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Showing papers by "Central Drug Research Institute published in 2002"


Journal ArticleDOI
TL;DR: The lipid lowering activity of Phyllanthus niruri has been studied in triton and cholesterol fed hyperlipemic rats and lowering in the lipids and apoprotein levels of VLDL and LDL in experimental animals was found.

272 citations


Journal ArticleDOI
TL;DR: In this article, Bacopa monniera and Ginkgo biloba extracts were used to evaluate the antidementic and anticholinesterase activities in adult male Swiss mice.
Abstract: Bacopa monniera and Ginkgo biloba are well-known cognitive enhancers in Indian and Chinese traditional medicine systems. Standardized extracts of B. monniera and G. biloba were used to evaluate the antidementic and anticholinesterase activities in adult male Swiss mice. Antidementic activity was tested against scopolamine (3 mg/kg ip)-induced deficits in passive avoidance test. Three different extracts of B. monniera (30 mg/kg) and extract of G. biloba (15, 30 and 60 mg/kg) were administered postoperatively, daily for 7 days and 60 min after the last dose, i.e., on Day 7, first trial was conducted. In passive avoidance test, increased transfer latency time (TLT) and no transfer response (NTR) were taken as criteria for learning. TLT and NTR were significantly increased and decreased in second trial, 24 h after the first trial in control group and scopolamine-dementia group, respectively. The B. monniera- and G. biloba-treated groups produced significant increase in TLT and NTR on second trial (40-80%) after scopolamine treatment, thus, attenuating its antidementic effect. Both the extracts showed a dose (10-1000 microg)-dependent inhibitory effect on acetylcholinesterase (AChE) activity (in vitro), performed spectrophotometrically. IC(50) of G. biloba was 268.33 microg, whereas none of the extracts of B. monniera showed more than 50% inhibition. At a dose concentration of 30 and 60 mg/kg, extracts of G. biloba showed a cognitive enhancing property and, at the same time, a significant decrease in AChE-specific activity in both per se and scopolamine-dementia groups. These extracts possess a significant anticholinesterase and antidementic properties, which may be useful in the treatment of dementia.

242 citations


Journal ArticleDOI
TL;DR: BBM has potential to modulate the activities of Hsp70, P450 and SOD thereby possibly allowing the brain to be prepared to act under adverse conditions such as stress.
Abstract: The antistress effect of bacosides of Brahmi (Bacopa monnieri, BBM), dissolved in distilled water, was -studied in adult male Sprague Dawley rats by administering oral doses of 20 and 40 mg/kg for 7 consecutive days. In half of the animals treated with 20 or 40 mg/kg of BBM, stress was given 2 h after the last dose. Stress was also administered to the animals treated with distilled water alone. BBM, at both doses, did not induce a significant change in the expression of Hsp70 in any brain region studied while stress alone produced a significant increase in the Hsp70 expression in all the brain regions. A significant decrease in the activity of superoxide dismutase (SOD) was evident in the hippocampus with the lower dose of BBM and in animals given stress alone, while an increase in the activity of SOD was observed in the brain regions with the higher dose of BBM. An increase in the activity of cytochrome P450 (P450) dependent 7-pentoxyresorufin-o-dealkylase (PROD) and 7-ethoxyresorufin-o-deethylase (EROD) was observed in all the brain regions after exposure to stress alone and with both doses of BBM although the magnitude of induction of P450 expression was less with a higher dose of BBM. Interestingly, stress when given to the animals pretreated with BBM for 7 days resulted in a decrease in Hsp70 expression in all the brain regions with a significant decrease occurring only in the hippocampus. Likewise the activity of SOD was found to be further reduced in all the brain regions in the animals treated with the lower dose of BBM followed by stress. However, when stress was given to the animals pretreated with the higher dose of BBM, a significant increase in the enzyme activity was observed in the cerebral cortex and in the rest of the brain while the activity of SOD was reduced to a much greater extent in the cerebellum and in the hippocampus. Likewise, the activity of P450 enzymes was found to be restored to almost control levels in the animals given stress and pretreated with the higher dose of BBM, while a lesser degree of induction, compared with animals treated with BBM or stress alone, was observed in the animals pretreated with the lower dose of BBM and given stress. The data indicate that BBM has potential to modulate the activities of Hsp70, P450 and SOD thereby possibly allowing the brain to be prepared to act under adverse conditions such as stress.

170 citations


Journal ArticleDOI
TL;DR: In this article, 4-thiazolidinones have been assembled by DCC mediated three-component reaction of amine, aldehyde and mercaptoacetic acid.

151 citations


Journal ArticleDOI
15 Mar 2002-Yeast
TL;DR: This study clearly demonstrates that these ABC transporters of C. albicans are phospholipid translocators and this function could represent one of the physiological functions of such large family of proteins.
Abstract: We have used fluorescent 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-tagged phospholipid analogues, NBD-PE (phosphatidylethanolamine), NBD-PC (phosphatidylcholine) and NBD-PS (phosphatidylserine), to demonstrate that Cdr1p and its other homologues, Cdr2p and Cdr3p, belonging to the ATP-binding cassette (ABC) superfamily behave as general phospholipid translocators. Interestingly, CDR1 and CDR2, whose overexpression leads to azole resistance in C. albicans, elicit in-to-out transbilayer phospholipid movement, while CDR3, which is not involved in drug resistance, carries out-to-in translocation of phospholipids between the two monolayers of plasma membrane. Cdr1p, Cdr2p and Cdr3p could be further distinguished on the basis of their sensitivities to different inhibitors. For example, the in-to-out activity associated with Cdr1p and Cdr2p is energy-dependent and sensitive to sulphydryl blocking agents such as N-ethylmaleimide (NEM) and cytoskeleton disrupting agent cytochalasin E, while Cdr3p-associated out-to-in activity is energy-dependent but insensitive to NEM and cytochalasin E. We found that certain drugs, such as fluconazole, cycloheximide and miconazole, to which Cdr1p confers resistance could also affect in-to-out transbilayer movement of NBD-PE, while the same drugs had no effect on Cdr3p-mediated out-to-in translocation of NBD-PE. The ineffectiveness of these drugs to affect Cdr3p mediated out-to-in phospholipid translocation further confirms the inherent difference in the directionality of phospholipid translocation between these pumps. Notwithstanding the role of some of the Cdrps in drug resistance, this study clearly demonstrates that these ABC transporters of C. albicans are phospholipid translocators and this function could represent one of the physiological functions of such large family of proteins.

111 citations


Journal ArticleDOI
TL;DR: It is shown that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines, but not the T cell-directed cytokine IL-12, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity.
Abstract: Macrophages from X-linked immunodeficient ( xid ) mice lacking functional Bruton’s tyrosine kinase (Btk) show poor NO induction and enhanced IL-12 induction, and contribute to delayed clearance of injected microfilaria (mf) in vivo We now show that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines (TNF-α, IL-1β), but not the T cell-directed cytokine IL-12 Induction of some transcriptional regulators of the NF-κB family, crucial for the expression of proinflammatory cytokines, is also poor in Btk-deficient macrophages Thus, Btk appears to be involved in signaling for inducible effector functions, but not APC functions, in macrophages Furthermore, adoptive transfer of T cells from mf-infected xid or wild-type mice did not alter the course of mf clearance in recipients, mf clearance was unaltered in IFN-γ-deficient mice, and improved mf clearance was seen only if greater inducibility of IL-12 was accompanied by greater NO secretion from macrophages, as seen in Ity r CD2 mice as compared with congenic Ity s BALB/c mice Thus, delayed mf clearance in xid mice was correlated not with the high IL-12/Th1 phenotype but with low NO induction levels Also, xid macrophages showed poor toxicity to mf in vitro as compared with wild-type macrophages Inhibition of NO production blocked this mf cytotoxicity, and an NF-κB inhibitor blocked both NO induction and mf cytotoxicity Thus, Btk is involved in inducing many macrophage effector functions, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity

109 citations


Journal ArticleDOI
TL;DR: Significant alterations in the antioxidant profile accompanied by elevated levels of MDA, a marker of free radical damage may be contributory to impaired wound healing in immunocompromised rats.
Abstract: The present investigation was undertaken to investigate the endogenous status of free radical scavengers during cutaneous wound healing in immunocompromised rats. Antioxidant contents and lipid peroxidation product in terms of malondialdehyde (MDA) have been monitored in the wound tissues of immunosuppressed rats at different time intervals (2, 7 and 14 days) following cutaneous injury. A significant increase in MDA content and decrease in glutathione and vitamin C content was observed in the skin of immunocompromised rats as compared to control subjects. Further, a significant decrease in vitamin C, vitamin E content, catalase and glutathione peroxidase activity was observed at 2 days postwounding in immunocompromised rats. A significant and time-dependent decrease in glutathione content was also observed at 7 and 14 days postwounding. However, the healing tissue on 2 and 7 days postwounding exhibited significantly elevated superoxide dismutase activity. The MDA content was augmented only at 2 days postwounding in immunosuppressed rats. Thus significant alterations in the antioxidant profile accompanied by elevated levels of MDA, a marker of free radical damage may be contributory to impaired wound healing in immunocompromised rats.

105 citations


Journal ArticleDOI
TL;DR: A series of novel 2-phenyl-3-substituted quinazolin-4(3H)-ones have been synthesized by treating methyl-N-(1,2,3,4, and 5)-one dithiocarbamate with different amines, the starting material was synthesized from anthranilic acid.
Abstract: A series of novel 2-methyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by treating (2-methyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid. The compounds synthesized were investigated for analgesic, anti-inflammatory and antibacterial activities. All the test compounds exhibited significant activity, the compounds VA2, VA3 and VA4 shown more potent analgesic activity, and the compounds VA3 and VA4 shown more potent anti-inflammatory activity than the reference compound diclofinac sodium.

105 citations


Journal ArticleDOI
TL;DR: In the course of the investigations of pyrimidines as antimycotic agents, a sub-class, with significant in vitro activity against mycobacteria is identified, and some of them 3j-n and 7a,b were found most potent against Aspergillus fumigatus and Trichophyton mentagrophytes.

86 citations


Journal ArticleDOI
TL;DR: Results of the present study for the first time indicate alterations the NOS activity in PMNs obtained form the patients of affective disorders.

81 citations


Journal ArticleDOI
TL;DR: The GdmCl-stabilized compact dimeric intermediate of GOD showed an enhanced stability against thermal and urea denaturation as compared to the native GOD dimer, which is the first report where violation of the 2-fold rule has been observed for a multimeric protein.
Abstract: We have carried out a systematic study on the guanidinium chloride- and urea-induced unfolding of glucose oxidase from Aspergillus niger, an acidic dimeric enzyme, using various optical spectroscopic techniques, enzymatic activity measurements, glutaraldehyde cross-linking, and differential scanning calorimetry. The urea-induced unfolding of GOD was a two-state process with dissociation and unfolding of the native dimeric enzyme molecule occurring in a single step. On the contrary, the GdmCl-induced unfolding of GOD was a multiphasic process with stabilization of a conformation more compact than the native enzyme at low GdmCl concentrations and dissociation along with unfolding of enzyme at higher concentrations of GdmCl. The GdmCl-stabilized compact dimeric intermediate of GOD showed an enhanced stability against thermal and urea denaturation as compared to the native GOD dimer. Comparative studies on GOD using GdmCl and NaCl demonstrated that binding of the Gdm+ cation to the enzyme results in stabiliza...

Journal ArticleDOI
TL;DR: In this paper, the first structure of the serine-bound form of SHMT has been presented, which allows identification of residues involved in serine binding and catalysis and provides evidence for a direct displacement mechanism for the hydroxymethyl transfer rather than a retroaldol cleavage.

Journal ArticleDOI
TL;DR: Though most of the compounds exhibited little activity, however, one showed significant activity against all the strains in cell culture and activity was confirmed by B actec method.

Journal ArticleDOI
TL;DR: Comparative studies of the effect of NaCl, GdmCl, and urea on BLC show that cation binding to negatively charged groups present in amino acid side chains of the enzyme leads to stabilization of an enzymatically active, folded dimer of BLC.
Abstract: Catalases, although synthesized from single genes and built up from only one type of subunit, exist in heterogeneous form with respect to their conformations and association states in biological systems. This heterogeneity is not of genetic origin, but rather reflects the instability of this oligomeric heme enzyme. To understand better the factors that stabilize the various association states of catalase, we performed studies on the multimeric intermediates that are stabilized during guanidine-hydrochloride- and urea-induced unfolding of bovine liver catalase (BLC). For the first time, we have observed an enzymatically active, folded dimer of native BLC. This dimer has slightly higher enzymatic activity and altered structural properties compared to the native tetramer. Comparative studies of the effect of NaCl, GdmCl, and urea on BLC show that cation binding to negatively charged groups present in amino acid side chains of the enzyme leads to stabilization of an enzymatically active, folded dimer of BLC. Besides the folded dimer, an enzymatically active expanded tetramer and a partially unfolded, enzymatically inactive dimer of BLC were also observed. A complete recovery of native enzyme was observed on refolding of expanded tetramers and folded dimers; however, a very low recovery (maximum of ∼5%) of native enzyme was observed on refolding of partially unfolded dimers and fully unfolded monomers.

Journal ArticleDOI
TL;DR: This study demonstrates for the first time some of the membrane proteins of M. tuberculosis, and underscores the problems associated with proteomic analysis of a complex membrane such as that of a mycobacterium.
Abstract: The plasma membrane of Mycobacterium tuberculosis is likely to contain proteins that could serve as novel drug targets, diagnostic probes or even components of a vaccine against tuberculosis. With this in mind, we have undertaken proteome analysis of the membrane of M. tuberculosis H37Rv. Isolated membrane vesicles were extracted with either a detergent (Triton X114) or an alkaline buffer (carbonate) following two of the protocols recommended for membrane protein enrichment. Proteins were resolved by 2D-GE using immobilized pH gradient (IPG) strips, and identified by peptide mass mapping utilizing the M. tuberculosis genome database. The two extraction procedures yielded patterns with minimal overlap. Only two proteins, both HSPs, showed a common presence. MALDI-MS analysis of 61 spots led to the identification of 32 proteins, 17 of which were new to the M. tuberculosis proteome database. We classified 19 of the identified proteins as 'membrane-associated'; 14 of these were further classified as 'membrane-bound', three of which were lipoproteins. The remaining proteins included four heat-shock proteins and several enzymes involved in energy or lipid metabolism. Extraction with Triton X114 was found to be more effective than carbonate for detecting 'putative' M. tuberculosis membrane proteins. The protocol was also found to be suitable for comparing BCG and M. tuberculosis membranes, identifying ESAT-6 as being expressed selectively in M. tuberculosis. While this study demonstrates for the first time some of the membrane proteins of M. tuberculosis, it also underscores the problems associated with proteomic analysis of a complex membrane such as that of a mycobacterium.

Journal ArticleDOI
TL;DR: The feasibility of inhibiting erythrocyte invasion with antibodies directed against receptor-binding domains of ery Throcyte binding proteins is examined to provide support for the development of recombinant vaccines based on the homologous binding domains of P. knowlesi.

Journal ArticleDOI
TL;DR: Among 80 compounds screened, six compounds showed in vitro activity against Mycobacterium tuberculosis (MABA) at a concentration of 50 and 25 microg/mL.

Journal ArticleDOI
TL;DR: In this paper, a one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e] pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions.

Journal ArticleDOI
TL;DR: The results further demonstrate the usefulness of tuftsin-bearing liposomes as drug vehicles in treatment of the macrophage-based infections and enhanced the drug accessibility to areas that are otherwise inaccessible to the free drug.
Abstract: Chemotherapeutic efficacy of the amphotericin B (Amp B), which is the drug of choice for treatment of the leishmanial infections (kala-azar) that become resistant to the conventional chemotherapy using antimonials, has been examined in the Leishmania donovani infected hamsters after encapsulating the drug in tuftsin-free as well as tuftsin-bearing liposomes. The activity was significantly increased (p < 0.05) by delivering Amp B in tuftsin-free liposomes. This antileishmanial effect of the liposomized Amp B was further increased (p < 0.05) by grafting the natural macrophage-activator tetrapeptide, tuftsin (Thr-Lys-Pro-Arg), on the liposome's surface. This could possibly be attributed to both the enhanced drug tolerance after liposomization as well as to the increased uptake of tuftsin-bearing Amp B-laden liposomes by the macrophages. In addition to the increased efficacy, encapsulation of Amp B in the tuftsin-bearing liposomes also enhanced the drug accessibility to areas (e.g. bone marrow) that are otherwise inaccessible to the free drug. These results further demonstrate the usefulness of tuftsin-bearing liposomes as drug vehicles in treatment of the macrophage-based infections that have been reviewed recently (Agrawal, A.K. and Gupta, C.M. (2000). Tuftsin-bearing liposomes in treatment of macrophage-based infections, Adv. Drug Deliv. Rev., 41, 135-146).

Journal ArticleDOI
TL;DR: Two 3D-QSAR models with three biophoric sites and four secondary sites, showed very good correlation between the observed and calculated or predicted activities.

Journal ArticleDOI
TL;DR: The effect of the divalent cations Ca2+ and Mg2+ on the structural and stability properties of GOD was reported and it was observed that the 3 M CaCl2-stabilized monomer of GOD retained about 70% secondary structure present in the native GOD dimer; however, there was a complete loss of cooperative interactions between these secondary structural elements present inThe enzyme.
Abstract: Glucose oxidase (GOD) from Aspergillus niger is a dimeric enzyme having high localization of negative charges on the enzyme surface and at the dimer interface. The monovalent cations induce compact...

Journal ArticleDOI
TL;DR: The in vivo induced antigen technology (IVIAT)(1) has been used for the identification of open reading frames (ORFs) which could be possible therapeutic targets and two of them appear to be potential targets for drug development.

Journal ArticleDOI
TL;DR: Photo-oxygenation of geraniol 2, an abundantly available allylic alcohol, furnished a mixture of mono- and di-hydroperoxy products; the latter have been used for the preparation of a novel series of hydroxy-functionalized anti-malarial 1,2,4-trioxanes (7a-d, 8a- d).

Journal ArticleDOI
TL;DR: The use of the triterpenoid lupeol as a scaffold for the synthesis of lupeo-based libraries is described and a 96-member library was screened for its in-vitro antimalarial activity against Plasmodium falciparum.

Journal ArticleDOI
TL;DR: Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions and evaluated for their antithrombin activity in vivo.

Journal ArticleDOI
TL;DR: In this article, a versatile method for the solid phase synthesis of differentially substituted quinazolin-4(3H)-ones using immobilized arylguanidines was developed.

Journal ArticleDOI
TL;DR: Among the compounds evaluated for their antimycobacterial activity, compound (10) showed the desired activity in the range of 3.125 microg/mL.

Journal ArticleDOI
TL;DR: In this article, a novel furan based scaffold 5-hydroxymethylfurfural has been identified for the generation of combinatorial libraries using template directed approach on solid phase.

Journal ArticleDOI
TL;DR: The Baylis−Hillman (BH) reaction of substituted 5-isoxazolecarboxaldehydes with cyclohexenone in the presence of TiCl4 invariably lead to the formation of hemiacetals beside the BH adducts as discussed by the authors.
Abstract: The Baylis−Hillman (BH) reaction of substituted 5-isoxazolecarboxaldehydes with cyclohexenone in the presence of TiCl4 invariably lead to the formation of hemiacetals beside the BH adducts. A similar reaction in the presence of DABCO, DBU, or 3-HQN yielded minor quantities of phenols in addition to the usual BH adducts. Similar to 5-isoxazolecarboxaldehydes, the TiCl4-mediated BH reaction of cyclohexenone with various benzaldehydes also furnishes hemiacetals in considerable yields. The reaction mechanism involving the formation of α-chloromethyl enone as an intermediate has been proposed. The synthesis of hemiacetals 5 and 14 from compound 4 in the presence of cyclohexenone and cyclopentenone, respectively, under acidic conditions indicates that enolization and aromatization of the cyclohexene ring are the key steps in the reaction mechanism.

Journal ArticleDOI
TL;DR: In this article, an efficient O-alkylation of alcoholic tosylates with amines in a K2CO3/CO2 system in the presence of tetrabutyl ammonium iodide (TBAI) provides exclusive formation of carbamates.