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591.
Yin W Majumder S Clayton T Petrou S VanLinn ML Namjoshi OA Ma C Cromer BA Roth BL Platt DM Cook JM 《Bioorganic & medicinal chemistry》2010,18(21):7548-7564
A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α(x)β(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two β-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the β-carbolines presented here. 相似文献
592.
S. Majumder S. Chatterjee Smarajit Pal J. Biswas T. Efferth Soumitra Kumar Choudhuri 《Biometals》2009,22(2):377-384
Multidrug resistance (MDR) is still a major threat to successful clinical application of cancer chemotherapy. Copper plays
an important role in biological systems, and copper is also involved in carcinogenesis. In the present investigation, we addressed
the question whether metal copper might be involved in drug resistance of murine and human tumors. By means of atomic absorption
spectroscopy, we determined serum copper concentrations. We found that the blood serum of tumor-bearing mice contained higher
amounts of copper than healthy mice with tumors. Secondly, mice bearing doxorubicin-resistant Ehrlich ascites carcinoma- or
cyclophosphamide-resistant Lewis lung carcinoma contained more copper in their serum than mice bearing the corresponding drug-sensitive
parental tumors. Furthermore, the analysis of patients with breast cancer, colon carcinoma or lung cancer showed that the
serum copper contents were higher in patients not responding to chemotherapy when compared to patients whose tumors responded
to treatment. The copper levels in serum of healthy volunteers were lower than in cancer patients irrespective of their response
to chemotherapy. Our results imply that the level of serum copper may be considered as a biomarker for treatment response. 相似文献
593.
Salinity poses a serious threat to yield performance of cultivated rice in South Asian countries. To understand the mechanism
of salt-tolerance of the wild halophytic rice, Porteresia coarctata in contrast to the salt-sensitive domesticated rice Oryza sativa, we have compared P. coarctata with the domesticated O. sativa rice varieties under salinity stress with respect to several physiological parameters and changes in leaf protein expression.
P. coarctata showed a better growth performance and biomass under salinity stress. Relative water content was conserved in Porteresia during stress and sodium ion accumulation in leaves was comparatively lesser. Scanning electron microscopy revealed presence
of two types of salt hairs on two leaf surfaces, each showing a different behaviour under stress. High salt stress for prolonged
period also revealed accumulation of extruded NaCl crystals on leaf surface. Changes induced in leaf proteins were studied
by two-dimensional gel electrophoresis and subsequent quantitative image analysis. Out of more than 700 protein spots reproducibly
detected and analyzed, 60% spots showed significant changes under salinity. Many proteins showed steady patterns of up- or
downregulation in response to salinity stress. Twenty protein spots were analyzed by MALDI-TOF, leading to identification
of 16 proteins involved in osmolyte synthesis, photosystem functioning, RubisCO activation, cell wall synthesis and chaperone
functions. We hypothesize that some of these proteins confer a physiological advantage on Porteresia under salinity, and suggest a pattern of salt tolerance strategies operative in salt-marsh grasses. In addition, such proteins
may turn out to be potential targets for recombinant cloning and introgression in salt-sensitive plants.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
594.
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596.
Swati Dubey Puja Majumder Aravind Penmatsa Abhijit A. Sardesai 《The Journal of biological chemistry》2021,297(4)
LysO, a prototypical member of the LysO family, mediates export of L-lysine (Lys) and resistance to the toxic Lys antimetabolite, L-thialysine (Thl) in Escherichia coli. Here, we have addressed unknown aspects of LysO function pertaining to its membrane topology and the mechanism by which it mediates Lys/Thl export. Using substituted cysteine (Cys) accessibility, here we delineated the membrane topology of LysO. Our studies support a model in which both the N- and C-termini of LysO are present at the periplasmic face of the membrane with a transmembrane (TM) domain comprising eight TM segments (TMSs) between them. In addition, a feature of intramembrane solvent exposure in LysO is inferred with the identification of membrane-located solvent-exposed Cys residues. Isosteric substitutions of a pair of conserved acidic residues, one E233, located in the solvent-exposed TMS7 and the other D261, in a solvent-exposed intramembrane segment located between TMS7 and TMS8, abolished LysO function in vivo. Thl, but not Lys, elicited proton release in inside-out membrane vesicles, a process requiring the presence of both E233 and D261. We postulate that Thl may be exported in antiport with H+ and that Lys may be a low-affinity export substrate. Our findings are compatible with a physiological scenario wherein in vivo LysO exports the naturally occurring antimetabolite Thl with higher affinity over the essential cellular metabolite Lys, thus affording protection from Thl toxicity and limiting wasteful export of Lys. 相似文献
597.
Rupamanjari Majumder Sayedeh Hussaini Vladimir S. Zykov Stefan Luther Eberhard Bodenschatz 《PLoS computational biology》2021,17(10)
Interruptions in nonlinear wave propagation, commonly referred to as wave breaks, are typical of many complex excitable systems. In the heart they lead to lethal rhythm disorders, the so-called arrhythmias, which are one of the main causes of sudden death in the industrialized world. Progress in the treatment and therapy of cardiac arrhythmias requires a detailed understanding of the triggers and dynamics of these wave breaks. In particular, two very important questions are: 1) What determines the potential of a wave break to initiate re-entry? and 2) How do these breaks evolve such that the system is able to maintain spatiotemporally chaotic electrical activity? Here we approach these questions numerically using optogenetics in an in silico model of human atrial tissue that has undergone chronic atrial fibrillation (cAF) remodelling. In the lesser studied sub-threshold illumination régime, we discover a new mechanism of wave break initiation in cardiac tissue that occurs for gentle slopes of the restitution characteristics. This mechanism involves the creation of conduction blocks through a combination of wavefront-waveback interaction, reshaping of the wave profile and heterogeneous recovery from the excitation of the spatially extended medium, leading to the creation of re-excitable windows for sustained re-entry. This finding is an important contribution to cardiac arrhythmia research as it identifies scenarios in which low-energy perturbations to cardiac rhythm can be potentially life-threatening. 相似文献
598.
599.
Bijay Shankar Jaiswal Kaushik Das Sudipta Saha Sandhya Rekha Dungdung Gopal C. Majumder 《Journal of cellular physiology》2010,222(1):254-263
Numerous reports have appeared on the occurrence of undefined protein factors in male reproductive fluids that promote motility of mature sperm and initiate forward motility in the immature (immotile) caput‐epididymal sperm. This study reports for the first time purification to apparent homogeneity of a motility initiating protein (MIP) from epididymal plasma and its characterization using the caprine sperm model. It is a 125 kDa (approximately) dimeric protein made up of two subunits: 70 and 54 kDa. MIP is an acidic protein with an isoelectric point of 4.75. The motility protein at 30 µg/ml (240 nM) level showed nearly maximal motility‐promoting activity. MIP is heat stable and it is maximally active at pH 8. It is a glycoprotein that binds with high affinity to concanavalin A and it contains mannose, galactose, and N‐acetyl glucosamine approximately in the ratios of 6:1:6. It is sensitive to the actions of α‐mannosidase and β‐N‐acetylglucoseaminidase thereby demonstrating that the sugar side chain of the glycoprotein is essential for its biological activity. Epididymal plasma is its richest source. It is also capable of enhancing forward motility of mature cauda‐sperm. Its antibody markedly inhibits sperm motility. MIP antibody is highly immunospecific and it recognizes both the subunits. MIP causes significant increase of the intrasperm level of cyclic AMP. MIP: the physiological motility‐activating protein has potential for use as a contraceptive vaccine and for solving some of the problems of human infertility and animal breeding. J. Cell. Physiol. 222:254–263, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
600.
Bhumika Sharma Pratik Deshmukh Srinibas Satapathy Shovan Kumar Majumder 《Luminescence》2023,38(4):410-420
Strontium sulphate (SrSO4) is a defect-based photoluminescence material, generally used in thermoluminescence applications, and has been studied for infrared (IR) stimulated visible emission. The SrSO4 particles were synthesized using a precipitation method. The orthorhombic phase of SrSO4 was confirmed from the X-ray diffraction pattern and the formation of micron-sized particles was authenticated from field emission scanning electron micrographs. The elemental composition of oxygen and strontium was determined using energy-dispersive X-ray analysis measurement that confirmed the presence of and intrinsic defects in the material. Photoluminescence investigations showed the presence of various defect bands in the band gap giving rise to intrinsic luminescence in SrSO4. The emission in the visible region was attributed to the defect band arising due to . Photoluminescence lifetime measurement confirmed the presence of stable defect states with a lifetime in microseconds. The SrSO4 sample was tested using IR lasers and a red–orange emission spot was observed from the powder sample when excited with IR lasers. The underlying principle for IR-to-visible conversion in the material is a defect-mediated phenomenon that has been described through the energy level diagram of the material. 相似文献