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91.
Adel Nefzi Jon Appel Sergey Arutyunyan Richard A. Houghten 《Bioorganic & medicinal chemistry letters》2009,19(17):5169-5175
Combinatorial chemistry offers a unique opportunity for the synthesis and screening of large numbers of compounds and significantly enhances the prospect of finding new drugs. Collaborative efforts with the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF), have led to the identification of submicromolar novel antitubercular hits. Chiral pentaamines and bis-heterocyclic compounds with 90–100% inhibition against Mycobacterium tuberculosis strain H37Rv were identified. Some of the identified compounds are more active than the existing drug ethambutol. 相似文献
92.
Hugues Massimba Dibama Igor Clarot Stéphane Fontanay Adel Ben Salem Maxime Mourer Chantal Finance Raphaël E. Duval Jean-Bernard Regnouf-de-Vains 《Bioorganic & medicinal chemistry letters》2009,19(10):2679-2682
A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities. 相似文献
93.
Mahendra Damarla Emile Hasan Adel Boueiz Anne Le Hyun Hae Pae Calypso Montouchet Todd Kolb Tiffany Simms Allen Myers Usamah S. Kayyali Matthias Gaestel Xinqi Peng Sekhar P. Reddy Rachel Damico Paul M. Hassoun 《PloS one》2009,4(2)
Mechanical ventilation, a fundamental therapy for acute lung injury, worsens pulmonary vascular permeability by exacting mechanical stress on various components of the respiratory system causing ventilator associated lung injury. We postulated that MK2 activation via p38 MAP kinase induced HSP25 phosphorylation, in response to mechanical stress, leading to actin stress fiber formation and endothelial barrier dysfunction. We sought to determine the role of p38 MAP kinase and its downstream effector MK2 on HSP25 phosphorylation and actin stress fiber formation in ventilator associated lung injury. Wild type and MK2−/− mice received mechanical ventilation with high (20 ml/kg) or low (7 ml/kg) tidal volumes up to 4 hrs, after which lungs were harvested for immunohistochemistry, immunoblotting and lung permeability assays. High tidal volume mechanical ventilation resulted in significant phosphorylation of p38 MAP kinase, MK2, HSP25, actin polymerization, and an increase in pulmonary vascular permeability in wild type mice as compared to spontaneous breathing or low tidal volume mechanical ventilation. However, pretreatment of wild type mice with specific p38 MAP kinase or MK2 inhibitors abrogated HSP25 phosphorylation and actin polymerization, and protected against increased lung permeability. Finally, MK2−/− mice were unable to phosphorylate HSP25 or increase actin polymerization from baseline, and were resistant to increases in lung permeability in response to HVT MV. Our results suggest that p38 MAP kinase and its downstream effector MK2 mediate lung permeability in ventilator associated lung injury by regulating HSP25 phosphorylation and actin cytoskeletal remodeling. 相似文献
94.
Steven T. Lott Nanyue Chen Dawn S. Chandler Qifeng Yang Luo Wang Marivonne Rodriguez Hongyan Xie Seetharaman Balasenthil Thomas A. Buchholz Aysegul A. Sahin Katrina Chaung Baili Zhang Shodimu-Emmanu Olufemi Jinyun Chen Henry Adams Vimla Band Adel K. El-Naggar Marsha L. Frazier Khandan Keyomarsi Kelly K. Hunt Subrata Sen Bruce Haffty Stephen M. Hewitt Ralf Krahe Ann McNeill Killary 《PLoS medicine》2009,6(5)
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease. 相似文献95.
Rose Y Ciblat S Reddy R Belley AC Dietrich E Lehoux D McKay GA Poirier H Far AR Delorme D 《Bioorganic & medicinal chemistry letters》2006,16(4):891-896
The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified. 相似文献
96.
McKay GA Reddy R Arhin F Belley A Lehoux D Moeck G Sarmiento I Parr TR Gros P Pelletier J Far AR 《Bioorganic & medicinal chemistry letters》2006,16(5):1286-1290
Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials. 相似文献
97.
98.
Hassan Reda Hassan Elsayed Mohammad El-Nablaway Basma Adel Khattab Rania N. Sherif Wagdi Fawzy Elkashef Asim Mohammed Abdalla Eman Mohammad El Nashar Mostafa Mohammed Abd-Elmonem Randa El-Gamal 《The journal of histochemistry and cytochemistry》2021,69(9):575
Non-alcoholic steatohepatitis (NASH) is a worldwide health problem. Alternate-day fasting (ADF), although thought to be aggressive, has proven safety and efficacy. We aimed to evaluate the effect of short-term ADF against already established high-fat-fructose (HFF)-induced NASH, independent of the amount of calorie intake, and to study the effect of ADF on lipogenesis, apoptosis, and hepatic inflammation. Male Sprague Dawley rats were divided into two groups: (1) negative control and (2) NASH group fed on HFF for 9 weeks, and then randomized into two subgroups of either HFF alone or with ADF protocol for 3 weeks. The ADF could improve HFF-related elevation in serum lactate dehydrogenase and could decrease the mRNA expression of lipogenesis genes; acetyl CoA carboxylase, peroxisome proliferator-activated receptor γ, and peroxisome proliferator-activated receptor α; apoptotic genes caspase-3, p53, and inflammatory cyclo-oxygenase 2; and immunohistochemical staining for their proteins in liver with upregulation of LC3 and downregulation of P62 immunoexpression. Moreover, ADF ameliorated HFF-induced steatosis, inflammation, ballooning, and fibrosis through hematoxylin and eosin, Oil Red O, and Sirius Red staining, confirmed by morphometric analysis, without significant weight loss. Significant correlation of morphometric parameters with levels of gene expression was found. These findings suggest ADF to be a safe effective therapeutic agent in the management of NASH 相似文献
99.
100.
Monier Abd El‐Ghani Abdel M. El‐Fiky Ashraf Soliman Adel Khattab 《African Journal of Ecology》2011,49(1):103-118
In generalized four sectors, 350 stands (water channels) in 50 selected and geo‐referenced sites with eighteen environmental factors were surveyed. The total number of recorded species varied from a sector to another: 21 in the northern, nineteen in the middle, seventeen in the western and sixteen in the eastern. New populations of Cyperus papyrus were explored. Vallisneria spiralis, Elodea canadensis and Najas armata were among seven extinct species that were not recorded few decades ago. The floristic composition alteration may be because of the addition of organic matter of plant and animal origin and the discharge of industrial and sewage effluents. Classification and ordination analyses (DCA) resulted in the segregation of seventeen vegetation groups (communities), three of them were repeatedly recorded; namely Phragmites australis‐Eichhornia crassipes, Phragmites australis‐Myriophyllum spicatum and Potamogeton pectinatus‐Myriophyllum spicatum. Phragmites australis‐Cyperus papyrus group was a new community spreading in the eastern sector of the Delta. Electric conductivity, Fe, Hg and chemical oxygen demand (COD) showed high significant variation (P < 0.001) among the vegetation groups. Other significant variables were Cl, Ca, NO3, pH and SO4 (P < 0.047). Redundancy analysis (RDA) was chosen as the appropriate ordination method to perform direct gradient analysis. Trace elements Cu, Fe, Hg and Pb participated in the floristic and chemical composition of each sector. 相似文献