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Khare P.,Central Drug Research Institute CDRI | Jaiswal A.K.,Central Drug Research Institute CDRI | Tripathi C.D.P.,Central Drug Research Institute CDRI | Joshi S.,Central Drug Research Institute CDRI | And 2 more authors.
Parasitology Research | Year: 2014

In visceral leishmaniasis (VL), Th1-type of immune responses play an important role which correlates with recovery from and resistance to disease resulting in lifelong immunity. Based on this rationale, the soluble leishmanial antigens that elicit cellular responses in peripheral blood mononuclear cells (PBMCs) from cured Leishmania patients were characterized through immunoproteomic approach which led to the identification of trypanothione reductase (TPR) (a cytosolic enzyme explored as a drug target), as one of the potent Th1 stimulatory protein. In this study, the immunogenicity of recombinant Leishmania donovani TPR (rLdTPR) was assessed in PBMCs of cured Leishmania-infected patients/hamsters and further evaluated its prophylactic efficacy against L. donovani challenges in hamsters. Substantial proliferative responses to rLdTPR, as compared to soluble L. donovani antigen, were observed in Leishmania-infected cured patients as well as in hamsters. Moreover, rLdTPR reasonably stimulated PBMCs of cured Leishmania patients to produce IFNγ, IL-12, and TNF-α but not IL-4 or IL-10. On the other hand, the protein downregulated LPS-induced IL-10 as well as soluble L. donovani antigen-induced IL-4 production in PBMCs of Leishmania patients. In case of cured hamsters, rLdTPR generates mixed Th1 and Th2 immune response. Vaccination with rLdTPR along with Bacillus Calmette-Guerin (BCG) was able to provide considerably good prophylactic efficacy (~60 %) against L. donovani challenge in hamsters. The efficacy was supported by the increased inducible NO synthase mRNA transcript and Th1-type cytokines IFNγ, IL-12, and TNF-α and downregulation of IL-4, IL-10, and TGF-β. Since rLdTPR protein is an important target, further attempts towards determination of immunodominant regions for designing fusion peptides may be taken up to optimize its prophylactic efficacy. © 2013 Springer-Verlag Berlin Heidelberg.


Kamat P.K.,Central Drug Research Institute CDRI | Tota S.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI | Ali S.,Jamia Hamdard University | And 2 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca 2+ and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca 2+ and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction. © 2011 Elsevier B.V. All rights reserved.


Kamat P.K.,Central Drug Research Institute CDRI | Tota S.,Central Drug Research Institute CDRI | Saxena G.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI | Nath C.,CSIR - Central Electrochemical Research Institute
Brain Research | Year: 2010

Okadaic acid (OKA) is a potent and selective inhibitor of protein phosphatases, PP2A and PP1. In the present study, we evaluated effect of intracerebroventricular (ICV) bilateral injection of OKA (100 and 200 ng) on memory function and oxidative stress in rats. ICV injection of OKA (200 ng) produced memory impairment as evidenced by no significant decrease in latency time to reach the hidden platform in water maze test. It produced increase in malondialdehyde (MDA), nitrite level, reactive oxygen species (ROS) generation, mitochondrial calcium ion [Ca2]i level and decreased glutathione (GSH) level in rat brain areas, indicating oxidative stress. Furthermore, we evaluated the effect of anti-dementia drugs memantine, a NMDA antagonist, and donepezil, a cholinesterase inhibitor, on OKA ICV induced memory impairment. Administration of memantine (10 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 13 days starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca2+]i level. This study demonstrates that the clinically used anti-dementic drugs are effective in OKA induced free radical generation and memory impairment in rats. Thus, OKA ICV induced memory impairment in rat appeared as a useful test model to screen anti-dementia drugs. © 2009 Elsevier B.V. All rights reserved.


Shameem M.,CSIR - Central Electrochemical Research Institute | Shameem M.,Central Drug Research Institute CDRI | Patel A.B.,CSIR - Central Electrochemical Research Institute
PLoS ONE | Year: 2012

Background and Purpose: The effects of nicotine on cerebral metabolism and its influence on smoking behavior is poorly understood. An understanding of the chronic effects of nicotine on excitatory and inhibitory metabolic demand, and corresponding neurotransmission may provide clues for designing strategies for the optimal smoking cessation intervention. The objective of the current study was to investigate neuronal and astroglial metabolism in mice exposed to nicotine (0.5 and 2.0 mg/kg, sc) three times in a day for 4 weeks. Experimental Approach/Principal Findings: Metabolic measurements were carried out by co-infusing [U-13C6]glucose and [2-13C]acetate, and monitoring 13C labeling of amino acids in brain tissue extract using 1H-[13C] and 13C-[1H]-NMR spectroscopy. Concentration of 13C-labeled glutamate-C4 was increased significantly from glucose and acetate with chronic nicotine treatment indicating an increase in glucose oxidation by glutamatergic neurons in all brain regions and glutamate-glutamine neurotransmitter cycle in cortical and subcortical regions. However, chronic nicotine treatment led to increased labeling of GABA-C2 from glucose only in the cortical region. Further, increased labeling of glutamine-C4 from [2-13C]acetate is suggestive of increased astroglial activity in subcortical and cerebellum regions of brain with chronic nicotine treatment. Conclusions and Significance: Chronic nicotine exposure enhanced excitatory activity in the majority of brain regions while inhibitory and astroglial functions were enhanced only in selected brain regions. © 2012 Shameem, Patel.


Konwar R.,Central Drug Research Institute CDRI | Manchanda P.K.,Ohio State University | Chaudhary P.,Central Drug Research Institute CDRI | Lakshma Nayak V.,Central Drug Research Institute CDRI | And 2 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2010

Glutathione S-transferases may be over expressed in benign prostate hyperplasia (BPH) but association of GST polymorphism with susceptibility to the disease is unclear. The objective of this study was to determine relationships between polymorphisms in the GSTM1, T1 and P1 genes with risk of symptomatic BPH and response to standard therapy. The study population comprised 160 symptomatic BPH patients with BPE (benign prostatic enlargement) and LUTS (lower urinary tract symptoms) and 200 age-matched controls. Patient inclusion criteria were: age >50 years; prostate size >30cm3; AUA (American Urological Association) score >7; and PVR volume ≤200 ml. Patients were treated with α-adrenergic blockers and 5α-reductase inhibitors for 6 months and subdivided based on significant improvement in parameters between pre and post combined therapy. The GSTT1 and GSTM1 variants genotyped with multiplex-PCR, whereas GSTP1 polymorphisms were determined with PCR-RFLP (polymerase chain reaction- restriction fragment length polymorphism). We observed a lack of any association with GSTT1 (p=0.45, OR=2.25, 95% CI=1.71-2.22) and GSTP1 (p=0.92 and 0.99) genes. There was a significant positive association with null alleles of the GSTM1 (p=0.000, OR=2.24, 95%CI =1.46-3.42) gene. Combined analysis of the three genotypes demonstrated further increase in the risk of symptomatic BPH (p=0.009, OR=8.31 95%CI=1.71-40.4). Polymorphisms of GST genes were not associated with rates for responders and non-responders. GSTM1 deletion is significantly associated with the increased risk of symptomatic BPH, but none of the GST polymorphisms appears associated with response to standard BPH therapy.


Manchanda P.K.,Ohio State University | Konwar R.,Central Drug Research Institute CDRI | Lakshma Nayak V.,Central Drug Research Institute CDRI | Singh V.,University of Lucknow | Bid H.K.,Central Drug Research Institute CDRI
Asian Pacific Journal of Cancer Prevention | Year: 2010

Several genetic studies worldwide have recommended VDR as candidate gene for determining risk of benign prostate hyperplasia (BPH). We investigated the association between VDR gene polymorphisms and the risk of BPH in an Indian male population. Three polymorphic sites of VDR gene, viz., Fok-I, Taq-I and Bsm-I were genotyped in 160 BPH patients and 160 controls. Logistic regression models were used to determine the genetic effects using SPSS statistical software. A statistically significant association between VDR genotype (Taq-I and Bsm-I) and BPH (p=0.02 & 0.03) was obtained. In exploratory analyses, we also examined the association with responder and non-responder subgroups of patients for association of VDR (Taq-I) genotype with drug responsiveness. Our results established that Taq-I and Bsm-I genetic variants of VDR gene influence susceptibility BPH in Indian population. VDR genotypes specifically, Taq-I polymorphic variant is significantly associated with the improvement of BPH patients with standard drug therapy.


PubMed | TD Medical College Hospital, Jawaharlal Institute of Postgraduate Medical Education & Research and Central Drug Research Institute CDRI
Type: Journal Article | Journal: Parasitology | Year: 2016

Human lymphatic filariasis (LF) is a major cause of disability globally. The success of global elimination programmes for LF depends upon effectiveness of tools for diagnosis and treatment. In this study on stage-specific antigen detection in brugian filariasis, L3, adult worm (AW) and microfilarial antigenaemia were detected in around 90-95% of microfilariae carriers (MF group), 50-70% of adenolymphangitis (ADL) patients, 10-25% of chronic pathology (CP) patients and 10-15% of endemic normal (EN) controls. The sensitivity of the circulating filarial antigen (CFA) detection in serum samples from MF group was up to 95%. In sera from ADL patients, unexpectedly, less antigen reactivity was observed. In CP group all the CFA positive individuals were from CP grade I and II only and none from grade III or IV, suggesting that with chronicity the AWs lose fecundity and start to disintegrate and die. Amongst EN subject, 10-15% had CFA indicating that few of them harbour filarial AWs, thus they might not be truly immune as has been conventionally believed. The specificity for antigen detection was 100% when tested with sera from various other protozoan and non-filarial helminthic infections.


Akhter F.,Integral University | Khan M.S.,Integral University | Singh S.,Central Drug Research Institute CDRI | Ahmad S.,Integral University
PLoS ONE | Year: 2014

Advanced glycation end products (AGEs) are thought to contribute to the abnormal lipoprotein profiles and increased risk of cardiovascular disease in patients with diabetes and renal failure. D-ribose is one of the naturally occurring pentose monosaccharide present in all living cells and is a key component of numerous biomolecules involved in many important metabolic pathways. Formation of D-ribose derived glycated low density lipoprotein (LDL) has been previously demonstrated but no studies have been performed to assess the immune complex deposition in the kidney of rabbits immunized with glycated LDL. In this study, LDL was glycated with D-ribose, and it was further used as an immunogen for immunizing NZW female rabbits. The results showed that female rabbits immunized with D-ribose modified LDL induced antibodies as detected by direct binding and competitive ELISA. The modified LDL was found to be highly immunogenic eliciting high titer immunogen-specific antibodies, while the native forms were moderately immunogenic. The induced antibodies from modified LDL exhibited wide range of heterogeneity in recognizing various proteins and amino acids conformers. Furthermore, our histopathological results illustrated the deposits of immune complex in glomerular basement membrane in rabbits immunized with D-ribose-LDL. © 2014 Akhter et al.


Tyagi E.,Central Drug Research Institute CDRI | Agrawal R.,Central Drug Research Institute CDRI | Nath C.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI
Innate Immunity | Year: 2010

This study investigated the influence of the cholinergic system on neuro-inflammation using nicotinic and muscarinic receptor agonists and antagonists. Intracerebroventricular (ICV) injection of lipopolysaccharide (LPS, 50 μg) was used to induce neuro-inflammation in rats and estimations of pro-inflammatory cytokines, α7 nicotinic acetylcholine receptor (nAChR) mRNA expression were done in striatum, cerebral cortex, hippocampus and hypothalamus at 24 h after LPS injection. Nicotine (0.2, 0.4 and 0.8 mg/kg, i.p.) or oxotremorine (0.2, 0.4 and 0.8 mg/kg, i.p.) were administered 2 h prior to sacrifice. We found that only nicotine was able to block the proinflammatory cytokines induced by LPS whereas, oxotremorine was found ineffective. Methyllycaconitine (MLA; 1.25, 2.5 and 5 mg/kg, i.p.), an α7 nAChR antagonist or dihydro-2-erythroidine (DH2E; 1.25, 2.5 and 5 mg/kg, i.p.), an α422 nAChR antagonist, was given 20 min prior to nicotine in LPS-treated rats. Methyllycaconitine antagonized the anti-inflammatory effect of nicotine whereas DH2E showed no effect demonstrating that α7 nAChR is responsible for attenuation of LPS-induced pro-inflammatory cytokines. This study suggests that the inhibitory role of the central cholinergic system on neuro-inflammation is mediated via α7 nicotinic acetylcholine receptor and muscarinic receptors are not involved. © 2010 SAGE Publications.


Kumar A.,Central Drug Research Institute CDRI | Gupta L.P.,Central Drug Research Institute CDRI | Kumar M.,Central Drug Research Institute CDRI
RSC Advances | Year: 2013

An efficient route for the synthesis of diaryl-pyridinium-azaarene- butenolate zwitterionic derivatives via metal-free, iodine-mediated C(sp 3)-H bond activation of alkyl-azaarenes on addition to the α,β-unsaturated carbonyls has been reported. This journal is © The Royal Society of Chemistry 2013.

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