kg perfused placental tissue) (n=5). Placental tissue was collected from three different placental compartments (amnion, chorion, and placenta) before and after perfusion. The placental tissues collected were homogenized and examined for IL-15 and IL-18 by ELISA. In addition, formalin-fixed and paraffin-embedded sections from term placentas before perfusion were stained by immunohistochemistry to characterize the cellular origin of placental IL-15 and IL-18. Statistical significance was determined using paired/unpaired t-test. p<0.05 was considered significant. Our results show that IL-15 and IL-18 are produced more by chorionic tissue, as compared to the amnion and placental tissues. Moreover, we show that IL-15 and IL-18 are expressed by epithelial cells of the amnion, chorionic cells of the chorion and decidual cells of the decidua. However, IL-15, but not IL-18, was expressed also by syncytiotrophoblasts of the villi. Perfusion of LPS did not affect the capacity of amnion, chorion and placental tissues to secrete IL-15 and IL-18, as compared to control. The expression of IL-15 and IL-18 in the different compartments of the human placenta suggests a possible role for these two cytokines in normal placental development, pregnancy and labor. Moreover, our results indicate that IL-15 and IL-18 are not part of the mechanism of the response of human placenta to LPS. 相似文献
64.
Aluminum was determined in serum samples obtained from 533 Saudi female pupils aged 6–8 years who attended primary public school in Riyadh City, Capital of Saudi Arabia. The aluminum mean value was 23.21 ± 15.25 g 1–1 in the range of 5.98–206.93 g 1–1. Serum aluminum levels of pupils attending the Northern school area were higher than levels found in pupils from other school areas (Southern, Eastern and Central). Renal variables had no correlation with serum aluminum. On the other hand, a significant positive correlation was found between serum aluminium above 49.2 g 1–1 and urea (r = 0.6, P < 0.002). Although 53% of the screened schools had aluminum in water above the European Union (EU) acceptable limit of 50 g 1–1, there were no differences in aluminum in water between the four different school areas in Riyadh. Factors such as drinking water, diet and the use of aluminum utensils may have contributed to this result. As there is a bulk of literature which highlights the adverse developmental effects of aluminum on children and infants, it would be advantageous to establish regular aluminum monitoring. 相似文献
65.
Michelle J. Pena Andreas Heinzel Georg Heinze Alaa Alkhalaf Stephan J. L. Bakker Tri Q. Nguyen Roel Goldschmeding Henk J. G. Bilo Paul Perco Bernd Mayer Dick de Zeeuw Hiddo J. Lambers Heerspink 《PloS one》2015,10(5)
ObjectiveWe aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy.ResultsPatients’ average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008).ConclusionsA novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort. 相似文献
66.
The ostracod genus Neonesidea is broadly distributed in shallow marine waters. The ontogeny of the N. schulzi (Bairdiidae) is described in detail by studying the development of the appendages and variations in carapace form, size and structure. Neonesidea schulzi has eight post-embryonic instars, and a gap in its ontogenetic development during instar A-6, where no new Anlage is added. The Anlagen of the copulatory organs and the forked terminal claw of second antenna appear in the seventh (A-1) instar, and the first thoracic legs of podocopid ostracods are shown to descend from the thoracic region. For the first time in ostracods, observations of moulting from sixth and seventh instars are presented. 相似文献
67.
Alaa Elkordy Eikan Mishima Kuniyasu Niizuma Yasutoshi Akiyama Miki Fujimura Teiji Tominaga Takaaki Abe 《Journal of neurochemistry》2018,146(5):560-569
68.
Ahmed Abdelmoniem Mousa Shinuo Cao Gabriel Oluga Aboge Mohamad Alaa Terkawi Ahmed El Kirdasy Akram Salama Mabrouk Attia Mahmoud Aboulaila Mo Zhou Ketsarin Kamyingkird Paul Franck Adjou Moumouni Tatsunori Masatani Sami Ahmed Abd El Aziz Waheed Mohammed Moussa Bayin Chahan Shinya Fukumoto Yoshifumi Nishikawa Salah Sayed El Ballal Xuenan Xuan 《Experimental parasitology》2013
Identification and molecular characterization of Babesia gibsoni proteins with potential antigenic properties are crucial for the development and validation of the serodiagnostic method. In this study, we isolated a cDNA clone encoding a novel B. gibsoni 76-kDa protein by immunoscreening of the parasite cDNA library. Computer analysis revealed that the protein presents a glutamic acid-rich region in the C-terminal. Therefore, the protein was designated as B. gibsoni glutamic acid-rich protein (BgGARP). A BLASTp analysis of a translated BgGARP polypeptide demonstrated that the peptide shared a significant homology with a 200-kDa protein of Babesia bigemina and Babesia bovis. A truncated BgGARP cDNA (BgGARPt) encoding a predicted 13-kDa peptide was expressed in Escherichia coli (E. coli), and mouse antisera against the recombinant protein were used to characterize a corresponding native protein. The antiserum against recombinant BgGARPt (rBgGARPt) recognized a 140-kDa protein in the lysate of infected erythrocytes, which was detectable in the cytoplasm of the parasites by confocal microscopic observation. In addition, the specificity and sensitivity of enzyme-linked immunosorbent assay (ELISA) with rBgGARPt were evaluated using B. gibsoni-infected dog sera and specific pathogen-free (SPF) dog sera. Moreover, 107 serum samples from dogs clinically diagnosed with babesiosis were examined using ELISA with rBgGARPt. The results showed that 86 (80.4%) samples were positive by rBgGARPt-ELISA, which was comparable to IFAT and PCR as reference test. Taken together, these results demonstrate that BgGARP is a suitable serodiagnostic antigen for detecting antibodies against B. gibsoni in dogs. 相似文献
69.
Research on feasible methods for the enhancement of bioremediation in soil contaminated by crude oil is vital in oil-exporting countries such as Kuwait, where crude oil is a major pollutant and the environment is hostile to biodegradation. This study investigated the possibility of enhancing crude oil bioremediation by supplementing soil with cost-effective organic materials derived from two widespread locally grown trees, Conocarpus and Tamarix. Amendments in soils increased the counts of soil microbiota by up to 98% and enhanced their activity by up to 95.5%. The increase in the biodegradation of crude oil (75%) and high levels of alkB expression substantiated the efficiency of the proposed amendment technology for the bioremediation of hydrocarbon-contaminated sites. The identification of crude-oil-degrading bacteria revealed the dominance of the genus Microbacterium (39.6%), Sphingopyxis soli (19.3%), and Bordetella petrii (19.6%) in unamended, Conocarpus-amended, and Tamarix-amended contaminated soils, respectively. Although soil amendments favored the growth of Gram-negative bacteria and reduced bacterial diversity, the structures of bacterial communities were not significantly altered. 相似文献
70.
Heavy metal concentrations in the breast milk of Saudi women 总被引:1,自引:0,他引:1
Lead, cadmium, and mercury concentrations were determined in breast milk of Saudi lactating mothers from Riyadh and Al-Ehssa
regions in Saudi Arabia who were not occupationally exposed. The mean levels for cadmium, lead, and mercury were 1.732 μg/L,
31.671 μg/L, and 3.100 μg/L, respectively. In contrast to mercury, mothers living in the Al-Ehssa region had significantly
higher cadmium and lead concentrations in their breast milk than those in the Riyadh region. The estimated weekly intakes
of cadmium, lead, and mercury of breast-fed infants in this study were in some cases higher than the Provisional Tolerance
Weekly Intake (PTWI) recommended by FAO/WHO, which pose a threat to their health. This necessitates the urgent need to undertake
a comprehensive study to determine the sources of exposure to these heavy metals. Breast-feeding is of great benefical value
for the infant’s development; therefore, efforts should be made to prevent its contamination with environmental pollutants. 相似文献