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41.
D. Rambabu Guttikonda Raja B. Yogi Sreenivas G.P.K. Seerapu K. Lalith Kumar Girdhar Singh Deora Devyani Haldar M.V.Basaveswara Rao Manojit Pal 《Bioorganic & medicinal chemistry letters》2013,23(5):1351-1357
Novel N-indolylmethyl substituted spiroindoline-3,2′-quinazolines were designed as potential inhibitiors of SIRT1. These compounds were synthesized in good yields by using Pd/C–Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues. 相似文献
42.
Raja Mohmed Beema Shafreen Chandrabose Selvaraj Sanjeev Kumar Singh Shunmugiah Karutha Pandian 《Journal of molecular recognition : JMR》2013,26(6):276-285
Quinolone resistance‐determining region is known to be the druggability site of the target protein that undergoes frequent mutation and thus renders quinolone resistance. In the present study, ligands were tested for their inhibitory activity against DNA gyrase of Streptococcus pyogenes involved in DNA replication. In silico mutational analysis on modelled gyrase A revealed that GLU85 had the most possible interactions with all the ligands used for the study. The amino acid residue GLU85 had also been predicted with an essential role of maintaining the three‐dimensional structure of the protein. When introduced with a mutation (GLU 85 LYS) on this particular residue, it had readily denatured the whole α‐helix (from 80 to 90 amino acids). This was confirmed through the molecular dynamics simulation and revealed that this single mutation can cause many functional and structural changes. Furthermore, LYS85 mutation has altered the original secondary structure of the protein, which in turn led to the steric hindrance during the ligand–receptor interaction. The results based on the G‐score revealed that ligands have reduced interaction with the mutant protein. The semisynthetic fluoroquinolone 6d, which is an exception, forms a strong interaction with the mutant protein and was experimentally verified using the antimicrobial test. Hence, the present study unravels the fact that mutation at the drug binding site is the major cause for different level of resistance by the S. pyogenes when exposed against the varying concentrations of the fluoroquinolones. Furthermore, a comparative assessment of quinolone derivative with the older generation fluoroquinolones will be of great impact for S. pyogenes–related infections. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
43.
44.
Erawan Borkham-Kamphorst Eddy van de Leur Henning W. Zimmermann Karlin Raja Karlmark Lidia Tihaa Ute Haas Frank Tacke Thorsten Berger Tak W. Mak Ralf Weiskirchen 《生物化学与生物物理学报:疾病的分子基础》2013,1832(5):660-673
Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2?/? mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2?/? mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2?/? mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl4 application), LCN2?/? mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead. 相似文献
45.
Sean A. Kidd Athena Madan Susmitha Rallabandi Donald C. Cole Elisha Muskat Shoba Raja David Wiljer David Aylward Kwame McKenzie 《PloS one》2016,11(3)
In the debate in global mental health about the most effective models for developing and scaling interventions, there have been calls for the development of a more robust literature regarding the "non-specific", science of delivery aspects of interventions that are locally, contextually, and culturally relevant. This study describes a rigorous, exploratory, qualitative examination of the key, non-specific intervention strategies of a diverse group of five internationally-recognized organizations addressing mental illness in middle income countries (MICs). A triangulated approach to inquiry was used with semi-structured interviews conducted with service recipients, service providers and leaders, and key community partners (N = 159). The interview focus was upon processes of implementation and operation. A grounded theory-informed analysis revealed cross cutting themes of: a holistic conceptualization of mental health problems, an intensive application of principles of leverage and creating the social, cultural, and policy “space” within which interventions could be applied and resourced. These findings aligned with key aspects of systems dynamic theory suggesting that it might be a helpful framework in future studies of mental health service implementation in MICs. 相似文献
46.
Francois-Xavier Mauvais Emmanuel Gonzales Anne Davit-Spraul Emmanuel Jacquemin Raja Brauner 《PloS one》2016,11(2)
Objectives
Cholestasis has been reported during the course of congenital hypothalamic-pituitary deficiency, but crucial information is lacking regarding both its origin and prognosis. We aimed to characterize the course of cholestasis and factors contributing to it in patients with deficiency due to pituitary stalk interruption syndrome (PSIS).Methods
We conducted a retrospective single-center, case-cohort study including 16 patients with PSIS diagnosed before one year of age. We collected clinical and biological parameters from medical records and compared the characteristics of the endocrine syndrome in PSIS patients with and without cholestasis.Results
5/16 patients had cholestasis, all with a neonatal onset and multiple hypothalamic-pituitary deficiency. Patients with cholestasis presented with lower Apgar score and higher rate of ophthalmic malformations: 3/5 vs 1/11, p = 0.03 and 5/5 vs 4/11, p = 0.02, respectively. The plasma cortisol level was strongly decreased in patients with cholestasis: 12.4 ng/mL (8–15 ng/mL) vs 79.4 ng/mL (10–210 ng/mL), p = 0.04. Cholestasis resolved within 9 months following hormone supplementation. No development of chronic liver disease was observed during a median follow-up of 9.4 years (range, 1.3–13.3 years).Conclusions
Cholestasis is a frequent symptom at presentation of PSIS during the neonatal period that may help earlier diagnosis and that indicates a profound cortisol deficiency. 相似文献47.
Tanushri Chatterji Suruchi Singh Manodeep Sen Ajai Kumar Singh Pradeep Kumar Maurya Nuzhat Husain Janmejai Kumar Srivastava Sudhir Kumar Mandal Raja Roy 《Metabolomics : Official journal of the Metabolomic Society》2016,12(8):130
Introduction
Meningitis, a morbidly infectious central nervous system pathology is accompanied by acute inflammation of the meninges, causing raised intracranial pressure linked with serious neurological sequelae.Objective
To observe the variation in the metabolic profile, that may occur in serum and urine along with CSF in adults using 1H NMR spectroscopy, with an attempt of appropriate and timely treatment regimen.Methods
The 1H NMR-based metabolomics has been performed in 115 adult subjects for differentiating bacterial meningitis (BM) and tubercular meningitis (TBM).Results
The discriminant function analysis (DFA) of the three bio-fluids collectively identified 3-hydroxyisovalerate, lactate, glucose, formate, valine, alanine, ketonic bodies, malonate and choline containing compounds (choline and GPC) as significant metabolites among cases versus control group. The differentiation of bacterial meningitis and tuberculous meningitis (BM vs. TBM) can be done on the basis of identification of 3-hydroxyisovalerate, isobutyrate and formate in case of CSF (with a correct classification of 78 %), alanine in serum (correct classification 60 %), valine and acetone in case of urine (correct classification 89.1 %). The NMR spectral bins based orthogonal signal correction principal component analysis score plots of significant metabolites obtained from DFA also provided group classification among cases versus control group in CSF, serum and urine samples. The variable importance in projection scores also identified similar significant metabolites as obtained from DFA, collectively in CSF, serum and urine samples, responsible for differentiation of meningitis.Conclusion
The CSF contained metabolites which are formed during infection and inflammation, and these were also found in significant quantity in serum and urine samples.48.
Sunaho Okada Sadaf A. Raja Jonathan Okerblom Aayush Boddu Yousuke Horikawa Supriyo Ray 《Cell cycle (Georgetown, Tex.)》2019,18(11):1268-1280
Caveolin-1 (Cav-1) is an integral membrane protein that plays an important role in proliferative and terminally differentiated cells. As a structural component of Caveolae, Cav-1 interacts with signaling molecules via a caveolin scaffolding domain (CSD) regulating cell signaling. Recent reports have shown that Cav-1 is a negative regulator in tumor metastasis. Therefore, we hypothesize that Cav-1 inhibits cell migration through its CSD. HeLa cells were engineered to overexpress Cav-1 (Cav-1 OE), Cav-1 without a functional CSD (?CSD), or enhanced green fluorescent protein (EGFP) as a control. HeLa cell migration was suppressed in Cav-1 OE cells while ?CSD showed increased migration, which corresponded to a decrease in the tight junction protein, zonula occludens (ZO-1). The migration phenotype was confirmed in multiple cancer cell lines. Phosphorylated STAT-3 was decreased in Cav-1 OE cells compared to control and ?CSD cells; reducing STAT-3 expression alone decreased cell migration. ?CSD blunted HeLa proliferation by increasing the number of cells in the G2/M phase of the cell cycle. Overexpressing the CSD peptide alone suppressed HeLa cell migration and inhibited pSTAT3. These findings suggest that Cav-1 CSD may be critical in controlling the dynamic phenotype of cancer cells by facilitating the interaction of specific signal transduction pathways, regulating STAT3 and participating in a G2/M checkpoint. Modulating the CSD and targeting specific proteins may offer potential new therapies in the treatment of cancer metastasis. 相似文献
49.
Ghulam Jilani Abida Akram Raja M. Ali Fauzia Y. Hafeez Imran H. Shamsi Arshad N. Chaudhry Abid G. Chaudhry 《Annals of microbiology》2007,57(2):177-184
Field experiment was conducted on fodder maize to explore the potential of integrated use of chemical, organic and biofertilizers for improving maize growth, beneficial microflora in the rhizosphere and the economic returns. The treatments were designed to make comparison of NPK fertilizer with different combinations of half dose of NP with organic and biofertilizers viz. biological potassium fertilizer (BPF), Biopower, effective microorganisms (EM) and green force compost (GFC). Data reflected maximum crop growth in terms of plant height, leaf area and fresh biomass with the treatment of full NPK; and it was followed by BPF+full NP. The highest uptake of NPK nutrients by crop was recorded as: N under half NP+Biopower; P in BPF+full NP; and K from full NPK. The rhizosphere microflora enumeration revealed that Biopower+EM applied along with half dose of GFC soil conditioner (SC) or NP fertilizer gave the highest count of N-fixing bacteria (Azotobacter, Azospirillum, Azoarcus andZoogloea). Regarding the P-solubilizing bacteria,Bacillus was having maximum population with Biopower+BPF+half NP, andPseudomonas under Biopower+EM+half NP treatment. It was concluded that integration of half dose of NP fertilizer with Biopower+BPF / EM can give similar crop yield as with full rate of NP fertilizer; and through reduced use of fertilizers the production cost is minimized and the net return maximized. However, the integration of half dose of NP fertilizer with biofertilizers and compost did not give maize fodder growth and yield comparable to that from full dose of NPK fertilizers. 相似文献
50.