Singh S

References (103)

Title : Neuroprotective effects of Embelin in an ethidium bromide-induced multiple sclerosis in rats: Modulation of p38 MAPK signaling pathway - Anika_2024_Int.Immunopharmacol_129_111639
Author(s) : Anika , Singh S , Rimpi
Ref : Int Immunopharmacol , 129 :111639 , 2024
Abstract : BACKGROUND: Multiple sclerosis (MS) is a debilitating inflammatory disease characterized by demyelination, varied remyelination conservation, and partial axonal retention in central nervous system (CNS) lesions. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of MS. Embelin (EMB), derived from the Embelia ribes plant, possesses diverse biological activities, including anti-inflammatory properties. OBJECTIVE: This study aimed to investigate the neuroprotective effects of EMB in an ethidium bromide (EB)-induced model of MS in Wistar rats. METHODS: Wistar rats were randomly divided into five groups (n = 8). MS-like manifestations were induced by injecting EB (0.1 %/10 microl) into the intracerebropeduncle (ICP) region of the rat brain for seven consecutive days. EMB was administered at doses of 1.25, 2.5, and 5 mg/kg. Behavioral assessments, neuroinflammatory cytokine analysis like tumor necrosis factor-alpha, interleukin-1-beta, interleukin-6 (TNF-alpha, IL-1beta, IL-6), oxidative stress marker measurements malondialdehyde, reduced glutathione, superoxide dismutase (MDA, GSH, SOD), and nitrite (NO), Acetylcholinesterase enzyme (AchE), and neurotransmitter level analysis, dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) were conducted. RESULTS: The study assessed behavioral, neurochemical, biochemical, and neuroinflammatory parameters, along with the modulation of p38 MAPK signaling. EMB administration significantly ameliorated neurological consequences induced by EB, improving motor coordination and gait abnormalities in rats. Furthermore, EMB effectively reduced neuroinflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and oxidative stress markers (AchE, SOD, MDA, GSH, nitrite). Notably, EMB exhibited a modulatory effect on neurotransmitter levels, increasing GABA, DA, and 5-HT, while reducing glutamate in EB-treated groups. CONCLUSION: This study demonstrates the neuroprotective potential of EMB against the EB-induced model of MS in rats. EMB administration mitigated neurological impairments, attenuated neuroinflammation, alleviated oxidative stress, and restored neurotransmitter balance. These findings highlight the promise of EMB as a therapeutic candidate for MS treatment, providing insights into its potential mechanism of action involving the modulation of p38 MAPK signaling.
ESTHER : Anika_2024_Int.Immunopharmacol_129_111639
PubMedSearch : Anika_2024_Int.Immunopharmacol_129_111639
PubMedID: 38335654

Title : Protective effects of Embelin in Benzo[alpha]pyrene induced cognitive and memory impairment in experimental model of mice - Goal_2024_Curr.Res.Neurobiol_6_100122
Author(s) : Goal A , Raj K , Singh S , Arora R
Ref : Curr Res Neurobiol , 6 :100122 , 2024
Abstract : Alzheimer's disease (AD) is a neurodegenerative disease that affects the neurons in the hippocampus, resulting in cognitive and memory impairment. The most prominent clinical characteristics of AD are the production of amyloid-beta (Abeta) plaques, neurofibrillary tangles, and neuroinflammation in neurons. It has been proven that embelin (Emb) possesses antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, we assessed the therapeutic potential of Emb in Benzo [alpha]pyrene (BaP)-induced cognitive impairment in experimental mice. BaP (5 mg/kg, i. p) was given to mice daily for 28 days, and Emb (2.5, 5, and 10 mg/kg, i. p) was given from 14 to 28 days of a protocol. In addition, locomotor activity was evaluated using open-field and spatial working, and non-spatial memory was evaluated using novel object recognition tasks (NORT), Morris water maze (MWM), and Y- maze. At the end of the study, the animal tissue homogenate was used to check biochemicals, neuroinflammation, and neurotransmitter changes. BaP-treated mice showed a significant decline in locomotor activity, learning and memory deficits and augmented oxidative stress (lipid peroxidation, nitrite, and GSH). Further, BaP promoted the release of inflammatory tissue markers, decreased acetylcholine, dopamine, GABA, serotonin, and norepinephrine, and increased glutamate concentration. However, treatment with Emb at dose-dependently prevented biochemical changes, improved antioxidant levels, reduced neuroinflammation, restored neurotransmitter concentration, and inhibited the NF-kappaB pathway. The current study's finding suggested that Emb improved cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms and inhibition of acetylcholinesterase (AChE) enzyme activities and Abeta-42 accumulation.
ESTHER : Goal_2024_Curr.Res.Neurobiol_6_100122
PubMedSearch : Goal_2024_Curr.Res.Neurobiol_6_100122
PubMedID: 38616958

Title : Types of memory, dementia, Alzheimer's disease, and their various pathological cascades as targets for potential pharmacological drugs - Akhtar_2024_Ageing.Res.Rev_96_102289
Author(s) : Akhtar A , Singh S , Kaushik R , Awasthi R , Behl T
Ref : Ageing Res Rev , 96 :102289 , 2024
Abstract : Alzheimer's disease (AD) is the most common type of dementia accounting for 90% of cases; however, frontotemporal dementia, vascular dementia, etc. prevails only in a minority of populations. The term dementia is defined as loss of memory which further takes several other categories of memories like working memory, spatial memory, fear memory, and long-term, and short-term memory into consideration. In this review, these memories have critically been elaborated based on context, duration, events, appearance, intensity, etc. The most important part and purpose of the review is the various pathological cascades as well as molecular levels of targets of AD, which have extracellular amyloid plaques and intracellular hyperphosphorylated tau protein as major disease hallmarks. There is another phenomenon that either leads to or arises from the above-mentioned hallmarks, such as oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic dysfunction, and insulin resistance. Several potential drugs like antioxidants, anti-inflammatory drugs, acetylcholinesterase inhibitors, insulin mimetics or sensitizers, etc. studied in various previous preclinical or clinical reports were put as having the capacity to act on these pathological targets. Additionally, agents directly or indirectly targeting amyloid and tau were also discussed. This could be further investigated in future research.
ESTHER : Akhtar_2024_Ageing.Res.Rev_96_102289
PubMedSearch : Akhtar_2024_Ageing.Res.Rev_96_102289
PubMedID: 38582379

Title : P2X(7) receptor-dependent increase in endocannabinoid 2-arachidonoyl glycerol production by neuronal cells in culture: Dynamics and mechanism - Singh_2024_Br.J.Pharmacol__
Author(s) : Singh S , Sarroza D , English A , Whittington D , Dong A , Malamas M , Makriyannis A , van der Stelt M , Li Y , Zweifel L , Bruchas MR , Land BB , Stella N
Ref : British Journal of Pharmacology , : , 2024
Abstract : BACKGROUND AND PURPOSE: Neurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2-arachidonoyl glycerol (2-AG). While it is known that extracellular ATP stimulates 2-AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real-time changes in eCB levels with the genetically encoded sensor, GRAB(eCB2.0), can address this shortfall. EXPERIMENTAL APPROACH: 2-AG and arachidonoylethanolamide (AEA) levels in Neuro2a (N2a) cells were measured by LC-MS, and GRAB(eCB2.0) fluorescence changes were detected using live-cell confocal microscopy and a 96-well fluorescence plate reader. KEY RESULTS: 2-AG and AEA increased GRAB(eCB2.0) fluorescence in N2a cells with EC(50) values of 81 and 58 nM, respectively; both responses were reduced by the cannabinoid receptor type 1 (CB(1)R) antagonist SR141617 and absent in cells expressing the mutant-GRAB(eCB2.0). ATP increased only 2-AG levels in N2a cells, as measured by LC-MS, and induced a transient increase in the GRAB(eCB2.0) signal within minutes primarily via activation of P2X(7) receptors (P2X(7)R). This response was dependent on diacylglycerol lipase beta activity, partially dependent on extracellular calcium and phospholipase C activity, but not controlled by the 2-AG hydrolysing enzyme, alpha/beta-hydrolase domain containing 6 (ABHD6). CONCLUSIONS AND IMPLICATIONS: Considering that P2X(7)R activation increases 2-AG levels within minutes, our results show how these molecular components are mechanistically linked. The specific molecular components in these signalling systems represent potential therapeutic targets for the treatment of neurological diseases, such as chronic pain, that involve dysregulated neurotransmission and neuroinflammation.
ESTHER : Singh_2024_Br.J.Pharmacol__
PubMedSearch : Singh_2024_Br.J.Pharmacol__
PubMedID: 38581262

Title : Neuroinflammation and Acetylcholinesterase Inhibitory Potentials of a Spiroketal-Enol Ether Polyyne Isolated from Artemisia pallens Wall. ex DC - Singh_2024_Chem.Biodivers__e202301762
Author(s) : Singh S , Bhatt D , Singh MK , Bisht S , Sundaresan V , Padalia RC , Bawankule DU , Verma RS
Ref : Chem Biodivers , :e202301762 , 2024
Abstract : Artemisia pallens Wall. ex DC (Asteraceae) is cultivated for the production of high-value essential oil from its aerial biomass. In this study, the chemical composition of the root (crop-residue) essential oil was investigated for the first time, using column-chromatography, GC-FID, GC-MS, LC-QTOF, and NMR techniques, which led to the identification of twenty constituents, with isolation of (E)-2-(2',4'-hexadiynylidene)-1,6-dioxaspiro [4.5]dec-3-ene (D6). The D6 was evaluated in vitro for neuroinflammation and acetylcholinesterase inhibitory potential. It showed inhibition of neuroinflammation in a concentration-dependent manner with significant inhibition of pro-inflammatory cytokines (TNF-alpha and IL-6) in LPS-stimulated BV2 microglial cells. D6 did not have any significant effect on the viability of the cells at the therapeutic concentrations. D6 also has shown acetylcholinesterase inhibitory potential (51.90+/-1.19%) at the concentration of log 106 nM. The results showed that D6 has a potential role in the resolution of neuroinflammation, and its acetylcholinesterase inhibitory potential directs further investigation of its role in the management of Alzheimer's disease-related pathogenesis.
ESTHER : Singh_2024_Chem.Biodivers__e202301762
PubMedSearch : Singh_2024_Chem.Biodivers__e202301762
PubMedID: 38263615

Title : Pirh2 modulates the mitochondrial function and cytochrome c-mediated neuronal death during Alzheimer's disease - Singh_2024_Cell.Death.Dis_15_331
Author(s) : Singh A , Tiwari S , Singh S
Ref : Cell Death Dis , 15 :331 , 2024
Abstract : Pirh2 is an E3 ubiquitin ligase known to regulate the DNA damage responses through ubiquitylation of various participating signaling factors. DNA damage is a key pathological contributor to Alzheimer's disease (AD), therefore, the role of Pirh2 was investigated in streptozotocin and oligomer Abeta(1-42) induced rodent experimental model of AD. Pirh2 protein abundance increased during AD conditions, and transient silencing of Pirh2 inhibited the disease-specific pathological markers like level of p-Tau, betaamyloid, acetylcholinesterase activity, and neuronal death. Biochemically, Pirh2 silencing significantly attenuated the oxidative stress, depleted mitochondrial membrane potential, cytochrome c translocation from mitochondria to cytosol, and depleted mitochondrial complex-I activity, and ATP level. Pirh2 silencing also inhibited the altered level of VDAC1, hsp75, hexokinase1, t-Bid, caspase-9, and altered level of apoptotic proteins (Bcl-2, Bax). MALDI-TOF/TOF, co-immunoprecipitation, and UbcH13-linked ubiquitylation assay confirmed the interaction of Pirh2 with cytochrome c and the role of Pirh2 in ubiquitylation of cytochrome c, along with Pirh2-dependent altered proteasome activity. Additionally, Pirh2 silencing further inhibited the translocation of mitochondrion-specific endonuclease G and apoptosis-inducing factors to the nucleus and DNA damage. In conclusion, findings suggested the significant implication of Pirh2 in disease pathogenesis, particularly through impaired mitochondrial function, including biochemical alterations, translocation of cytochrome c, endonuclease G and apoptosis-inducing factor, DNA damage, and neuronal apoptosis.
ESTHER : Singh_2024_Cell.Death.Dis_15_331
PubMedSearch : Singh_2024_Cell.Death.Dis_15_331
PubMedID: 38740775

Title : Sunset Yellow induced biochemical and histopathological alterations in rat brain sub-regions - Bhatt_2024_Acta.Histochem_126_152155
Author(s) : Bhatt D , Vyas K , Singh S , John PJ , Soni IP
Ref : Acta Histochemica , 126 :152155 , 2024
Abstract : Sunset Yellow, a synthetic orange azo food dye was examined in this study for its impact on the Wistar rat brain sub-regions. The dye was administered orally to weanling rats at the Acceptable Daily Intake level (4 mg/kg/bw) for 40 days, and brain sub-regions viz., frontal cortex, cerebellum and hippocampus were examined for biochemical and histopathological changes. The results showed a significant decrease in tissue protein levels, superoxide dismutase, and catalase activity, as well as a significant increase in lipid peroxide levels in all brain sub-regions. Glutathione-S-transferase and Glutathione Reductase activities decreased, while Glutathione peroxidase activity increased. The biogenic amine levels and Acetylcholinesterase activity were also altered, with the frontal cortex and hippocampus being the most affected. Additionally, the dye caused histopathological damage in all brain sub-regions examined. This study indicates that the ADI level of Sunset Yellow may adversely affect brain tissue by causing oxidative damage.
ESTHER : Bhatt_2024_Acta.Histochem_126_152155
PubMedSearch : Bhatt_2024_Acta.Histochem_126_152155
PubMedID: 38489857

Title : Alpha-Lipoic acid alleviates imidacloprid-induced neuro-behavioral deficits in rats via Nrf2\/HO-1 pathway - Nema_2023_Toxicol.Mech.Methods__1
Author(s) : Nema M , Dutta BJ , Singh S
Ref : Toxicol Mech Methods , :1 , 2023
Abstract : Imidacloprid (IMI), a widely used pesticide in agriculture and a potential food contaminant, poses significant health concerns. This study sought to comprehensively evaluate its neurotoxic effects while investigating the potential protective role of alpha-lipoic acid (ALA), a naturally occurring dietary antioxidant renowned for its capacity to combat oxidative stress, support cardiovascular health, and maintain optimal nerve function. In this study, 28 rats were divided evenly into four groups and administered oral treatments of corn oil, IMI, IMI + ALA, and ALA, respectively. The results of the study indicated that rats exposed to IMI exhibited significant neurobehavioral impairments, decreased levels of antioxidant enzymes and acetylcholinesterase activity, reduced expression of HO-1 and Nrf2, and increased levels of pro-inflammatory cytokines like IL-6 and TNF-alpha in their hippocampal tissues. Furthermore, histopathological analysis of the brain tissues, specifically cortex and hippocampus, from the IMI-treated group revealed varying degrees of neuronal degeneration. In contrast, rats co-administered ALA alongside IMI showed noticeable improvements in all the assessed toxicological parameters. This study underscores the vital significance of ALA as a potential therapeutic adjunct in mitigating the adverse neurobehavioral consequences of insecticide exposure. By harnessing the Nrf2/HO-1 pathway, ALA demonstrates its ability to shield against IMI-induced neurotoxicity, offering a promising avenue for enhancing public health and safety. As a result, our findings advocate for the incorporation of ALA as a daily dietary supplement to fortify resilience against oxidative stress-related neurobehavioral deficits linked to pesticide exposure, thereby advancing our understanding of neuroprotection strategies in the face of environmental challenges.
ESTHER : Nema_2023_Toxicol.Mech.Methods__1
PubMedSearch : Nema_2023_Toxicol.Mech.Methods__1
PubMedID: 37904548

Title : Cellular Distribution of Secreted Phospholipase A2 in Lungs of IPF Patients and Its Inhibition in Bleomycin-Induced Pulmonary Fibrosis in Mice - Jaiswal_2023_Cells_12_
Author(s) : Jaiswal A , Rehman R , Dutta J , Singh S , Ray A , Shridhar M , Jaisankar J , Bhatt M , Khandelwal D , Sahoo B , Ram A , Mabalirajan U
Ref : Cells , 12 : , 2023
Abstract : Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, there is a need to understand the novel pathophysiology. Phospholipase A2 (PLA2) could be the ideal candidate to study in IPF, as they have a role in both inflammation and fibrosis. In the present study, we have shown the expression profile of various secretory Phospholipase A2 (PLA2) isoforms by analyzing publicly available transcriptome data of single cells from the lungs of healthy individuals and IPF patients. Among 11 members of sPLA2, PLA2G2A is found to be increased in the fibroblasts and mesothelial cells while PLA2G5 is found to be increased in the fibroblasts of IPF patients. We identified a subset of fibroblasts expressing high PLA2G2A with moderate expression of PLA2G5 and which are specific to IPF only; we named it as PLA2G2A+ IPF fibroblast. Pathway analysis revealed that these PLA2G2A+ IPF fibroblast have upregulation of both inflammatory and fibrosis-related pathways like the TGF-beta signaling pathway, IL-17 signaling, the arachidonic acid metabolism pathway and ECM-receptor interaction. In addition to this, we found elevated levels of sPLA2-IIA in plasma samples of IPF patients in our cohort. PLA2G3, PLA2G10 and PLA2G12B are found in to be increased in certain epithelial cells of IPF patients. Thus, these findings indicate that these five isoforms have a disease-dominant role along with innate immune roles as these isoforms are found predominantly in structural cells of IPF patients. Further, we have targeted sPLA2 in mice model of bleomycin-induced lung fibrosis by pBPB, a known sPLA2 inhibitor. pBPB treatment attenuated lung fibrosis induced by bleomycin along with a reduction in TGF-beta and deposition of extracellular matrix in lung. Thus, these findings indicate that these sPLA2 isoforms especially PLA2G2A may serve as a therapeutic target in lung fibrosis.
ESTHER : Jaiswal_2023_Cells_12_
PubMedSearch : Jaiswal_2023_Cells_12_
PubMedID: 37048117

Title : ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache - Liktor-Busa_2023_Front.Pain.Res.(Lausanne)_4_1171188
Author(s) : Liktor-Busa E , Levine AA , Palomino SM , Singh S , Wahl J , Vanderah TW , Stella N , Largent-Milnes TM
Ref : Front Pain Res (Lausanne) , 4 :1171188 , 2023
Abstract : INTRODUCTION: The high prevalence and severe symptoms of migraines in humans emphasizes the need to identify underlying mechanisms that can be targeted for therapeutic benefit. Clinical Endocannabinoid Deficiency (CED) posits that reduced endocannabinoid tone may contribute to migraine development and other neuropathic pain conditions. While strategies that increase levels of the endocannabinoid n-arachidonoylethanolamide have been tested, few studies have investigated targeting the levels of the more abundant endocannabinoid, 2-arachidonoylgycerol, as an effective migraine intervention. METHODS: Cortical spreading depression was induced in female Sprague Dawley rats via KCl (potassium chloride) administration, followed by measures of endocannabinoid levels, enzyme activity, and neuroinflammatory markers. Efficacy of inhibiting 2-arachidonoylglycerol hydrolysis to mitigate periorbital allodynia was then tested using reversal and prevention paradigms. RESULTS: We discovered reduced 2-arachidonoylglycerol levels in the periaqueductal grey associated with increased hydrolysis following headache induction. Pharmacological inhibition of the 2-arachidonoylglycerol hydrolyzing enzymes, alpha/beta-hydrolase domain-containing 6 and monoacylglycerol lipase reversed and prevented induced periorbital allodynia in a cannabinoid receptor-dependent manner. DISCUSSION: Our study unravels a mechanistic link between 2-arachidonoylglycerol hydrolysis activity in the periaqueductal grey in a preclinical, rat model of migraine. Thus, 2-arachidonoylglycerol hydrolysis inhibitors represent a potential new therapeutic avenue for the treatment of headache.
ESTHER : Liktor-Busa_2023_Front.Pain.Res.(Lausanne)_4_1171188
PubMedSearch : Liktor-Busa_2023_Front.Pain.Res.(Lausanne)_4_1171188
PubMedID: 37287623
Gene_locus related to this paper: human-ABHD6 , human-MGLL

Title : Insights into molecular mechanism of plasticizer biodegradation in Dietzia kunjamensis IITR165 and Brucella intermedia IITR166 isolated from a solid waste dumpsite - Singh_2023_J.Appl.Microbiol__
Author(s) : Singh S , Thakur RS , Manickam N
Ref : J Appl Microbiol , : , 2023
Abstract : AIMS: Isolation of phthalate esters (PAEs) degrading bacteria from a solid waste dumpsite could degrade many plasticizers efficiently and to investigate their degrading kinetics, pathways, and genes. METHODS AND RESULTS: Based on their 16S rRNA gene sequence the strains were identified as Dietzia kunjamensis IITR165 and Brucella intermedia IITR166, which showed a first-order degradation kinetic model under lab conditions. The quantification of phthalates and their intermediate metabolites identification were done by using UHPLC and GC-MS/MS respectively. Both the bacteria utilized > 99% dibutyl phthalate at a high concentration of 100-400 mg L-1 within 192 hrs as monitored by UHPLC. GC-MS/MS revealed the presence of metabolites dimethyl phthalate (DMP), phthalic acid (PA), and benzoic acid (BA) during DBP degradation by IITR165 while monobutyl phthalate (MBP) and PA were identified in IITR166. Phthalate esters degrading gene cluster in IITR165 comprised two novel genes coding for carboxylesterase (dkca1) and mono-alkyl phthalate hydrolase (maph), having only 37.47% and 47.74% homology respectively with reported phthalate degradation genes, along with terephthalate dioxygenase system (tphA1, A2, A3, and B). However, IITR166 harboured different gene clusters comprising di-alkyl phthalate hydrolase (dph_bi), and phthalate dioxygenase (ophA, B, and C) genes. CONCLUSIONS: Two novel bacterial strains, Dietzia kunjamensis IITR165 and Brucella intermedia IITR166, were isolated and found to efficiently degrade DBP, at high concentrations. The degradation followed first-order kinetics, and both strains exhibited a removal efficiency of over 99%. Metabolite analysis revealed that both bacteria utilized de-methylation, de-esterification, and decarboxylation steps during degradation.
ESTHER : Singh_2023_J.Appl.Microbiol__
PubMedSearch : Singh_2023_J.Appl.Microbiol__
PubMedID: 37838476

Title : The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice - Mudgal_2023_Front.Neurol_14_1130575
Author(s) : Mudgal R , Sharma S , Singh S , Ravichandiran V
Ref : Front Neurol , 14 :1130575 , 2023
Abstract : Imidacloprid (IMI) is not only a neurotoxic agricultural pesticide but also a possible food contaminant. The aims of this study were to (1) explore the relationship between recurrent IMI administration and neuronal toxicity in mice and (2) evaluate the potential neuroprotective effect of ascorbic acid (AA), a substance with significant free radical scavenger and having property to block the inflammatory pathways. Mice were categorized as naive controls (administered vehicles for 28 days); the IMI-treatment animal group (administered po 45-mg/kg body weight of IMI per day for 28 days); and the IMI + AA treatment animal group (administered the same IMI dose + 200 mg/kg of AA orally for 28 days). On day 28, memory losses were assessed using the Y-maze and novel target identification behavioral tests. Mice were sacrificed 24 h after the final IMI treatments, as well as hippocampus tissues, were utilized to determine histological assessments, oxidative stress biomarkers, and Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression levels. The findings demonstrated that IMI-treated mice had substantial impairment of spatial and non-spatial memory functions, as well as reduced antioxidant enzyme and acetylcholinesterase activity. The AA neuroprotective action was achieved through the suppression of the HO-1 expression as well as the stimulation of Nrf2 expression in hippocampal tissues. In summary, recurrent IMI exposure causes oxidative stress and neurotoxicity in mice, and the administration of AA significantly reduces the IMI toxicity possibly by the activation of the HO-1/Nrf2 pathway.
ESTHER : Mudgal_2023_Front.Neurol_14_1130575
PubMedSearch : Mudgal_2023_Front.Neurol_14_1130575
PubMedID: 37153653

Title : EphH, a unique epoxide hydrolase encoded by Rv3338 is involved in the survival of Mycobacterium tuberculosis under in vitro stress and vacuolar pH-induced changes - Garg_2023_Front.Microbiol_13_1092131
Author(s) : Garg T , Das S , Singh S , Imran M , Mukhopadhyay A , Gupta UD , Chopra S , Dasgupta A
Ref : Front Microbiol , 13 :1092131 , 2023
Abstract : INTRODUCTION: Mycobacterium tuberculosis (Mtb), one of the deadliest human pathogen, has evolved with different strategies of survival inside the host, leading to a chronic state of infection. Phagosomally residing Mtb encounters a variety of stresses, including increasing acidic pH. To better understand the host-pathogen interaction, it is imperative to identify the role of various genes involved in the survivability of Mtb during acidic pH environment. METHODS: Bio-informatic and enzymatic analysis were used to identify Mtb gene, Rv3338, as epoxide hydrolase. Subsequently, CRISPRi knockdown strategy was used to decipher its role for Mtb survival during acidic stress, nutrient starvation and inside macrophages. Confocal microscopy was used to analyse its role in subverting phagosomal acidification within macrophage. RESULTS: The present work describes the characterization of Rv3338 which was previously known to be associated with the aprABC locus induced while encountering acidic stress within the macrophage. Bio-informatic analysis demonstrated its similarity to epoxide hydrolase, which was confirmed by enzymatic assays, thus, renamed EphH. Subsequently, we have deciphered its indispensable role for Mtb in protection from acidic stress by using the CRISPRi knockdown strategy. Our data demonstrated the pH dependent role of EphH for the survival of Mtb during nutrient starvation and in conferring resistance against elevated endogenous ROS levels during stress environment. CONCLUSION: To the best of our knowledge, this is the first report of an EH of Mtb as a crucial protein for bacterial fitness inside the host, a phenomenon central to its pathogenesis.
ESTHER : Garg_2023_Front.Microbiol_13_1092131
PubMedSearch : Garg_2023_Front.Microbiol_13_1092131
PubMedID: 36777032
Gene_locus related to this paper: myctu-MT3441

Title : Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment - Gupta_2023_RSC.Adv_13_26344
Author(s) : Gupta SM , Behera A , Jain NK , Tripathi A , Rishipathak D , Singh S , Ahemad N , Erol M , Kumar D
Ref : RSC Adv , 13 :26344 , 2023
Abstract : Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Abeta) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Abeta and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC(50): 4.16 +/- 0.063 microM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Abeta aggregation at 0.5, 10 and 20 microM doses. Approximately, 50% of AChE-induced Abeta aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.
ESTHER : Gupta_2023_RSC.Adv_13_26344
PubMedSearch : Gupta_2023_RSC.Adv_13_26344
PubMedID: 37671344

Title : Intranasally Co-administered Berberine and Curcumin Loaded in Transfersomal Vesicles Improved Inhibition of Amyloid Formation and BACE-1 - Mishra_2022_ACS.Omega_7_43290
Author(s) : Mishra G , Awasthi R , Singh AK , Singh S , Mishra SK , Singh SK , Nandi MK
Ref : ACS Omega , 7 :43290 , 2022
Abstract : Selective permeability of the blood-brain barrier restricts the treatment efficacy of neurologic diseases. Berberine (BBR) and curcumin (CUR)-loaded transferosomes (TRANS) were prepared for the effective management of Alzheimer's disease (AD). The study involved the syntheses of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS by the film hydration method. Vesicles were characterized to ensure the formation of drug-loaded vesicles and their in vivo performance. The particle sizes of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS were 139.2 +/- 7, 143.4 +/- 8, and 165.3 +/- 6.5 nm, respectively. The presence of diffused rings in the SED image indicates the crystalline nature of the payload. Low surface roughness in an AFM image could be associated with the presence of a surface lipid. BBR-CUR-TRANS showed 41.03 +/- 1.22 and 47.79 +/- 3.67% release of BBR and 19.22 +/- 1.47 and 24.67 +/- 1.94% release of CUR, respectively, in phosphate buffer saline (pH 7.4) and acetate buffer (pH 4.0). Formulations showed sustained release of both loaded drugs. BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS exhibited a lower percentage of hemolysis than pure BBR and CUR, indicating the safety of the payload from delivery vesicles. Lower percentages of binding were recorded from BBR-CUR-TRANS than BBR-TRANS and CUR-TRANS. Acetylcholinesterase inhibition activity of the prepared transferosomes was greater than that of pure drugs, which are thought to have good cellular penetration. The spatial memory was improved in treated mice models. The level of malondialdehyde decreased in AD animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS, respectively, as compared to the scopolamine-induced AD animals. BBR-CUR-TRANS-treated animals showed the highest decrease in the NO level. The catalase level was significantly restored in scopolamine-intoxicated animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS. The immunohistochemistry result suggested that the BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS have significantly decreased the regulation of expression of BACE-1 through antioxidant activity. In conclusion, the study highlights the utility of formulated transferosomes as promising carriers for the co-delivery of drugs to the brain.
ESTHER : Mishra_2022_ACS.Omega_7_43290
PubMedSearch : Mishra_2022_ACS.Omega_7_43290
PubMedID: 36467923

Title : Design, Synthesis, and Pharmacological Evaluation of N-Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease - Kumar_2022_ACS.Chem.Neurosci__
Author(s) : Kumar B , Dwivedi AR , Arora T , Raj K , Prashar V , Kumar V , Singh S , Prakash J
Ref : ACS Chem Neurosci , : , 2022
Abstract : Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC(50) value of 0.04 +/- 0.002 microM. VP15 with an IC(50) value of 0.04 +/- 0.003 microM and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15.HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.
ESTHER : Kumar_2022_ACS.Chem.Neurosci__
PubMedSearch : Kumar_2022_ACS.Chem.Neurosci__
PubMedID: 35797244

Title : AChE as a Spark in the Alzheimer's Blaze - Antagonizing Effect of a Cyclized Variant - Behl_2022_Ageing.Res.Rev__101787
Author(s) : Behl T , Kaur I , Sehgal A , Singh S , Sharma N , Gupta S , Albratty M , Najmi A , Alhazmi HA , Bungau S
Ref : Ageing Res Rev , :101787 , 2022
Abstract : The amyloid precursor protein (APP), presenilin 1 (PS1), amyloid beta (A), and GSK3 are the effectors, which are significantly associated with progression of Alzheimer's Disease (AD) and its symptoms. A significant protein, acetylcholinesterase (AChE) becomes dysfunctional as a result of cholinergic neuronal loss in AD pathology. However, certain associated peptides potentiate the release of primary neuropathological hallmarks, i.e., senile plaque and neurofibrillary tangles (NFTs), by modulating the alpha 7 acetylcholinesterase receptor (7nAChR). The AChE variants, T30 and T14 have also been found to be elevated in AD patients and mimic the toxic actions of pathological events in patients. The manuscript discusses the significance of AChE inhibitors in AD therapeutics, by indicating the disastrous role of molecular alterations and elevation of AChE, accompanied with the downstream effects instigated by the peptide, supported by clinical evidence and investigations. The cyclized variant of AChE peptide, NBP14 has been identified as a novel candidate that reverses the harmful effects of T30, T14 and A, mainly calcium influx, cell viability and AChE release. The review aims to grab the attention of neuro-researchers towards the significance of triggering effectors in propagating AD and role of AChE in regulating them, which can potentially ace the development of reliable therapeutic candidates, similar to NBP14, to mitigate neurodegeneration.
ESTHER : Behl_2022_Ageing.Res.Rev__101787
PubMedSearch : Behl_2022_Ageing.Res.Rev__101787
PubMedID: 36368649

Title : Guanabenz mitigates the neuropathological alterations and cell death in Alzheimer's disease - Singh_2022_Cell.Tissue.Res__
Author(s) : Singh A , Gupta P , Tiwari S , Mishra A , Singh S
Ref : Cell Tissue Research , : , 2022
Abstract : Alzheimer's disease (AD) pathology is characterized by cognitive impairment, increased acetylcholinesterase (AChE) activity, and impaired neuronal communication. Clinically, AChE inhibitors are being used to treat AD patients; however, these remain unable to prevent the disease progression. Therefore, further development of new therapeutic molecules is required having broad spectrum effects on AD-related various neurodegenerative events. Since repurposing is a quick mode to search the therapeutic molecules; henceforth, this study was conducted to evaluate the anti-Alzheimer activity of drug guanabenz which is already in use for the management of high blood pressure in clinics. The study was performed employing both cellular and rat models of AD along with donepezil as reference drug. Guanabenz treatment in both the experimental models showed significant protection against AD-specific behavioral and pathological indicators like AChE activity, tau phosphorylation, amyloid precursor protein, and memory retention. In conjunction, guanabenz also attenuated the AD-related oxidative stress, impaired mitochondrial functionality (MMP, cytochrome-c translocation, ATP level, and mitochondrial complex I activity), endoplasmic reticulum stress (GRP78, GADD153, cleaved caspase-12), neuronal apoptosis (Bcl-2, Bax, cleaved caspase-3), and DNA fragmentation. In conclusion, findings suggested the panoptic protective effect of guanabenz on disease-related multiple degenerative markers and signaling. Furthermore, clinical trial may shed light and expedite the availability of new therapeutic anti-Alzheimer's molecule for the wellbeing of AD patients.
ESTHER : Singh_2022_Cell.Tissue.Res__
PubMedSearch : Singh_2022_Cell.Tissue.Res__
PubMedID: 35195784

Title : Unravelling consensus genomic regions associated with quality traits in wheat using meta-analysis of quantitative trait loci - Gudi_2022_Planta_255_115
Author(s) : Gudi S , Saini DK , Singh G , Halladakeri P , Kumar P , Shamshad M , Tanin MJ , Singh S , Sharma A
Ref : Planta , 255 :115 , 2022
Abstract : Meta-analysis in wheat for three major quality traits identified 110 meta-QTL (MQTL) with reduced confidence interval (CI). Five GWAS validated MQTL (viz., 1A.1, 1B.2, 3B.4, 5B.2, and 6B.2), each involving more than 20 initial QTL and reduced CI (95%) (< 2 cM), were selected for quality breeding programmes. Functional characterization including candidate gene mining and expression analysis discovered 44 high confidence candidate genes associated with quality traits. A meta-analysis of quantitative trait loci (QTL) associated with dough rheology properties, nutritional traits, and processing quality traits was conducted in wheat. For this purpose, as many as 2458 QTL were collected from 50 interval mapping studies published during 2013-2020. Of the total QTL, 1126 QTL were projected onto the consensus map saturated with 249,603 markers which led to the identification of 110 meta-QTL (MQTL). These MQTL exhibited an 18.84-fold reduction in the average CI compared to the average CI of the initial QTL (ranging from 14.87 to 95.55 cM with an average of 40.35 cM). Of the 110, 108 MQTL were physically anchored to the wheat reference genome, including 51 MQTL verified with marker-trait associations (MTAs) reported from earlier genome-wide association studies. Candidate gene (CG) mining allowed the identification of 2533 unique gene models from the MQTL regions. In-silico expression analysis discovered 439 differentially expressed gene models with > 2 transcripts per million expressions in grains and related tissues, which also included 44 high-confidence CGs involved in the various cellular and biochemical processes related to quality traits. Nine functionally characterized wheat genes associated with grain protein content, high-molecular-weight glutenin, and starch synthase enzymes were also found to be co-localized with some of the MQTL. Synteny analysis between wheat and rice MQTL regions identified 23 wheat MQTL syntenic to 16 rice MQTL associated with quality traits. Furthermore, 64 wheat orthologues of 30 known rice genes were detected in 44 MQTL regions. Markers flanking the MQTL identified in the present study can be used for marker-assisted breeding and as fixed effects in the genomic selection models for improving the prediction accuracy during quality breeding. Wheat orthologues of rice genes and other CGs available from MQTLs can be promising targets for further functional validation and to better understand the molecular mechanism underlying the quality traits in wheat.
ESTHER : Gudi_2022_Planta_255_115
PubMedSearch : Gudi_2022_Planta_255_115
PubMedID: 35508739
Gene_locus related to this paper: wheat-a0a3b6sjs2

Title : The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation - Singh_2021_Eur.J.Neurosci__
Author(s) : Singh S , Kamat SS
Ref : European Journal of Neuroscience , : , 2021
Abstract : Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.
ESTHER : Singh_2021_Eur.J.Neurosci__
PubMedSearch : Singh_2021_Eur.J.Neurosci__
PubMedID: 34727579
Gene_locus related to this paper: human-ABHD12 , mouse-abd12

Title : Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs - Khandelwal_2021_Cell.Chem.Biol__
Author(s) : Khandelwal N , Shaikh M , Mhetre A , Singh S , Sajeevan T , Joshi A , Balaji KN , Chakrapani H , Kamat SS
Ref : Cell Chemical Biology , : , 2021
Abstract : In humans, lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.
ESTHER : Khandelwal_2021_Cell.Chem.Biol__
PubMedSearch : Khandelwal_2021_Cell.Chem.Biol__
PubMedID: 33571455
Gene_locus related to this paper: human-ABHD12

Title : ABHD6 Controls Amphetamine-Stimulated Hyperlocomotion: Involvement of CB(1) Receptors - Deng_2021_Cannabis.Cannabinoid.Res__
Author(s) : Deng L , Viray K , Singh S , Cravatt B , Stella N
Ref : Cannabis Cannabinoid Res , : , 2021
Abstract : Introduction: Activation of cannabinoid 1 receptors (CB(1)Rs) by endocannabinoids (eCBs) is controlled by both eCB production and eCB inactivation. Accordingly, inhibition of eCB hydrolyzing enzymes, monoacylglycerol lipase (MAGL) and alpha/beta-hydrolase domain containing 6 (ABHD6), enhances eCB accumulation and CB(1)R activation. It is known that inhibition of MAGL regulates select CB(1)R-dependent behaviors in mice, including locomotor behaviors and their modulation by psychostimulants, but much less is known about the effect of inhibiting ABHD6 activity on such behaviors. Methods: We report a new mouse line that carries a genetic deletion of Abhd6 and evaluated its effect on spontaneous locomotion measured in a home cage monitoring system, motor coordination measured on a Rotarod, and amphetamine-stimulated hyperlocomotion and amphetamine sensitization (AS) measured in an open-field chamber. Results: ABHD6 knockout (KO) mice reached adulthood without exhibiting overt behavioral impairment, and we measured only mild reduction in spontaneous locomotion and motor coordination in adult ABHD6 KO mice compared to wild-type (WT) mice. Significantly, amphetamine-stimulated hyperlocomotion was enhanced by twofold in ABHD6 KO mice compared to WT mice and yet ABHD6 KO mice expressed AS to the same extent as WT mice. A twofold increase in amphetamine-stimulated hyperlocomotion was also measured in ABHD6 heterozygote mice and in WT mice treated with the ABHD6 inhibitor KT-182. It is known that amphetamine-stimulated hyperlocomotion is not affected by the CB(1)R antagonist, SR141617, and we discovered that the enhanced amphetamine-stimulated hyperlocomotion resulting from ABHD6 inhibition is blocked by SR141617. Conclusions: Our study suggests that ABHD6 controls amphetamine-stimulated hyperlocomotion by a mechanistic switch to a CB(1)R-dependent mechanism.
ESTHER : Deng_2021_Cannabis.Cannabinoid.Res__
PubMedSearch : Deng_2021_Cannabis.Cannabinoid.Res__
PubMedID: 34705543
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6

Title : Bioprospecting of gut microflora for plastic biodegradation - Cf_2021_Bioengineered_12_1040
Author(s) : Cf SF , Rebello S , Mathachan Aneesh E , Sindhu R , Binod P , Singh S , Pandey A
Ref : Bioengineered , 12 :1040 , 2021
Abstract : The problem of plastic prevalence and associated pollution has grasped the entire planet drastically, putting all fields of science on the stake seeking remedies to this global havoc. To address this crisis, with a single remediation strategy is often found to be baseless, thereby much interest has been evoked in the development of multidisciplinary approaches - involving physico-chemical and biological strategies to nullify the aftermath of plastic pollution in all possible means. Even amidst, the availability of different approaches, the use of biological methods to combat plastic degradation has gained momentum. The most frequently used plastics appear in wide forms such as polyethylene plastic bags, polypropylene-based bottles, polyvinyl chloride pipes and polystyrene styrene cups. Plastic nicknamed as one of the toughest polymers viz. polycarbonate, acrylonitrile butadiene styrene (ABS) and Polydicyclopentadiene; quite often are called so as they resist degradation in normal environmental strategies. They are often degraded in non-hostile and harsh environments of pH, temperature, radiation etc. However, not always it is possible to create such harsh environments for plastic degradation. In such a scenario, the use of gut microbes that can withstand the harsh atmosphere of gut environment could serve as promising candidates for plastic biodegradation. The current article envisages the various gut microbes of various biological agents and their role in plastic remediation. The current review compiles the techniques available for plastic remediation, the microbial prospects of plastic remediation, its challenges, and possible breakthroughs to effective plastic remediation.
ESTHER : Cf_2021_Bioengineered_12_1040
PubMedSearch : Cf_2021_Bioengineered_12_1040
PubMedID: 33769197

Title : Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signaling - Gupta_2021_Biochem.J__
Author(s) : Gupta P , Tiwari S , Singh A , Pal A , Mishra A , Singh S
Ref : Biochemical Journal , : , 2021
Abstract : Rivastigmine is clinical drug for patients of Alzheimer's disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Further the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.
ESTHER : Gupta_2021_Biochem.J__
PubMedSearch : Gupta_2021_Biochem.J__
PubMedID: 33660768

Title : AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function - Skolnick_2021_J.Chem.Inf.Model__
Author(s) : Skolnick J , Gao M , Zhou H , Singh S
Ref : J Chem Inf Model , : , 2021
Abstract : AlphaFold 2 (AF2) was the star of CASP14, the last biannual structure prediction experiment. Using novel deep learning, AF2 predicted the structures of many difficult protein targets at or near experimental resolution. Here, we present our perspective of why AF2 works and show that it is a very sophisticated fold recognition algorithm that exploits the completeness of the library of single domain PDB structures. It has also learned local side chain packing rearrangements that enable it to refine proteins to high resolution. The benefits and limitations of its ability to predict the structures of many more proteins at or close to atomic detail are discussed.
ESTHER : Skolnick_2021_J.Chem.Inf.Model__
PubMedSearch : Skolnick_2021_J.Chem.Inf.Model__
PubMedID: 34586808

Title : Protective effect of andrographolide against STZ induced Alzheimer's disease in experimental rats: possible neuromodulation and Abeta((1-42)) analysis - Patel_2021_Inflammopharmacology__
Author(s) : Patel R , Kaur K , Singh S
Ref : Inflammopharmacology , : , 2021
Abstract : STZ is a glucosamine-nitrosourea compound, causes dysfunctioning of insulin receptors in the brain and disrupts glucose metabolism, produces cognitive decline and AD-like symptoms. ICV injection of STZ causes accumulation of Abeta and cognitive dysfunctions. Andrographolide (ANDRO) is a major bioactive constituent of Andrographis paniculata, has various biological activities such as antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties. The study aimed to evaluate the neuroprotective effect of ANDRO against ICV-STZ induced AD-like symptoms in rats. To conduct the study, the Wistar rat received two injections of STZ (3 mg/kg) through the ICV route. Rats were treated with three different doses of ANDRO (15, 30, and 60 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 14 days. The behavioral impairments were analyzed on weekly basis. Subsequently, rats were sacrificed for the assessment of biochemical (MDA, Nitrite, GSH, SOD, Catalase and AChE), neuroinflammatory markers (IL-1beta, IL-16, and TNF-alpha), neurotransmitters (glutamate and GABA), level of Abeta(1-42) and p tau in the hippocampus on day 21st. Our result indicated that ANDRO treatment provided a protective effect against STZ induced behavioral deficits and changes in the biochemical, neuroinflammatory mediators, and neurotransmitters of the hippocampus. Further, ANDRO also reduced the level of Abeta(1-42) and p tau in the rat hippocampus. These findings suggested that the antioxidant, anti-inflammatory, anti-cholinesterase potential of ANDRO contributed to its neuroprotective effect as well as promising therapeutic candidate for the treatment of cognitive impairment and AD-like symptoms.
ESTHER : Patel_2021_Inflammopharmacology__
PubMedSearch : Patel_2021_Inflammopharmacology__
PubMedID: 34235591

Title : Neuroprotective Effect of Fucoxanthin against Intracerebroventricular Streptozotocin (ICV-STZ) Induced Cognitive Impairment in Experimental Rats - Dhami_2021_Curr.Alzheimer.Res__
Author(s) : Dhami M , Raj K , Singh S
Ref : Curr Alzheimer Res , : , 2021
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurological disorder characterized by loss of memory and cognitive functions caused by oxidative stress, neuroinflammation, change in neuro- transmitter levels, and excessive deposition of Abeta(1-42) plaques. Fucoxanthin is a carotenoid with potential antioxidant, anti-inflammatory, and neuroprotective actions. OBJECTIVE: In the present study, fucoxanthin was employed as a protective strategy in Intracere- broventricular Streptozotocin (ICV-STZ) induced experimental model of cognitive impairment. METHODS: STZ was injected twice ICV (3 mg/kg) on alternate days 1 and 3, and Wistar rats were evaluated for the memory analysis using Morris water maze and elevated plus-maze. Fucoxanthin at low 50 mg/kg, p.o. and high dose 100 mg/kg, p.o. was administered for 14 days. All animals were sacrificed on day 29, and brain hippocampus tissue after isolation was used for biochemical (MDA, nitrite, GSH, SOD and Catalase), neuroinflammatory (TNF-alpha, IL-1beta, and IL-6), neurotrans- mitters (ACh, GABA Glutamate), Abeta(1-42) and Tau protein measurements. RESULTS: STZ-infused rats showed significant impairment in learning and memory, increased oxida- tive stress (MDA, nitrite), reduced antioxidant defense (GSH, SOD and Catalase), promoted cy- tokine release, and change in neurotransmitter levels. However, fucoxanthin improved cognitive functions, restored antioxidant levels, reduced inflammatory markers dose-dependently, and res- tored neurotransmitters concentration. CONCLUSION: The finding of the current study suggests that fucoxanthin could be the promising compound for improving cognitive functions through antioxidant, anti-inflammatory, and neuropro- tective mechanisms, and inhibition of acetylcholinesterase (AChE) enzyme activities, Abeta(1-42) accu- mulation, and tau protein.
ESTHER : Dhami_2021_Curr.Alzheimer.Res__
PubMedSearch : Dhami_2021_Curr.Alzheimer.Res__
PubMedID: 34792011

Title : Age-dependent altered redox homeostasis in the chronodisrupted rat model and moderation by melatonin administration - Verma_2020_Chronobiol.Int__1
Author(s) : Verma AK , Singh S , Rizvi SI
Ref : Chronobiol Int , :1 , 2020
Abstract : Circadian disruption or chronodisruption (CD) occurs when day-night cycles and other internal rhythms are not adjusted to environmental light-dark regimens and are unable to synchronize among each other. Artificial light-induced oxidative stress is a major concern as the circadian physiology of the cell is chronically altered due to suppression of the time-keeping hormone, melatonin. The relationship between age-related impaired redox status and disrupted circadian rhythms is still not fully understood. The present study evaluated the effect of artificial light at night (ALAN) with respect to aging and role of melatonin supplementation. This study was conducted on young (3 months) and old (24 months) male Wistar rats subdivided into four groups control (C), melatonin treated (MLT), artificial light at night (ALAN), and ALAN+MLT group. Pronounced changes were observed in the old compared to the young rats. Reactive oxygen species (ROS), malondialdehyde (MDA), plasma membrane redox system (PMRS), protein carbonyl (PCO), and sialic acid (SA) were significantly (p <= 0.05) increased, while ferric reducing ability of plasma (FRAP) and reduced glutathione (GSH) were significantly (p <= 0.05) suppressed in light-exposed young and old animals compared to their age-matched controls. Advanced oxidation protein products (AOPP) increased non-significantly in young rats of the ALAN group; however, significant (p <= 0.05) changes were observed in the old rats of the ALAN group compared to their respective controls. Advanced glycation end products (AGEs) increased and acetylcholinesterase (AChE) activity decreased, significantly (p <= 0.05) in young animals of the ALAN group, while nonsignificant changes of both parameters were recorded in the old animals of the ALAN groups compared with their age-matched controls. Melatonin supplementation resulted in maintenance of the normal redox homeostasis in both young and old animal groups. Our study suggests that aged rats are more susceptible to altered photoperiod as their circadian redox homeostasis is under stress subsequent to ALAN. Melatonin supplementation could be a promising means of alleviating age-related circadian disturbances, especially in light-polluted areas.
ESTHER : Verma_2020_Chronobiol.Int__1
PubMedSearch : Verma_2020_Chronobiol.Int__1
PubMedID: 32731777

Title : In silico strategies for probing novel DPP-IV inhibitors as anti-diabetic agents - Sharma_2020_J.Biomol.Struct.Dyn__1
Author(s) : Sharma S , Srivastav S , Singh G , Singh S , Malik R , Alam MM , Shaqiquzamman M , Ali S , Akhter M
Ref : J Biomol Struct Dyn , :1 , 2020
Abstract : Identification of new DPP-IV inhibitors by integrating validated in silico approach is being presented herein. Novel hits were identified by combining pharmacophore and structure based virtual screening of ZINC and Knowledge Base in house database followed by ADME profiling, consensus docking studies. Six potential hits were identified and analysed for their synthetic accessibility score, novelty analysis and pan assay interference compounds filtration. Out of six, three hits viz., ZINC25060187, ZINC53746227 and KB-10 were analysed for stability studies using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Molecular Dynamics (MD) simulation. The simulation studies of the identified hits revealed that these hits have good selectivity and stability in DPP-IV binding pocket. Important interactions with amino acids viz., Tyr547, Glu205 and Glu206 similar to co-crystallized ligand were also observed. One of the hits viz., KB-10 was synthesized and evaluated for its biological potential. The compound KB-10 showed good DPP-IV inhibition in both in vitro and in vivo studies with IC50: 22.69 microM. This study supports the fact that these techniques hold potential for efficient screening of compounds with unknown affinity for DPP-IV that could serve as candidates for therapeutic development.
ESTHER : Sharma_2020_J.Biomol.Struct.Dyn__1
PubMedSearch : Sharma_2020_J.Biomol.Struct.Dyn__1
PubMedID: 32248758

Title : Mapping the neuroanatomy of ABHD16A-ABHD12 & lysophosphatidylserines provides new insights into the pathophysiology of the human neurological disorder PHARC - Singh_2020_Biochemistry_59_2299
Author(s) : Singh S , Joshi A , Kamat SS
Ref : Biochemistry , 59 :2299 , 2020
Abstract : Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology. In vivo, the metabolic serine hydrolases ABHD16A and ABHD12 are major lipases that biosynthesize and degrade lyso-PS respectively. Of biomedical relevance, deleterious mutations to ABHD12 causes accumulation of lyso-PS in the brain, and this deregulated lyso-PS metabolism leads to the human genetic neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). While the roles of ABHD16A and ABHD12 in lyso-PS metabolism in the mammalian brain are well established, the anatomical and (sub)cellular localizations of both lipases, and the functional cross-talk between them towards regulating lyso-PS lipids remain under investigated. Here, using subcellular organelle fractionation, biochemical assays and immunofluorescence based high resolution microscopy, we show that the PS lipase ABHD16A is an endoplasmic reticulum (ER) localized enzyme, an organelle intricately regulating cellular PS levels. Further, leveraging immunohistochemical analysis using genetic ABHD16A and ABHD12 knockout mice as important controls, we map the anatomical distribution of both these lipases in tandem in the murine brain, and show for the first time, the distinct localization of these lipases to different regions and cells of the cerebellum. We complement the aforementioned immunohistochemical studies by quantitatively measuring lyso-PS concentrations in various brain regions using mass spectrometry, and find that the cerebellar lyso-PS levels are most affected by ABHD16A (decreased) or ABHD12 (increased) deletion. Taken together, our studies provide new insights into lyso-PS signaling in the cerebellum, the most atrophic brain region in human PHARC subjects.
ESTHER : Singh_2020_Biochemistry_59_2299
PubMedSearch : Singh_2020_Biochemistry_59_2299
PubMedID: 32462874
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A

Title : Low acetylcholine during early sleep is important for motor memory consolidation - Inayat_2020_Sleep_43_
Author(s) : Inayat S , Nazariahangarkolaee M , Singh S , McNaughton BL , Whishaw IQ , Mohajerani MH
Ref : Sleep , 43 : , 2020
Abstract : The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would weaken motor memory consolidation. We trained separate groups of adult mice on the rotarod walking task and the single pellet reaching task, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing showed that physostigmine impaired motor skill acquisition of both tasks. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. Additional experiments showed that: (1) the impaired performance associated with physostigmine was not due to its effects on sleep structure, as 1 h of sleep deprivation after training did not impair rotarod performance, (2) a reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep did not affect rotarod performance, and (3) stimulating or blocking muscarinic and nicotinic acetylcholine receptors did not impair rotarod performance. Taken together, the experiments suggest that the increased slow wave activity and inactivation of both muscarinic and nicotinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.
ESTHER : Inayat_2020_Sleep_43_
PubMedSearch : Inayat_2020_Sleep_43_
PubMedID: 31825510

Title : Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines - Castelli_2020_J.Med.Chem_63_1261
Author(s) : Castelli R , Scalvini L , Vacondio F , Lodola A , Anselmi M , Vezzosi S , Carmi C , Bassi M , Ferlenghi F , Rivara S , Moller IR , Rand KD , Daglian J , Wei D , Dotsey EY , Ahmed F , Jung KM , Stella N , Singh S , Mor M , Piomelli D
Ref : Journal of Medicinal Chemistry , 63 :1261 , 2020
Abstract : We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function, and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.
ESTHER : Castelli_2020_J.Med.Chem_63_1261
PubMedSearch : Castelli_2020_J.Med.Chem_63_1261
PubMedID: 31714779

Title : Synthesis of flavor esters by a novel lipase from Aspergillus niger in a soybean-solvent system - Cong_2019_3.Biotech_9_244
Author(s) : Cong S , Tian K , Zhang X , Lu F , Singh S , Prior B , Wang ZX
Ref : 3 Biotech , 9 :244 , 2019
Abstract : To find a lipase for synthesis of flavor esters in food processing, a total of 35 putative lipases from Aspergillus niger F0215 were heterologously expressed and their esterification properties in crude preparations were examined. One of them, named An-lipase with the highest esterification rate (23.1%) was selected for further study. The purified An-lipase had the maximal activity at 20s degreesC and pH 6.5 and the specific activity of 1293sU/mg. Sixty percent of the activity was maintained in a range of temperatures of 0-30s degreesC and pHs of 3.0-8.5. The highest hydrolysis activity of An-lipase was towards pNPC (C8), followed by pNPB (C4) and pNPA (C2), then pNPL (C12). K (m), V (max), k (cat,) and k (cat)/K (m) towards pNPC were 26.7smmol/L, 129.9smmol/(Lsh), 23.2ss(-1), and 0.8/mM/s, respectively. The ethyl lactate, butyl butyrate, and ethyl caprylate flavor esters were produced by esterification of the corresponding acids with conversion efficiencies of 15.8, 37.5, and 24.7%, respectively, in a soybean-oil-based solvent system. In conclusion, An lipase identified in this study significantly mediated synthesis of predominant flavor esters (ethyl lactate, butyl butyrate, and ethyl caprylate) in a soybean-oil-lacking other toxic organic solvents, which has potential application in food industries.
ESTHER : Cong_2019_3.Biotech_9_244
PubMedSearch : Cong_2019_3.Biotech_9_244
PubMedID: 31168437
Gene_locus related to this paper: aspnc-cuti1

Title : A chemical-genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase - Kelkar_2019_Nat.Chem.Biol_15_169
Author(s) : Kelkar DS , Ravikumar G , Mehendale N , Singh S , Joshi A , Sharma AK , Mhetre A , Rajendran A , Chakrapani H , Kamat SS
Ref : Nat Chemical Biology , 15 :169 , 2019
Abstract : Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, oxidative stress results, in which excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a proapoptotic 'eat me' signal, is produced in response to elevated ROS, yet little is known regarding its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells. We used this molecule to detect, characterize and study oxidized PS in mammalian cells. We developed a chemical-genetic screen to identify enzymes that regulate oxidized PS in mammalian cells and found that the lipase ABHD12 hydrolyzes oxidized PS. We validated these findings in different physiological settings including primary peritoneal macrophages and brains from Abhd12(-/-) mice under inflammatory stress, and in the process, we functionally annotated an enzyme regulating oxidized PS in vivo.
ESTHER : Kelkar_2019_Nat.Chem.Biol_15_169
PubMedSearch : Kelkar_2019_Nat.Chem.Biol_15_169
PubMedID: 30643283
Gene_locus related to this paper: human-ABHD12

Title : Rapamycin Confers Neuroprotection Against Aging-Induced Oxidative Stress, Mitochondrial Dysfunction, and Neurodegeneration in Old Rats Through Activation of Autophagy - Singh_2019_Rejuvenation.Res_22_60
Author(s) : Singh AK , Singh S , Tripathi VK , Bissoyi A , Garg G , Rizvi SI
Ref : Rejuvenation Res , 22 :60 , 2019
Abstract : Brain aging is an intricate and natural phenomenon exclusively characterized by oxidative stress, accumulation of oxidatively damaged macromolecules, and alterations in structure and function of neurons that further increase the risk factor for most of the neurodegenerative diseases. In addition, age-dependent defective autophagy has also been implicated to favor the pathogenesis and prevalence of the neurological diseases. Therefore, the development of strategies that delay aging and the concomitant neurological disorders remain elusive. Thus, the present study was undertaken to investigate the effect of rapamycin-induced activation of autophagy on aging-related oxidative stress, cell death, neuroinflammation, and neurodegeneration in rat brain. Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity, including the activities of ion channel transporters (Na(+)/K(+)-ATPase and Ca(2+)-ATPase) and acetylcholinesterase in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration. Thus, our data confirmed that autophagy plays a pivotal role in delaying brain aging plausibly by maintaining the cellular homeostasis, and structural and functional integrity of cells in the brain.
ESTHER : Singh_2019_Rejuvenation.Res_22_60
PubMedSearch : Singh_2019_Rejuvenation.Res_22_60
PubMedID: 29943667

Title : Identification of alpha,beta-Hydrolase Domain Containing Protein 6 as a Diacylglycerol Lipase in Neuro-2a Cells - van Esbroeck_2019_Front.Mol.Neurosci_12_286
Author(s) : van Esbroeck ACM , Kantae V , Di X , van der Wel T , den Dulk H , Stevens AF , Singh S , Bakker AT , Florea BI , Stella N , Overkleeft HS , Hankemeier T , van der Stelt M
Ref : Front Mol Neurosci , 12 :286 , 2019
Abstract : The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in neuronal differentiation. This study aimed to identify the biosynthetic enzymes responsible for 2-AG production during retinoic acid (RA)-induced neurite outgrowth of Neuro-2a cells. First, we confirmed that RA stimulation of Neuro-2a cells increases 2-AG production and neurite outgrowth. The diacylglycerol lipase (DAGL) inhibitor DH376 blocked 2-AG production and reduced neuronal differentiation. Surprisingly, CRISPR/Cas9-mediated knockdown of DAGLalpha and DAGLbeta in Neuro-2a cells did not reduce 2-AG levels, suggesting another enzyme capable of producing 2-AG in this cell line. Chemical proteomics revealed DAGLbeta and alpha,beta-hydrolase domain containing protein (ABHD6) as the only targets of DH376 in Neuro-2a cells. Biochemical, genetic and lipidomic studies demonstrated that ABHD6 possesses DAGL activity in conjunction with its previously reported monoacylglycerol lipase activity. RA treatment of Neuro-2a cells increased by three-fold the amount of active ABHD6. Our study shows that ABHD6 exhibits significant DAG lipase activity in Neuro-2a cells in addition to its known MAG lipase activity and suggest it is involved in neuronal differentiation.
ESTHER : van Esbroeck_2019_Front.Mol.Neurosci_12_286
PubMedSearch : van Esbroeck_2019_Front.Mol.Neurosci_12_286
PubMedID: 31849602
Gene_locus related to this paper: human-ABHD6

Title : Assessment of acute toxicity and biochemical responses to chlorpyrifos, cypermethrin and their combination exposed earthworm, Eudrilus eugeniae - Tiwari_2019_Toxicol.Rep_6_288
Author(s) : Tiwari RK , Singh S , Pandey RS
Ref : Toxicol Rep , 6 :288 , 2019
Abstract : Recurrent application of chemical pesticides in the agricultural fields have adverse impact on flora and fauna of soil ecosystem. Earthworms immensely contribute in increasing the fertility of soil. They may act as a bioindicator for the ecotoxicological analysis of pesticide induced soil pollution. Earthworms, Eudrilus eugeniae were exposed to different concentrations of pesticides chlorpyrifos (OP), cypermethrin (a pyrethroid) and their combination for 48 h by paper contact toxicity method. The LC50 for commercial grade of chlorpyrifos, cypermethrin and combined pesticides were determined as 0.165, 0.066 and 0.020 mug/cm(2), respectively. To assess the sub-lethal effect of these pesticides, E. eugeniae were exposed to 5% and 10% of LC50 of the pesticides for 48 h. Variation in morpho-behavioural changes such as coiling, clitellar swelling, mucus release, bleeding and body fragmentation in earthworms were observed after exposure of both pesticides and their combination. Various biochemical estimations such as specific activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione -S-transferase (GST); levels of lipid peroxidation (LPO) and reduced glutathione (GSH) were carried out in different body segments. Significant changes in these stress markers were observed at low and high sub-acute concentration of pesticides exposed earthworm, Eudrilus eugeniae. Such changes indicate potential health risk to E. eugeniae if exposed to the high concentrations of these pesticides accumulated in soil.
ESTHER : Tiwari_2019_Toxicol.Rep_6_288
PubMedSearch : Tiwari_2019_Toxicol.Rep_6_288
PubMedID: 30989054

Title : Biochemical characterization of the PHARC-associated serine hydrolase ABHD12 reveals its preference for very-long-chain lipids - Joshi_2018_J.Biol.Chem_293_16953
Author(s) : Joshi A , Shaikh M , Singh S , Rajendran A , Mhetre A , Kamat SS
Ref : Journal of Biological Chemistry , 293 :16953 , 2018
Abstract : Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare genetic human neurological disorder caused by null mutations to the Abhd12 gene, which encodes the integral membrane serine hydrolase enzyme ABHD12. Although the role that ABHD12 plays in PHARC is understood, the thorough biochemical characterization of ABHD12 is lacking. Here, we report the facile synthesis of mono-1-(fatty)acyl-glycerol lipids of varying chain lengths and unsaturation and use this lipid substrate library to biochemically characterize recombinant mammalian ABHD12. The substrate profiling study for ABHD12 suggested that this enzyme requires glycosylation for optimal activity and that it has a strong preference for very-long-chain lipid substrates. We further validated this substrate profile against brain membrane lysates generated from WT and ABHD12 knockout mice. Finally, using cellular organelle fractionation and immunofluorescence assays, we show that mammalian ABHD12 is enriched on the endoplasmic reticulum membrane, where most of the very-long-chain fatty acids are biosynthesized in cells. Taken together, our findings provide a biochemical explanation for why very-long-chain lipids (such as lysophosphatidylserine lipids) accumulate in the brains of ABHD12 knockout mice, which is a murine model of PHARC.
ESTHER : Joshi_2018_J.Biol.Chem_293_16953
PubMedSearch : Joshi_2018_J.Biol.Chem_293_16953
PubMedID: 30237167
Gene_locus related to this paper: human-ABHD12

Title : N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging - Garg_2018_Can.J.Physiol.Pharmacol_96_1189
Author(s) : Garg G , Singh S , Singh AK , Rizvi SI
Ref : Canadian Journal of Physiology & Pharmacology , 96 :1189 , 2018
Abstract : N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na(+)/K(+)-ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-alpha, IL-1beta, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.
ESTHER : Garg_2018_Can.J.Physiol.Pharmacol_96_1189
PubMedSearch : Garg_2018_Can.J.Physiol.Pharmacol_96_1189
PubMedID: 30107137

Title : Evaluation of acute toxicity of triazophos and deltamethrin and their inhibitory effect on AChE activity in Channa punctatus - Singh_2018_Toxicol.Rep_5_85
Author(s) : Singh S , Tiwari RK , Pandey RS
Ref : Toxicol Rep , 5 :85 , 2018
Abstract : Pesticides are applied to control the pests indoor and outdoor; however, their remarkable amount reaches to the aquatic system through various routes like run-off, leaching, spray-drift, effluent from factories. These are reported to have negative metabolic impact on different non-target aquatic organisms like fishes. Thus, present study is aimed to evaluate the acute toxicity of two groups of pesticides, organophosphate and pyrethroid, namely triazophos and deltamethrin, respectively. The test was conducted for 96h period in a freshwater teleost, Channa punctatus. The LC50 values for triazophos and deltamethrin after 96h treatment was found to be 0.069mg/L and 7.33mug/L. The deltamethrin was found to be about ten times more toxic than triazophos to the fish. In treated fish, alterations in various behavioural patterns were observed with increasing concentrations of both the pesticides as compared to control. Further, tissue specific as well as dose dependent inhibition in the acetylcholinesterase (AChE, EC activity was found in brain, muscle and gills in Channa punctatus exposed to both the insecticides. However, the effect was more pronounced in triazophos treated fishes than the deltamethrin. A futuristic approach on biochemical and molecular studies may throw light on the mechanism of action of these pesticides.
ESTHER : Singh_2018_Toxicol.Rep_5_85
PubMedSearch : Singh_2018_Toxicol.Rep_5_85
PubMedID: 29379743

Title : Whey protein concentrate supplementation protects rat brain against aging-induced oxidative stress and neurodegeneration - Garg_2018_Appl.Physiol.Nutr.Metab_43_437
Author(s) : Garg G , Singh S , Singh AK , Rizvi SI
Ref : Appl Physiol Nutr Metab , 43 :437 , 2018
Abstract : Whey protein concentrate (WPC) is a rich source of sulfur-containing amino acids and is consumed as a functional food, incorporating a wide range of nutritional attributes. The purpose of this study is to evaluate the neuroprotective effect of WPC on rat brain during aging. Young (4 months) and old (24 months) male Wistar rats were supplemented with WPC (300 mg/kg body weight) for 28 days. Biomarkers of oxidative stress and antioxidant capacity in terms of ferric reducing antioxidant potential (FRAP), lipid hydroperoxide (LHP), total thiol (T-SH), protein carbonyl (PC), reactive oxygen species (ROS), nitric oxide (NO), and acetylcholinesterase (AChE) activity were measured in brain of control and experimental (WPC supplemented) groups. In addition, gene expression and histopathological studies were also performed. The results indicate that WPC augmented the level of FRAP, T-SH, and AChE in old rats as compared with the old control. Furthermore, WPC-treated groups exhibited significant reduction in LHP, PC, ROS, and NO levels in aged rats. WPC supplementation also downregulated the expression of inflammatory markers (tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6), and upregulated the expression of marker genes associated with autophagy (Atg3, Beclin-1, LC3B) and neurodegeneration (neuron specific enolase, Synapsin-I, MBP-2). The findings suggested WPC to be a potential functional nutritional food supplement that prevents the progression of age-related oxidative damage in Wistar rats.
ESTHER : Garg_2018_Appl.Physiol.Nutr.Metab_43_437
PubMedSearch : Garg_2018_Appl.Physiol.Nutr.Metab_43_437
PubMedID: 29199432

Title : Antiaging Effect of Metformin on Brain in Naturally Aged and Accelerated Senescence Model of Rat - Garg_2017_Rejuvenation.Res_20_173
Author(s) : Garg G , Singh S , Singh AK , Rizvi SI
Ref : Rejuvenation Res , 20 :173 , 2017
Abstract : Metformin, a biguanide, is a widely used antidiabetic drug, which inhibits gluconeogenesis and is used to treat hyperglycemia in type 2 diabetes. Through activation of AMPK (AMP-activated protein kinase) pathway, metformin also mimics caloric restriction health benefits. Aging causes substantial molecular to morphological changes in brain, the brain cells being more susceptible toward oxidative stress mediated damages due to the presence of high lipid content and higher oxygen consumption. Wistar rats (naturally aged and d-galactose induced rat model) were supplemented with metformin (300 mg/kg b.w. orally) for 6 weeks. The biomarkers of oxidative stress such as antioxidant capacity (ferric reducing antioxidant potential [FRAP]), malondialdehyde (MDA), reduced glutathione (GSH), protein carbonyl (PCO), reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, and nitric oxide (NO) were measured in brain tissues of control and experimental groups. The results indicate that metformin treatment augmented the levels of FRAP and GSH in naturally aged, and d-gal induced aging model groups compared to the respective controls. In contrast, metformin treated groups exhibited significant reduction in MDA, PCO, ROS, and NO levels and a significant increase in AChE activity in induced aging rats. The administration of d-galactose upregulated the expression of sirtuin-2, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) and downregulated the expression of Beclin-1. Metformin supplementation downregulated the d-galactose induced expressions of sirtuin-2, IL-6, and TNF-alpha expression, whereas upregulated the Beclin-1 expression. Our data confirm that metformin restores the antioxidant status and improves healthy brain aging through the activation of autophagy and reduction in inflammation.
ESTHER : Garg_2017_Rejuvenation.Res_20_173
PubMedSearch : Garg_2017_Rejuvenation.Res_20_173
PubMedID: 27897089

Title : Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology - Biswas_2017_Cell.Signal_42_211
Author(s) : Biswas J , Gupta S , Verma DK , Gupta P , Singh A , Tiwari S , Goswami P , Sharma S , Singh S
Ref : Cell Signal , 42 :211 , 2017
Abstract : The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment.
ESTHER : Biswas_2017_Cell.Signal_42_211
PubMedSearch : Biswas_2017_Cell.Signal_42_211
PubMedID: 29126976

Title : Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes - Singh_2017_Rejuvenation.Res_20_420
Author(s) : Singh AK , Garg G , Singh S , Rizvi SI
Ref : Rejuvenation Res , 20 :420 , 2017
Abstract : Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.
ESTHER : Singh_2017_Rejuvenation.Res_20_420
PubMedSearch : Singh_2017_Rejuvenation.Res_20_420
PubMedID: 28514891

Title : Assessment of the acute toxicity of chlorpyrifos and cypermethrin to Heteropneustes fossilis and their impact on acetylcholinesterase activity - Tiwari_2017_Drug.Chem.Toxicol__1
Author(s) : Tiwari RK , Singh S , Pandey RS
Ref : Drug & Chemical Toxicology , :1 , 2017
Abstract : In the present study, the acute toxicity of chlorpyrifos (an organophosphate, OP) and cypermethrin (a pyrethroid) pesticides was estimated for 96 h in Heteropneustes fossilis. The LC50 for chlorpyrifos (CPF) and cypermethrin was found to be 1.90 mg/L and 0.085 mg/L, respectively. The acetylcholinesterase (AChE, EC activity in Heteropneustes fossilis exposed to both the insecticides was assayed in brain, muscle and gills. In general, tissue specific as well as dose-dependent decrease in the AChE activity was exhibited by both pesticides. In response to the increasing concentrations of chlorpyrifos and cypermethrin as well, a significant decrease in the activity of AChE was found in brain while muscle and gills exhibited lesser inhibition. Thus, the brain was the main target organ for both insecticides, followed by muscle and gills. Between the two pesticides chlorpyrifos acted as more potent AChE inhibitor than cypermethrin since more intense changes in behavioral pattern was observed with the chlorpyrifos. These changes indicate that the effects of these pesticides are at neural as well as neuromuscular level.
ESTHER : Tiwari_2017_Drug.Chem.Toxicol__1
PubMedSearch : Tiwari_2017_Drug.Chem.Toxicol__1
PubMedID: 29258333

Title : Towards enzymatic breakdown of complex plant xylan structures: State of the art - Biely_2016_Biotechnol.Adv_34_1260
Author(s) : Biely P , Singh S , Puchart V
Ref : Biotechnol Adv , 34 :1260 , 2016
Abstract : Significant progress over the past few years has been achieved in the enzymology of microbial degradation and saccharification of plant xylan, after cellulose being the most abundant natural renewable polysaccharide. Several new types of xylan depolymerizing and debranching enzymes have been described in microorganisms. Despite the increasing variety of known glycoside hydrolases and carbohydrate esterases, some xylan structures still appear quite recalcitrant. This review focuses on the mode of action of different types of depolymerizing endoxylanases and their cooperation with beta-xylosidase and accessory enzymes in breakdown of complex highly branched xylan structures. Emphasis is placed on the enzymatic hydrolysis of alkali-extracted deesterified polysaccharide as well as acetylated xylan isolated from plant cell walls under non-alkaline conditions. It is also shown how the combination of selected endoxylanases and debranching enzymes can determine the nature of prebiotic xylooligosaccharides or lead to complete hydrolysis of the polysaccharide. The article also highlights the possibility for discovery of novel xylanolytic enzymes, construction of multifunctional chimeric enzymes and xylanosomes in parallel with increasing knowledge on the fine structure of the polysaccharide.
ESTHER : Biely_2016_Biotechnol.Adv_34_1260
PubMedSearch : Biely_2016_Biotechnol.Adv_34_1260
PubMedID: 27620948

Title : Streptozotocin Induced Neurotoxicity Involves Alzheimer's Related Pathological Markers: a Study on N2A Cells - Biswas_2016_Mol.Neurobiol_53_2794
Author(s) : Biswas J , Goswami P , Gupta S , Joshi N , Nath C , Singh S
Ref : Molecular Neurobiology , 53 :2794 , 2016
Abstract : Intracerebroventricular (icv) injection of streptozotocin (STZ) in rat brain causes prolonged impairment of brain energy metabolism and oxidative damage and leads to cognitive dysfunction; however, its mechanistic specific effects on neurons are not known. The present study was conducted to investigate the STZ-induced cellular and molecular alterations in mouse neuronal N2A cells. The N2A cells were treated with STZ (10, 50, 100, 1000 muM) for 48 h, and different assays were performed. STZ treatment caused significant decrease in cell viability, choline levels, increased acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation. STZ treatment also led to low levels of glucose uptake, elevated mitochondrial stress, translocation of cytochrome c in cytosol, phosphatidylserine externalization, increased expression of caspase-3 and DNA damage. Co-treatment of clinically used drug donepezil (1 muM) offered significant protection against STZ induced neurotoxicity. Donepezil treatment significantly inhibited the STZ induced neurotoxicity, altered choline level, AChE activity, lowered glucose uptake and mitochondrial stress. However, the caspase-3 expression remains unaltered with co-treatment of donepezil. In conclusion, findings showed that STZ treated N2A cells exhibited the Alzheimer's disease (AD) related pathological markers which are attenuated with co-treatment of donepezil. Findings of the study suggested the potent use of STZ treated N2A cells as in vitro experimental test model to study the disease mechanism at cellular level.
ESTHER : Biswas_2016_Mol.Neurobiol_53_2794
PubMedSearch : Biswas_2016_Mol.Neurobiol_53_2794
PubMedID: 25823512

Title : The influence of organophosphate and carbamate on sperm chromatin and reproductive hormones among pesticide sprayers - Jamal_2016_Toxicol.Ind.Health_32_1527
Author(s) : Jamal F , Haque QS , Singh S , Rastogi SK
Ref : Toxicol Ind Health , 32 :1527 , 2016
Abstract : This study is aimed at evaluating the association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality as well as levels of reproductive and thyroid hormones of pesticide sprayers in Malihabad, Lucknow, Uttar Pradesh, India. Thirty-five healthy men (unexposed group) and 64 male pesticide sprayers (exposed group) were recruited for clinical evaluation of fertility status. Fresh semen samples were evaluated for sperm quality and analyzed for DNA fragmentation index (DFI) by flow cytometry. Pesticide exposure was assessed by measuring erythrocyte acetylcholinesterase and plasma butyrylcholinesterase (BuChE) with a Test-mate ChE field kit. Serum levels of total testosterone (Tt), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) were analyzed using enzyme immunoassay kits. Evidence of pesticide exposure was found in 88.5% of sprayers and significant increments were observed in sperm DFI with significant decrease in some semen parameters. DFI was negatively correlated with BuChE, sperm concentration, morphology, and vitality in these pesticide sprayers. The levels of Tt, PRL, FT4, and TSH appeared to be normal; however, there was a tendency for increased LH and FSH levels in exposed workers. The results confirm the potential impact of chronic occupational exposure to OP and CB pesticides on male reproductive function, which may cause damage to sperm chromatin, decrease semen quality, and produce alterations in reproductive hormones, leading to adverse reproductive health outcomes.
ESTHER : Jamal_2016_Toxicol.Ind.Health_32_1527
PubMedSearch : Jamal_2016_Toxicol.Ind.Health_32_1527
PubMedID: 25647813

Title : The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides - Singh_2016_Environ.Toxicol_31_1017
Author(s) : Singh S , Prakash A , Kaur S , Ming LC , Mani V , Majeed AB
Ref : Environ Toxicol , 31 :1017 , 2016
Abstract : Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.
ESTHER : Singh_2016_Environ.Toxicol_31_1017
PubMedSearch : Singh_2016_Environ.Toxicol_31_1017
PubMedID: 25864908

Title : Synthesis and immunopotentiating activity of novel isoxazoline functionalized coumarins - Ismail_2016_Eur.J.Med.Chem_123_90
Author(s) : Ismail T , Shafi S , Singh S , Sidiq T , Khajuria A , Rouf A , Yadav M , Saikam V , Singh PP , Alam MS , Islam N , Sharma K , Kumar HM
Ref : Eur Journal of Medicinal Chemistry , 123 :90 , 2016
Abstract : A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz. toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-gamma, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2, 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis-heterocycle based novel, therapeutically selective and effective immunopotentiators.
ESTHER : Ismail_2016_Eur.J.Med.Chem_123_90
PubMedSearch : Ismail_2016_Eur.J.Med.Chem_123_90
PubMedID: 27474926

Title : Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems - Chatterjee_2015_Pharm.Biol_53_1850
Author(s) : Chatterjee M , Verma R , Kumari R , Singh S , Verma AK , Dwivedi AK , Palit G
Ref : Pharm Biol , 53 :1850 , 2015
Abstract : CONTEXT: Schizophrenia is a chronic disabling psychiatric disorder affecting 1% of the population worldwide. Due to the adverse effects of available antipsychotic medications, recent investigations have focused on the search for well-tolerated, safe molecules from natural resources to control the severity and progression of schizophrenia. OBJECTIVE: To screen the standardized extract of Bacopa monniera Linn. (Scrophulariaceae) (BM) for its antipsychotic potential in the ketamine-induced psychosis model with mice. MATERIALS AND
METHODS: Graded dose of BM (40, 80, and 120 mg/kg, p.o.) were given to the mice 1 h prior to ketamine administration and tested for positive symptoms and cognitive deficits. A chronic ketamine treatment regimen was used to study the effect of BM on negative symptoms such as immobility enhancement. Each mouse was used once for the behavioral studies.
RESULTS: BM reduced ketamine-induced hyperactivity with an EC50 value of 76.60 mg/kg. The 80 mg/kg dose was used for all other behavior analysis. Pretreatment with BM at 80 mg/kg showed two-fold increases in transfer latency time (TLT) in passive avoidance task. Chronic BM pretreatment (80 mg/kg p.o. daily x 10 d) ameliorated the ketamine-induced enhanced immobility effect by 21% in the forced swim test. BM treatment reversed ketamine-induced increase in monoamine oxidase activity in both cortex and striatum and normalized the acetylcholinesterase activity and the glutamate levels in the hippocampus. DISCUSSION AND CONCLUSION: Overall our findings suggest that BM possesses antipsychotic properties which might be due to its modulatory action on dopamine, serotonin, and glutamate neurotransmission.
ESTHER : Chatterjee_2015_Pharm.Biol_53_1850
PubMedSearch : Chatterjee_2015_Pharm.Biol_53_1850
PubMedID: 25856700

Title : Effects of acute organophosphate poisoning on pituitary target gland hormones at admission, discharge and three months after poisoning: A hospital based pilot study - Dutta_2015_Indian.J.Endocrinol.Metab_19_116
Author(s) : Dutta P , Kamath SS , Bhalla A , Shah VN , Srinivasan A , Gupta P , Singh S
Ref : Indian J Endocrinol Metab , 19 :116 , 2015
Abstract : BACKGROUND: Organophosphate compound (OPC) poisoning is common in the developing countries such as India. The acute and later effects of OPC poisoning on pituitary and target gland hormones is largely unknown. MATERIALS AND
METHODS: This prospective study was conducted at Postgraduate Institute of Medical Education and Research between January 2012 and March 2013. Fourteen patients (8 males, age 18-50 years) with acute OPC poisoning were included in the study based on the history and clinical features, documented decreased in plasma cholinesterase activity or presence of the OPC in gastric lavage/blood samples. The hormonal parameters were done at baseline, at the time of discharge and at three months of follow-up.
RESULTS: A total of 14 patients out of 46 with the mean age of 30.1 +/- 10.3 years were finally eligible for the study. Hormonal alterations at admission were similar to sick euhormonal syndrome. Overall 7 of them had nine hormonal deficits at three months of follow up, 4 having sub normal basal cortisol level and two each had low testosterone and growth hormone and only one had thyroxine deficiency. CONCLUSION: Acute organophosphate poisoning results in endocrine dysfunction akin to sick euhormonal syndrome. However, in a small subset of patients, varying level of hormonal insufficiency may occur either at admission or later. These observations need re-validation in a larger group of patients with specific OPC.
ESTHER : Dutta_2015_Indian.J.Endocrinol.Metab_19_116
PubMedSearch : Dutta_2015_Indian.J.Endocrinol.Metab_19_116
PubMedID: 25593838

Title : Effect of acyl chain length on selective biocatalytic deacylation on O-aryl glycosides and separation of anomers - Aggarwal_2014_Bioorg.Chem_53_83
Author(s) : Aggarwal N , Arya A , Mathur D , Singh S , Tyagi A , Kumar R , Rana N , Singh R , Prasad AK
Ref : Bioorg Chem , 53 :83 , 2014
Abstract : It has been demonstrated that Lipozyme TL IM (Thermomyces lanuginosus lipase immobilised on silica) can selectively deacylate the ester function involving the C-5' hydroxyl group of alpha-anomers over the other acyl functions of anomeric mixture of peracylated O-aryl alpha,beta-D-ribofuranoside. The analysis of results of biocatalytic deacylation reaction revealed that the reaction time decreases with the increase in the acyl chain length from C1 to C4. The unique selectivity of Lipozyme TL IM has been harnessed for the separation of anomeric mixture of peracylated O-aryl alpha,beta-D-ribofuranosides, The lipase mediated selective deacylation methodology has been used for the synthesis of O-aryl alpha-D-ribofuranosides and O-aryl beta-D-ribofuranosides in pure forms, which can be used as chromogenic substrate for the detection of pathogenic microbial parasites containing glycosidases.
ESTHER : Aggarwal_2014_Bioorg.Chem_53_83
PubMedSearch : Aggarwal_2014_Bioorg.Chem_53_83
PubMedID: 24632507

Title : Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity - Kaur_2014_Can.J.Physiol.Pharmacol_92_893
Author(s) : Kaur S , Singh S , Chahal KS , Prakash A
Ref : Canadian Journal of Physiology & Pharmacology , 92 :893 , 2014
Abstract : Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.
ESTHER : Kaur_2014_Can.J.Physiol.Pharmacol_92_893
PubMedSearch : Kaur_2014_Can.J.Physiol.Pharmacol_92_893
PubMedID: 25348489

Title : Effect of Resveratrol and Nicotine on PON1 Gene Expression: In Vitro Study - Gupta_2014_Indian.J.Clin.Biochem_29_69
Author(s) : Gupta N , Kandimalla R , Priyanka K , Singh G , Gill KD , Singh S
Ref : Indian J Clinical Biochemistry , 29 :69 , 2014
Abstract : Dietary and lifestyle factors have been shown to have a profound effect on paraoxonase-1 (PON1) activity. Cigarette smoke has been shown to inhibit its mass and activity where as resveratrol has been shown to enhance it. We exposed hepatoma derived cell line (HepG2) to resveratrol and nicotine in varying doses and measured PON1 enzymatic activity and PON1 gene expression. In addition, total protein content of HepG2 cells was also measured. Resveratrol in a dose of 15 mumol/l or above significantly increased the PON1 enzyme activity (p > 0.001) where as nicotine in a dose of 1 mumol/l or higher significantly reduced it (p < 0.05). The resveratrol in this dose also enhanced the PON1 gene expression whereas nicotine decreased it as compared to controls. However, the protein conent of cells was not changed suggesting that they were not cytotoxic in the doses used. Till date the antioxidant vitamins have shown disappointing results against LDL oxidation and cardiovascular protection. However, the effect of resveratrol on PON1 gene expression and activity was significant, suggesting increase in PON1 activity and enhanced gene expression may be its alternative mechanism for offering protection against cardiovascular disease and may be an potential pharmacological agent which can be used for this.
ESTHER : Gupta_2014_Indian.J.Clin.Biochem_29_69
PubMedSearch : Gupta_2014_Indian.J.Clin.Biochem_29_69
PubMedID: 24478552

Title : Cold-active hydrolases producing bacteria from two different sub-glacial Himalayan lakes - Sahay_2013_J.Basic.Microbiol_53_703
Author(s) : Sahay H , Babu BK , Singh S , Kaushik R , Saxena AK , Arora DK
Ref : J Basic Microbiol , 53 :703 , 2013
Abstract : Microorganisms, native to the cold environments have successfully acclimatized their physiological, metabolic, and biological features, exhibiting uniqueness in their enzymes, proteins, and membrane structures. These cold-active enzymes have immense biotechnological potential. The diversity of culturable bacteria in two different water lakes (the sub-glacial freshwater and the brackish) of Himalayas was analyzed using SYBR green staining and cultural methods. A total of 140 bacteria were isolated and were grouped as psychrophiles, psychrotrophs, and psychrotolerant organisms, based on their optimal temperature for growth. The amplified ribosomal DNA restriction analysis using three restriction enzymes facilitated the grouping of these isolates into 96 genotypes at >/=85% polymorphism. Phylogenetic analysis using 16S rRNA gene sequences revealed that the bacterial strains from both lakes belonged to Firmicutes, Proteobacteria (alpha, beta, and gamma) or Actinobacteria. Screening of the germplasm for the activity of different cold-active hydrolases such as protease, amylase, xylanase, and cellulase, revealed that about 16 isolates were positive, and exhibiting a wide range of stability at various temperature and pH. Our results suggest that the distinctly different ecosystems of sub-glacial freshwater and brackish water lakes have diverse groups of bacteria, which can be an excellent source of extracellular hydrolases with a wide range of thermal stability.
ESTHER : Sahay_2013_J.Basic.Microbiol_53_703
PubMedSearch : Sahay_2013_J.Basic.Microbiol_53_703
PubMedID: 22961722

Title : Identification and characterisation of small-molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia - Saxena_2013_Int.J.Antimicrob.Agents_42_27
Author(s) : Saxena AK , Roy KK , Singh S , Vishnoi SP , Kumar A , Kashyap VK , Kremer L , Srivastava R , Srivastava BS
Ref : Int J Antimicrob Agents , 42 :27 , 2013
Abstract : The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC(50)) 500 g/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen-depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis.
ESTHER : Saxena_2013_Int.J.Antimicrob.Agents_42_27
PubMedSearch : Saxena_2013_Int.J.Antimicrob.Agents_42_27
PubMedID: 23684389
Gene_locus related to this paper: myctu-Rv3097c

Title : Anti-cholinergic alkaloids as potential therapeutic agents for Alzheimer's disease: an in silico approach - Naaz_2013_Indian.J.Biochem.Biophys_50_120
Author(s) : Naaz H , Singh S , Pandey VP , Singh P , Dwivedi UN
Ref : Indian J Biochem Biophys , 50 :120 , 2013
Abstract : Alzheimer's disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms is biochemically characterized by a significant decrease in the brain neurotransmitter acetylcholine (ACh). Plant-derived metabolites, including alkaloids have been reported to possess neuroprotective properties and are considered to be safe, thus have potential for developing effective therapeutic molecules for neurological disorders, such as AD. Therefore, in the present study, thirteen plant-derived alkaloids, namely pleiocarpine, kopsinine, pleiocarpamine (from Pleiocarpa mutica, family: Annonaceae), oliveroline, noroliveroline, liridonine, isooncodine, polyfothine, darienine (from Polyalthia longifolia, family: Apocynaceae) and eburnamine, eburnamonine, eburnamenine and geissoschizol (from Hunteria zeylanica, family: Apocynaceae) were analyzed for their anti-cholinergic action through docking with acetylcholinesterase (AChE) as target. Among the alkaloids, pleiocarpine showed promising anti-cholinergic potential, while its amino derivative showed about six-fold higher anti-cholinergic potential than pleiocarpine. Pleiocarpine and its amino derivative were found to be better inhibitors of AChE, as compared to commonly used drugs tacrine (brand name: Cognex) and rivastigmine (brand name: Exelon), suggesting development of these molecules as potential therapeutics in future.
ESTHER : Naaz_2013_Indian.J.Biochem.Biophys_50_120
PubMedSearch : Naaz_2013_Indian.J.Biochem.Biophys_50_120
PubMedID: 23720886

Title : Multiple Genome Sequences of Helicobacter pylori Strains of Diverse Disease and Antibiotic Resistance Backgrounds from Malaysia - Rehvathy_2013_Genome.Announc_1_e00687
Author(s) : Rehvathy V , Tan MH , Gunaletchumy SP , Teh X , Wang S , Baybayan P , Singh S , Ashby M , Kaakoush NO , Mitchell HM , Croft LJ , Goh KL , Loke MF , Vadivelu J
Ref : Genome Announc , 1 : , 2013
Abstract : Helicobacter pylori causes human gastroduodenal diseases, including chronic gastritis and peptic ulcer disease. It is also a major microbial risk factor for the development of gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty-one strains with different ethnicity, disease, and antimicrobial susceptibility backgrounds were sequenced by use of Illumina HiSeq and PacBio RS platforms.
ESTHER : Rehvathy_2013_Genome.Announc_1_e00687
PubMedSearch : Rehvathy_2013_Genome.Announc_1_e00687
PubMedID: 24051312

Title : Influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to organophosphate pesticides - Singh_2012_Mutat.Res_741_101
Author(s) : Singh S , Kumar V , Singh P , Banerjee BD , Rautela RS , Grover SS , Rawat DS , Pasha ST , Jain SK , Rai A
Ref : Mutat Res , 741 :101 , 2012
Abstract : Previous studies have revealed that organophosphate pesticides (OPs) are primarily metabolized by xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticides-exposed workers. Present study was designed to determine the influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to OPs. We examined 268 subjects including 134 workers occupationally exposed to OPs and an equal number of normal healthy controls. The DNA damage was evaluated using alkaline comet assay and genotyping was done using individual polymerase chain reaction (PCR) or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Acetylcholinesterase and paraoxonase activity were found to be significantly lowered in workers as compared to control subjects which were analyzed as biomarkers of toxicity due to OPs exposure (p<0.001). Workers showed significantly higher DNA tail moment (TM) compared to control subjects (14.32+/-2.17 vs. 6.24+/-1.37 tail % DNA, p<0.001). GSTM1 null genotype was found to influence DNA TM in workers (p<0.05). DNA TM was also found to be increased with concomitant presence of NAT2 slow acetylation and CYP2C9*3/*3 or GSTM1 null genotypes (p<0.05). DNA TM was found increased in NAT2 slow acetylators with mild and heavy smoking habits in control subjects and workers, respectively (p<0.05). The results of this study suggest that GSTM1 null genotypes, and an association of NAT2 slow acetylation genotypes with CYP2C9*3/*3 or GSTM1 null genotypes may modulate DNA damage in workers occupationally exposed to OPs.
ESTHER : Singh_2012_Mutat.Res_741_101
PubMedSearch : Singh_2012_Mutat.Res_741_101
PubMedID: 22108250

Title : Low serum PON1 activity: an independent risk factor for coronary artery disease in North-West Indian type 2 diabetics - Gupta_2012_Gene_498_13
Author(s) : Gupta N , Binu KB , Singh S , Maturu NV , Sharma YP , Bhansali A , Gill KD
Ref : Gene , 498 :13 , 2012
Abstract : The paraoxonase (PON1) gene polymorphisms are known to affect the PON1 activity and coronary artery disease (CAD) risk. Studies done so far have given conflicting results. In the present study, we determined the role of PON1 genetic variants and PON1 activity in the development of CAD in North-West Indian Punjabis, a distinct ethnic group, having high incidence of both CAD and type 2 diabetes. 300 angiographically proven CAD with type 2 diabetics and 250 type 2 diabetics with no clinically evident CAD were enrolled. Serum PON1 activity and genotyping of coding (Q192R, L55M) and promoter (-909G/C, -162A/G, -108C/T) region polymorphisms were carried out and haplotypes were determined using PHASE software. The serum PON1 activity was significantly lower in CAD with type 2 diabetics as compared to diabetics alone (51.0 vs. 114.2nmol/min/ml). In logistic regression model after adjusting for confounding variables, lower PON1 activity was found to be significantly associated with CAD risk in type 2 diabetics with OR being 16.8 (95% CI: 10.2-27.7). The lower serum PON1 activity, irrespective of genotypes and haplotypes is a risk factor for development of CAD in North-West Indian Punjabis with type 2 diabetics.
ESTHER : Gupta_2012_Gene_498_13
PubMedSearch : Gupta_2012_Gene_498_13
PubMedID: 22333293

Title : Evaluation of the antipsychotic potential of Panax quinquefolium in ketamine induced experimental psychosis model in mice - Chatterjee_2012_Neurochem.Res_37_759
Author(s) : Chatterjee M , Singh S , Kumari R , Verma AK , Palit G
Ref : Neurochem Res , 37 :759 , 2012
Abstract : The search for novel pharmacotherapy from medicinal plants for psychiatric illnesses has progressed significantly from the past few decades and their therapeutic potential has been assessed in a variety of animal models. The aim of our study was to screen one such plant, Panax quinquefolium (PQ), with significant neuroactive properties for its antipsychotic potential. A graded dose study with PQ at 12.5-200 mg/kg, p. o. showed differential effects against the ketamine induced hyperactivity in the Digiscan animal activity monitor. Nevertheless at 100 mg/kg, p.o., PQ blocked ketamine induced memory impairment in the passive avoidance paradigm. In the chronic studies, PQ reduced the ketamine induced enhanced immobility in the forced swim test and did not show extra-pyramidal side effects in bar test and wood block test of catalepsy. These behavioural effects were compared with standard drugs haloperidol and clozapine. Further PQ reduced DA and 5-HT content after chronic treatment, but not after acute administration. In addition, PQ extract reduced acetylcholinesterase activity and nitrate levels, however increased glutamate levels in hippocampus. Overall our findings suggest that PQ possess antipsychotic like properties, which may leads to future studies with its specific constituents which may particularly be beneficial in predominant negative and cognitive symptoms of schizophrenia.
ESTHER : Chatterjee_2012_Neurochem.Res_37_759
PubMedSearch : Chatterjee_2012_Neurochem.Res_37_759
PubMedID: 22189635

Title : Regeneration of Red Cell Cholinesterase Activity Following Pralidoxime (2-PAM) Infusion in First 24 h in Organophosphate Poisoned Patients - Goel_2012_Indian.J.Clin.Biochem_27_34
Author(s) : Goel P , Gupta N , Singh S , Bhalla A , Sharma N , Gill KD
Ref : Indian J Clinical Biochemistry , 27 :34 , 2012
Abstract : Oximes such as pralidoxime chloride reactivate acetylcholinesterase. However their role in management of organophosphate poisoning is controversial. The study was carried out to find effectiveness of pralidoxime chloride (2-PAM) in regenerating red cell acetyl cholinesterase in first 24 h following administration of it in dose recommended by WHO. Eight patients with OPP [chlorpyriphos (3), phorate (3), dichlorvos (1) and monocrotophos (1) who fulfilled the criteria for inclusion were investigated. In addition to decontamination and atropine, all these patients were administered 30 mg/kg body wt of 2-PAM as bolus dose followed by 7.5 mg/kg body wt/h with maximum dose being 500 mg/h as continuous infusion till first 24 h. Red cell AChE activity was estimated every 15 min for first 4 h, one hourly for next 4 h and then 2 hourly till 24 h and subsequently without 2-PAM every 12 h till 7 days or discharge or death which ever earlier. In all the patients maximum increase in activity was observed in first 4 h following which rise was very slow despite continued 2-PAM infusion and reaching a steady state in 20 h in all the cases. The increase in red cell AChE activity observed in diethyl group at 24 h of 2-PAM infusion was 154% vs. 81% in dimethyl group. At 7 days the increase in activity was 215% vs. 118% respectively. However on multiple repeated ANOVA, no statistically significant difference was observed between diethyl and dimethyl groups at admission and discharge (P > 0.05). Similarly no significant difference was observed in three groups when patients were categorized according to WHO classification of organophosphates (P > 0.05). The maximum increase in red cell AChE activity occurs in first 4 h of 2-PAM administration followed by a slow increase despite 2-PAM infusion till 24 h.
ESTHER : Goel_2012_Indian.J.Clin.Biochem_27_34
PubMedSearch : Goel_2012_Indian.J.Clin.Biochem_27_34
PubMedID: 23277710

Title : O-Aryl alpha,beta-d-ribofuranosides: synthesis & highly efficient biocatalytic separation of anomers and evaluation of their Src kinase inhibitory activity - Sharma_2012_Bioorg.Med.Chem_20_6821
Author(s) : Sharma RK , Singh S , Tiwari R , Mandal D , Olsen CE , Parmar VS , Parang K , Prasad AK
Ref : Bioorganic & Medicinal Chemistry , 20 :6821 , 2012
Abstract : A series of peracetylated O-aryl alpha,beta-d-ribofuranosides have been synthesized and an efficient biocatalytic methodology has been developed for the separation of their anomers which was otherwise almost impossible by column chromatographic or other techniques. The incubation of 2,3,5-tri-O-acetyl-1-O-aryl-alpha,beta-d-ribofuranoside with Lipozyme TL IM immobilized on silica led to the selective deacetylation of only one acetoxy group, viz the C-5'-O-acetoxy group of the alpha-anomer over the other acetoxy groups derived from the two secondary hydroxyl groups present in the molecule and also over three acetoxy groups (derived from one primary and two secondary hydroxyls of the beta-anomer). This methodology led to the easy synthesis of both, alpha- and beta-anomers of O-aryl d-ribofuranosides. All the arylribofuranosides were screened for inhibition of Src kinase. 1-O-(3-Methoxyphenyl)-beta-d-ribofuranoside exhibited the highest activity for inhibition of Src kinase (IC(50)=95.0 M).
ESTHER : Sharma_2012_Bioorg.Med.Chem_20_6821
PubMedSearch : Sharma_2012_Bioorg.Med.Chem_20_6821
PubMedID: 23098606

Title : RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes - Singh_2011_Eur.J.Pharmacol_652_157
Author(s) : Singh S , Roy S , Sethi S , Benjamin B , Sundaram S , Khanna V , Kandalkar SR , Pal C , Kant R , Patra AK , Rayasam G , Mittra S , Saini KS , Paliwal J , Chugh A , Ahmed S , Sattigeri J , Cliff I , Ray A , Bansal VS , Bhatnagar PK , Davis JA
Ref : European Journal of Pharmacology , 652 :157 , 2011
Abstract : Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect ( approximately 25% AUC of big up tri, open blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.
ESTHER : Singh_2011_Eur.J.Pharmacol_652_157
PubMedSearch : Singh_2011_Eur.J.Pharmacol_652_157
PubMedID: 20540938

Title : Serum paraoxonase-1 (PON1) activities (PONase\/AREase) and polymorphisms in patients with type 2 diabetes mellitus in a North-West Indian population - Gupta_2011_Gene_487_88
Author(s) : Gupta N , Binukumar BK , Singh S , Sunkaria A , Kandimalla R , Bhansali A , Gill KD
Ref : Gene , 487 :88 , 2011
Abstract : OBJECTIVE: Paraoxonase-1 (PON1), an HDL-C associated enzyme, protects lipoproteins from oxidation. There is evidence that PON1 enzyme activity is reduced in the patients with type 2 diabetes mellitus (T2DM). North-West Indian Punjabis, a distinct ethnic group has high incidence of T2DM. However till date there is no information regarding PON1 enzyme activities and PON1 polymorphisms in T2DM patients of this ethnic group.
METHODS: We identified polymorphisms in the coding Q192R, L55M and promoter -909G/C, -162A/G, -108C/T of the PON1 gene by using PCR-RFLP, multiplex PCR and allele specific oligonucleotide PCR assays in 250 T2DM patients and 300 healthy controls. We also assessed paraoxonase (PONase) and arylesterase (AREase) activities of PON1 enzyme.
RESULTS: The serum PONase (114.2 vs. 178.0nmol/min/ml) and AREase (62.7 vs. 82.5mumol/min/ml) activities were significantly lower (p<0.0001) in patients as compared to controls. PONase activity was affected by all the studied PON1 polymorphisms. However, AREase activity was not affected by any of these polymorphisms. Coding Q192R and promoter -909G/C polymorphisms showed significant differences in genotypic distribution. QR, RR (Q192R) and GC, CC (-909G/C) genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes showed significant association with type 2 diabetes. No significant linkage disequilibrium was observed among the five polymorphisms. CONCLUSION: Both PONase and AREase activities are lower in patients and this could lead to increased lipid peroxidation and accelerated atherosclerosis in them. PONase activity, but not AREase activity is influenced by PON1 polymorphisms. QR, RR, GC, CC genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes are commoner in diabetics as compared to controls and may be related to genetic susceptibility to type 2 diabetes.
ESTHER : Gupta_2011_Gene_487_88
PubMedSearch : Gupta_2011_Gene_487_88
PubMedID: 21803130

Title : Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis - Gupta_2011_PLoS.One_6_e17805
Author(s) : Gupta N , Singh S , Maturu VN , Sharma YP , Gill KD
Ref : PLoS ONE , 6 :e17805 , 2011
Abstract : BACKGROUND: Human serum paraoxonase-1 (PON1) prevents oxidation of low density lipoprotein cholesterol (LDL-C) and hydrolyzes the oxidized form, therefore preventing the development of atherosclerosis. The polymorphisms of PON1 gene are known to affect the PON1 activity and thereby coronary artery disease (CAD) risk. As studies are lacking in North-West Indian Punjabi's, a distinct ethnic group with high incidence of CAD, we determined PON1 activity, genotypes and haplotypes in this population and correlated them with the risk of CAD. METHODOLOGY/PRINCIPAL FINDINGS: 350 angiographically proven (>/= 70% stenosis) CAD patients and 300 healthy controls were investigated. PON1 activity was determined towards paraoxon (Paraoxonase; PONase) and phenylacetate (Arylesterase; AREase) substrates. In addition, genotyping was carried out by using multiplex PCR, allele specific oligonucleotide -PCR and PCR-RFLP methods and haplotyping was determined by PHASE software. The serum PONase and AREase activities were significantly lower in CAD patients as compared to the controls. All studied polymorphisms except L55M had significant effect on PONase activity. However AREase activity was not affected by them. In a logistic regression model, after adjustment for the conventional risk factors for CAD, QR (OR: 2.73 (1.57-4.72)) and RR (OR, 16.24 (6.41-41.14)) genotypes of Q192R polymorphism and GG (OR: 2.07 (1.02-4.21)) genotype of -162A/G polymorphism had significantly higher CAD risk. Haplotypes L-T-G-Q-C (OR: 3.25 (1.72-6.16)) and L-T-G-R-G (OR: 2.82 (1.01-7.80)) were also significantly associated with CAD.
CONCLUSIONS: In conclusion this study shows that CAD patients had lower PONase and AREase activities as compared to the controls. The coding Q192R polymorphism, promoter -162A/G polymorphism and L-T-G-Q-C and L-T-G-R-G haplotypes are all independently associated with CAD.
ESTHER : Gupta_2011_PLoS.One_6_e17805
PubMedSearch : Gupta_2011_PLoS.One_6_e17805
PubMedID: 21629682

Title : Genetic polymorphisms of GSTM1, GSTT1 and GSTP1 and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides - Singh_2011_Mutat.Res_725_36
Author(s) : Singh S , Kumar V , Singh P , Thakur S , Banerjee BD , Rautela RS , Grover SS , Rawat DS , Pasha ST , Jain SK , Rai A
Ref : Mutat Res , 725 :36 , 2011
Abstract : GSTM1, T1 and P1 are important enzymes of glutathione S-transferases (GSTs), involved in the metabolism of many endogenous and exogenous compounds. Individual genetic variation in these metabolizing enzymes may influence the metabolism of their substrates. The present study was designed to determine the genotoxic effects using DNA damage and its association with GSTM1, GSTT1, and GSTP1 (Ile105Val) genetic polymorphisms in workers occupationally exposed to organophosphate pesticides (OPs). We examined 230 subjects including 115 workers occupationally exposed to OPs and an equal number of normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using individual PCR or PCR-RFLP. Significantly higher DNA tail moment (TM) was observed in workers as compared to control subjects (14.41 +/- 2.25 vs. 6.36 +/- 1.41 tail % DNA, p<0.001). The results revealed significantly higher DNA TM in workers with GSTM1 null genotype than those with GSTM1 positive (15.18 vs. 14.15 tail % DNA, p=0.03). A significantly higher DNA TM was also observed in workers with homozygous Ile-Ile GSTP1 genotype than heterozygous (Ile-Val) and mutant (Val-Val) GSTP1 genotype (p=0.02). In conclusion, the results show that null deletion of GSTM1 and homozygote wild GSTP1 genotype could be related to inter-individual differences in DNA damage arises from the gene-environment interactions in workers occupationally exposed to OPs.
ESTHER : Singh_2011_Mutat.Res_725_36
PubMedSearch : Singh_2011_Mutat.Res_725_36
PubMedID: 21736951

Title : DNA damage and cholinesterase activity in occupational workers exposed to pesticides - Singh_2011_Environ.Toxicol.Pharmacol_31_278
Author(s) : Singh S , Kumar V , Thakur S , Banerjee BD , Chandna S , Rautela RS , Grover SS , Rawat DS , Pasha ST , Jain SK , Ichhpujani RL , Rai A
Ref : Environ Toxicol Pharmacol , 31 :278 , 2011
Abstract : The present study was designed to evaluate genotoxicity, acetyl cholinesterase (AChE) activity, hepatic and renal toxicity in occupational workers exposed to mixture of pesticides (n=70) with same number of healthy subjects as controls. The mean comet tail DNA % (TD %) and tail moment (TM) were used to measure DNA damage, while AChE activity and other biochemical parameters such as markers of nephrotoxicity (urea and creatinine) and hepatotoxicity (AST, ALT and ALP) were measured as biomarkers for toxicity due to exposure of pesticides. The occupational workers were continuously exposed to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion on a regular interval as per usage and activity. The comet assay using lymphocytes of exposed workers showed significantly higher TD percentage value (60.43% vs. 31.86%, p<0.001) and TM value (14.48 mum vs. 6.42 mum, p<0.001) in occupational workers as compared to controls. AChE activity in erythrocytes was found to be decreased (3.45 KAU/L vs. 9.55 KAU/L in controls, p<0.001) and associated with the duration of exposure to pesticides used by the workers. Enzyme levels for hepatic and renal functions were also found significantly different in occupational workers than healthy controls (p<0.001). These results suggest that the exposure to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion may induce DNA damage, decrease in AChE activity, hepatotoxicity as well as nephrotoxicity. Periodic biomonitoring of these biomarkers along with imparting education and training to occupational workers for safe application of pesticides is recommended for its potential hazards.
ESTHER : Singh_2011_Environ.Toxicol.Pharmacol_31_278
PubMedSearch : Singh_2011_Environ.Toxicol.Pharmacol_31_278
PubMedID: 21787695

Title : Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides - Singh_2011_Toxicol.Appl.Pharmacol_252_130
Author(s) : Singh S , Kumar V , Thakur S , Banerjee BD , Rautela RS , Grover SS , Rawat DS , Pasha ST , Jain SK , Ichhpujani RL , Rai A
Ref : Toxicol Appl Pharmacol , 252 :130 , 2011
Abstract : Human paraoxonase 1 (PON1) is a lipoprotein-associated enzyme involved in the detoxification of organophosphate pesticides (OPs) by hydrolyzing the bioactive oxons. Polymorphisms of the PON1 gene are responsible for variation in the expression and catalytic activity of PON1 enzyme. In the present study, we have determined (a) the prevalence of two common PON1 polymorphisms, (b) the activity of PON1 and acetylcholinesterase enzymes, and (c) the influence of PON1 genotypes and phenotypes variation on DNA damage in workers exposed to OPs. We examined 230 subjects including 115 workers exposed to OPs and an equal number of normal healthy controls. The results revealed that PON1 activity toward paraoxon (179.19+/-39.36 vs. 241.52+/-42.32nmol/min/ml in controls) and phenylacetate (112.74+/-17.37 vs. 134.28+/-25.49mumol/min/ml in controls) was significantly lower in workers than in control subjects (p<0.001). No significant difference was observed in the distribution of genotypes and allelic frequencies of PON1(192)QR (Gln/Arg) and PON1(55)LM (Leu/Met) in workers and control subjects (p>0.05). The PON1 activity toward paraoxonase was found to be significantly higher in the R/R (Arg/Arg) genotypes than Q/R (Gln/Arg) and lowest in Q/Q (Gln/Gln) genotypes in both workers and control subjects (p<0.001). For PON1(55)LM (Leu/Met), PON1 activity toward paraoxonase was observed to be higher in individuals with L/L (Leu/Leu) genotypes and lowest in individuals with M/M (Met/Met) genotypes in both groups (p<0.001). No influence of PON1 genotypes and phenotypes was seen on the activity of acetylcholinesterase and arylesterase. The DNA damage was observed to be significantly higher in workers than in control subjects (p<0.05). Further, the individuals who showed least paraoxonase activity i.e., those with (Q/Q [Gln/Gln] and M/M [Met/Met]) genotypes showed significantly higher DNA damage compared to other isoforms in workers exposed to OPs (p<0.05). The results indicate that the individuals with PON1 Q/Q and M/M genotypes are more susceptible toward genotoxicity. In conclusion, the study suggests wide variation in enzyme activities and DNA damage due to polymorphisms in PON1 gene, which might have an important role in the identification of individual risk factors in workers occupationally exposed to OPs.
ESTHER : Singh_2011_Toxicol.Appl.Pharmacol_252_130
PubMedSearch : Singh_2011_Toxicol.Appl.Pharmacol_252_130
PubMedID: 21291901

Title : Nature of action of Sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals - Davis_2010_Indian.J.Pharmacol_42_229
Author(s) : Davis JA , Singh S , Sethi S , Roy S , Mittra S , Rayasam G , Bansal V , Sattigeri J , Ray A
Ref : Indian J Pharmacol , 42 :229 , 2010
Abstract : OBJECTIVE: The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model. MATERIALS AND
METHODS: DPP-IV enzyme assay was carried out in human plasma (10 muL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC(50) values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC(50) values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o.
RESULTS: Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin. CONCLUSION: The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.
ESTHER : Davis_2010_Indian.J.Pharmacol_42_229
PubMedSearch : Davis_2010_Indian.J.Pharmacol_42_229
PubMedID: 20927248

Title : Plasticity of animal genome architecture unmasked by rapid evolution of a pelagic tunicate - Denoeud_2010_Science_330_1381
Author(s) : Denoeud F , Henriet S , Mungpakdee S , Aury JM , Da Silva C , Brinkmann H , Mikhaleva J , Olsen LC , Jubin C , Canestro C , Bouquet JM , Danks G , Poulain J , Campsteijn C , Adamski M , Cross I , Yadetie F , Muffato M , Louis A , Butcher S , Tsagkogeorga G , Konrad A , Singh S , Jensen MF , Huynh Cong E , Eikeseth-Otteraa H , Noel B , Anthouard V , Porcel BM , Kachouri-Lafond R , Nishino A , Ugolini M , Chourrout P , Nishida H , Aasland R , Huzurbazar S , Westhof E , Delsuc F , Lehrach H , Reinhardt R , Weissenbach J , Roy SW , Artiguenave F , Postlethwait JH , Manak JR , Thompson EM , Jaillon O , Du Pasquier L , Boudinot P , Liberles DA , Volff JN , Philippe H , Lenhard B , Roest Crollius H , Wincker P , Chourrout D
Ref : Science , 330 :1381 , 2010
Abstract : Genomes of animals as different as sponges and humans show conservation of global architecture. Here we show that multiple genomic features including transposon diversity, developmental gene repertoire, physical gene order, and intron-exon organization are shattered in the tunicate Oikopleura, belonging to the sister group of vertebrates and retaining chordate morphology. Ancestral architecture of animal genomes can be deeply modified and may therefore be largely nonadaptive. This rapidly evolving animal lineage thus offers unique perspectives on the level of genome plasticity. It also illuminates issues as fundamental as the mechanisms of intron gain.
ESTHER : Denoeud_2010_Science_330_1381
PubMedSearch : Denoeud_2010_Science_330_1381
PubMedID: 21097902
Gene_locus related to this paper: oikdi-ACHE , oikdi-cholike.1 , oikdi-cholike.2 , oikdi-e4wug8 , oikdi-e4ww04 , oikdi-e4wxm9 , oikdi-e4x0y9 , oikdi-e4x1t6 , oikdi-e4x2c7.1 , oikdi-e4x2c7.2 , oikdi-e4x4v7 , oikdi-e4x5i7 , oikdi-e4x5s6 , oikdi-e4x6c7 , oikdi-e4x6i0 , oikdi-e4x7y6 , oikdi-e4xa91 , oikdi-e4xe86 , oikdi-e4xeg3 , oikdi-e4xgg8 , oikdi-e4xiw0 , oikdi-e4xk51 , oikdi-e4xl53 , oikdi-e4xm24 , oikdi-e4xm43 , oikdi-e4xn79 , oikdi-e4xp62 , oikdi-e4xpy1 , oikdi-e4xqm4 , oikdi-e4xtm1 , oikdi-e4xug7 , oikdi-e4xv59 , oikdi-e4xw55 , oikdi-e4xwt6 , oikdi-e4xxh8 , oikdi-e4y5n1 , oikdi-e4y7j8 , oikdi-e4y8s7 , oikdi-e4ya76 , oikdi-e4ydw0 , oikdi-e4yi65 , oikdi-e4yp15 , oikdi-e4yp69 , oikdi-e4yst1 , oikdi-e4yvr0 , oikdi-e4yvu0 , oikdi-e4x630 , oikdi-e4ykb2 , oikdi-e4wt97 , oikdi-e4ws23

Title : Epigenetic states and expression of imprinted genes in human embryonic stem cells - Li_2010_World.J.Stem.Cells_2_97
Author(s) : Li SS , Yu SL , Singh S
Ref : World J Stem Cells , 2 :97 , 2010
Abstract : AIM: To investigate the epigenetic states and expression of imprinted genes in five human embryonic stem cell (hESC) lines derived in Taiwan. METHODS: The heterozygous alleles of single nucleotide polymorphisms (SNPs) at imprinted genes were analyzed by sequencing genomic DNAs of hESC lines and the monoallelic expression of the imprinted genes were confirmed by sequencing the cDNAs. The expression profiles of 32 known imprinted genes of five hESC lines were determined using Affymetrix human genome U133 plus 2.0 DNA microarray. RESULTS: The heterozygous alleles of SNPs at seven imprinted genes, IPW, PEG10, NESP55, KCNQ1, ATP10A, TCEB3C and IGF2, were identified and the monoallelic expression of these imprinted genes except IGF2 were confirmed. The IGF2 gene was found to be imprinted in hESC line T2 but partially imprinted in line T3 and not imprinted in line T4 embryoid bodies. Ten imprinted genes, namely GRB10, PEG10, SGCE, MEST, SDHD, SNRPN, SNURF, NDN, IPW and NESP55, were found to be highly expressed in the undifferentiated hESC lines and down-regulated in differentiated derivatives. The UBE3A gene abundantly expressed in undifferentiated hESC lines and further up-regulated in differentiated tissues. The expression levels of other 21 imprinted genes were relatively low in undifferentiated hESC lines and five of these genes (TP73, COPG2, OSBPL5, IGF2 and ATP10A) were found to be up-regulated in differentiated tissues. CONCLUSION: The epigenetic states and expression of imprinted genes in hESC lines should be thoroughly studied after extended culture and upon differentiation in order to understand epigenetic stability in hESC lines before their clinical applications.
ESTHER : Li_2010_World.J.Stem.Cells_2_97
PubMedSearch : Li_2010_World.J.Stem.Cells_2_97
PubMedID: 21607126

Title : Paraoxonases: structure, gene polymorphism & role in coronary artery disease - Gupta_2009_Indian.J.Med.Res_130_361
Author(s) : Gupta N , Gill K , Singh S
Ref : Indian J Med Res , 130 :361 , 2009
Abstract : Paraoxonases (PONs) i.e. PON1, PON2, PON3 are basically lactonases. Of these, PON1 in addition has an efficient esterase activity and can hydrolyze organophosphates. The PONs prevent low density lipoprotein cholesterol (LDL-C) from peroxidation, thereby preventing atherosclerosis. The PON1 is exclusively associated with high density lipoprotein cholesterol (HDL-C) and its antioxidant activity is largely attributed to PON1 located on it. At present, PON1 status i.e. its activity and concentration, is considered to be more important than polymorphism alone, in prevention of coronary artery disease (CAD). Its activity has been found to be affected by a number of pharmacological agents, diet and other factors, thereby becoming a promising target for pharmacological intervention. The PON2 prevents cell mediated lipid peroxidation. However, little is known about the role of PON3. This review describes the structure, gene polymorphism, and factors affecting the activity of PONs, and their role in prevention of CAD.
ESTHER : Gupta_2009_Indian.J.Med.Res_130_361
PubMedSearch : Gupta_2009_Indian.J.Med.Res_130_361
PubMedID: 19942738

Title : Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design - Liang_2008_Bioorg.Med.Chem.Lett_18_3706
Author(s) : Liang GB , Qian X , Biftu T , Singh S , Gao YD , Scapin G , Patel S , Leiting B , Patel R , Wu J , Zhang X , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :3706 , 2008
Abstract : Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.
ESTHER : Liang_2008_Bioorg.Med.Chem.Lett_18_3706
PubMedSearch : Liang_2008_Bioorg.Med.Chem.Lett_18_3706
PubMedID: 18524582
Gene_locus related to this paper: human-DPP4

Title : Discovery of conformationally rigid 3-azabicyclo[3.1.0]hexane-derived dipeptidyl peptidase-IV inhibitors - Sattigeri_2008_Bioorg.Med.Chem.Lett_18_4087
Author(s) : Sattigeri JA , Andappan MM , Kishore K , Thangathirupathy S , Sundaram S , Singh S , Sharma S , Davis JA , Chugh A , Bansal VS
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :4087 , 2008
Abstract : The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.
ESTHER : Sattigeri_2008_Bioorg.Med.Chem.Lett_18_4087
PubMedSearch : Sattigeri_2008_Bioorg.Med.Chem.Lett_18_4087
PubMedID: 18602260

Title : (3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)- 1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Biftu_2007_Bioorg.Med.Chem.Lett_17_49
Author(s) : Biftu T , Feng D , Qian X , Liang GB , Kieczykowski G , Eiermann G , He H , Leiting B , Lyons K , Petrov A , Sinha-Roy R , Zhang B , Scapin G , Patel S , Gao YD , Singh S , Wu J , Zhang X , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :49 , 2007
Abstract : Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
ESTHER : Biftu_2007_Bioorg.Med.Chem.Lett_17_49
PubMedSearch : Biftu_2007_Bioorg.Med.Chem.Lett_17_49
PubMedID: 17055272
Gene_locus related to this paper: human-DPP4

Title : Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin - Biftu_2007_Bioorg.Med.Chem.Lett_17_3384
Author(s) : Biftu T , Scapin G , Singh S , Feng D , Becker JW , Eiermann G , He H , Lyons K , Patel S , Petrov A , Sinha-Roy R , Zhang B , Wu J , Zhang X , Doss GA , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :3384 , 2007
Abstract : Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
ESTHER : Biftu_2007_Bioorg.Med.Chem.Lett_17_3384
PubMedSearch : Biftu_2007_Bioorg.Med.Chem.Lett_17_3384
PubMedID: 17433672
Gene_locus related to this paper: human-DPP4

Title : Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice - Saxena_2007_Pharmacol.Biochem.Behav_86_797
Author(s) : Saxena G , Singh SP , Pal R , Singh S , Pratap R , Nath C
Ref : Pharmacol Biochem Behav , 86 :797 , 2007
Abstract : Gugulipid, an ethyl acetate extract of the resin of plant Commiphora whighitii is an established hypolipidemic agent in clinical practice. The major constituent of gugulipid is guggulsterone [4, 17 (20)-pregnadiene-3, 16-dione]. It has been observed recently that patients receiving lipid-lowering drugs like statins have a reduced risk of dementia. Therefore, the present study was planned to explore the potential of gugulipid as cognitive enhancer. Gugulipid (12.5, 25 and 50 mg/kg, p.o.) showed dose dependent improvement in scopolamine-induced deficits in passive avoidance test. The maximal effective dose of gugulipid i.e. 50 mg/kg, p.o. was used for further studies on streptozotocin (STZ) model of dementia in mice. Gugulipid was investigated for its effect on learning and memory, parameters of oxidative stress (GSH and MDA) and acetylcholinesterase (AChE) activity in the STZ (ic)-treated mice. Intracerebral (ic) injections of STZ (0.5 mg/kg) on 1st and 3rd day caused significant deficit in memory in passive avoidance and Morris water maze test after the 14th day of first dose. In passive avoidance, transfer latency time (TLT) was not increased on retention trials in STZ (ic) group while gugulipid treatment resulted in significant increase in TLT on retention trials in STZ (ic)-treated mice. In Morris water maze test the latency time to reach platform in STZ (ic)-treated mice was significantly higher than control and vehicle (artificial CSF). Pre-treatment of gugulipid (50 mg/kg, p.o.) daily for 14 days started with the first dose of STZ (ic), significantly prevented STZ (ic)-induced memory deficit. Post-treatment i.e. after 14 days of first dose of STZ (ic) of gugulipid (50 mg/kg, p.o.) significantly decreased the latency time indicating anti-dementia activity. Effect of gugulipid and STZ in visible platform test was similar to those seen with hidden platform. Gugulipid and STZ-treated mice did not cause significant change in locomotor activity. Furthermore, STZ (ic) resulted into increase in AChE activity, low level of GSH and high concentration of MDA in brain on 21st day as compared to control. Gugulipid treatment caused significant decrease in AChE activity, low level of MDA and high concentration of GSH in brain following STZ (ic) as compared to vehicle administration in STZ (ic)-treated mice. The study demonstrated that gugulipid has significant protective affect against streptozotocin-induced memory deficits model of dementia that can be attributed to anti-oxidant and anti-AChE activity of gugulipid. These observations suggest gugulipid as a potential anti-dementia drug (CDRI, Lucknow has obtained US patent No. 6896901 for use of gugulipid as cognitive enhancer).
ESTHER : Saxena_2007_Pharmacol.Biochem.Behav_86_797
PubMedSearch : Saxena_2007_Pharmacol.Biochem.Behav_86_797
PubMedID: 17477963

Title : Hyperamylasemia and acute pancreatitis following anticholinesterase poisoning - Singh_2007_Hum.Exp.Toxicol_26_467
Author(s) : Singh S , Bhardwaj U , Verma SK , Bhalla A , Gill K
Ref : Hum Exp Toxicol , 26 :467 , 2007
Abstract : A prospective study was undertaken to find the incidence of hyperamylasemia and acute pancreatitis in patients with anticholinesterase poisoning. This was done by serial estimation of total serum amylase and pancreatic imaging by ultrasonography and confirmed, if necessary, by computerized tomography. Anticholinesterase poisoning was caused by either ingestion or accidental exposure to organophosphates or carbamates; it was diagnosed when patients presented with features of cholinergic crisis, depressed serum butyrylcholinesterase activity of >50% and showed improvement following administration of atropine alone or atropine and 2-PAM. All the patients admitted with anticholinesterase poisoning between July 2001 and June 2005 were prospectively studied for elevated serum amylase. The serum amylase levels were estimated daily up to 10 days in survivors and in nonsurvivors till they survived. Ultrasonography of the abdomen was carried out in all to find swelling of the pancreas. Computerized tomography was undertaken in those who had a swollen pancreas or whose serum amylase levels were elevated significantly (> or =800 S.U). Of the 86 patients enrolled, 79 were taken up for analysis as data were incomplete in 7. Of the 79 patients, serum amylase was found to be elevated that is, >200 S.U. in 37 patients (46.95%). In three patients it was 800 S.U. One of them showed swollen pancreas on ultrasonography, which was confirmed by computerized tomography. This patient had ingested propoxyfur. In the other two patients, evidence of acute pancreatitis was not observed (on autopsy in one who died and on imaging in the other who survived). They had ingested chlorpyrifos. There was no significant correlation between the nature of the compounds (organophosphate or carbamates), inhibition of serum BUChE at admission, duration and severity of cholinergic syndrome and increase and time course of increase in serum amylase. Except for fenthion, significant persistent increase in serum amylase was not observed with individual compounds. The other associated abnormalities were polymorphonuclear leukocytosis (TLC >11,000/cumm) in all 37 patients who had elevated amylase, hyperglycemia (6/37) and, elevated transaminases (6/37). Mild elevation of serum amylase is common in patients with anticholinesterase poisoning. However, acute pancreatitis is rare.
ESTHER : Singh_2007_Hum.Exp.Toxicol_26_467
PubMedSearch : Singh_2007_Hum.Exp.Toxicol_26_467
PubMedID: 17698941

Title : Combination of dipeptidylpeptidase IV inhibitor and low dose thiazolidinedione: preclinical efficacy and safety in db\/db mice - Roy_2007_Life.Sci_81_72
Author(s) : Roy S , Khanna V , Mittra S , Dhar A , Singh S , Mahajan DC , Priyadarsiny P , Davis JA , Sattigeri J , Saini KS , Bansal VS
Ref : Life Sciences , 81 :72 , 2007
Abstract : Thiazolidinediones (TZDs) are currently the most efficacious class of oral antidiabetics. However, they carry the burden of weight gain and haemodilution, which may lead to cardiovascular complications. The present study was designed to ascertain whether a combination of dipeptidyl peptidase IV (DPP IV) inhibitor with low dose of a thiazolidinedione absolves TZD associated weight gain and oedema without compromising its efficacy. In this study, we examined the efficacy and safety of lower dose (1 mg/kg/day) of rosiglitazone, a thiazolidinedione, in combination with 5 mg/kg/day dose of LAF-237 (vildagliptin), a known DPP IV inhibitor, in aged db/db mice after 14 days of treatment and compared the combination with therapeutic dose (10 mg/kg) of rosiglitazone. The combination therapy showed similar efficacy as that of 10 mg/kg/day rosiglitazone in lowering random blood glucose (53.8%, p<0.001 and 54.3%, p<0.001 respectively), AUC ((0-120) min) during oral glucose tolerance test (OGTT) (38.6 %, p<0.01; 38.3%, p<0.01 respectively) and triglyceride levels (63.9% and 61% respectively; p<0.01). Plasma active glucagon like peptide-1 (GLP-1) and insulin levels were found to be elevated significantly (p<0.01 and p<0.05 respectively) in both LAF-237 and combination treated groups following oral glucose load. LAF-237 alone had no effect on random glucose and glucose excursion during OGTT in severely diabetic db/db mice. Interestingly, the combination treatment showed no significant increase in body weight as compared to the robust weight gain by therapeutic dose of rosiglitazone. Rosiglitazone at 10 mg/kg/day showed significant reduction (p<0.05) in haematocrit, RBC count, haemoglobin pointing towards haemodilution associated with increased mRNA expression of Na(+), K(+)-ATPase-alpha and epithelial sodium channel gamma (ENaCgamma) in kidney. The combination therapy escaped these adverse effects. The results suggest that combination of DPP IV inhibitor with low dose of thiazolidinedione can interact synergistically to represent a therapeutic advantage for the clinical treatment of type 2 diabetes without the adverse effects of haemodilution and weight gain associated with thiazolidinediones.
ESTHER : Roy_2007_Life.Sci_81_72
PubMedSearch : Roy_2007_Life.Sci_81_72
PubMedID: 17532347

Title : Study of the experimental conditions for the lipase production by a newly isolated strain of Pseudomonas aeruginosa for the enantioselective hydrolysis of (+\/-)-methyl trans-3(4-methoxyphenyl) glycidate - Singh_2006_Bioprocess.Biosyst.Eng_28_341
Author(s) : Singh S , Kaur G , Chakraborti AK , Jain RK , Banerjee UC
Ref : Bioprocess Biosyst Eng , 28 :341 , 2006
Abstract : A lipase producing bacterium has been isolated from the soil to enantiospecifically hydrolyze the (+/-)-methyl trans-3(4-methoxyphenyl) glycidate (MPGM), an intermediate in the synthesis of cardiovascular drug, diltiazem. This hydrolysis provided the desired (-)-MPGM in 44% yield with 99% enantiomeric excess. The organism was identified and confirmed as Pseudomonas aeruginosa by 16S rRNA sequencing. The various physiochemical parameters have been optimized for the maximum production of lipase in shake flask. Beef extract was found to be the best nitrogen source for lipase production. The optimized cultivation conditions were 30 degrees C with an initial medium pH 8 in shake flask. Both inoculum age and inoculum concentration have positive effect on the lipase production and (+/-)-MPGM (3 mM) was found to be the optimal inducer.
ESTHER : Singh_2006_Bioprocess.Biosyst.Eng_28_341
PubMedSearch : Singh_2006_Bioprocess.Biosyst.Eng_28_341
PubMedID: 16411073

Title : Myasthenic crisis: a retrospective study - Panda_2004_Neurol.India_52_453
Author(s) : Panda S , Goyal V , Behari M , Singh S , Srivastava T
Ref : Neurol India , 52 :453 , 2004
Abstract : BACKGROUND AND OBJECTIVE: Myasthenic crisis (MC) is one of the important and common complications in the natural history of myasthenia gravis (MG). MC can be precipitated by multiple factors including deficiency or excess of the acetylcholinesterase inhibitors (AChEI). Any episode of MC is an emergency requiring aggressive therapy. We studied the demographic, clinical and treatment-related characteristics of patients who developed MC. MATERIALS AND
METHODS: A retrospective study was conducted in patients with MC admitted during a 31-month period from February 1999 to August 2001, at a tertiary care center in India.
RESULTS: Eleven patients (9.69% of the total 114 patients with MG) were admitted with 12 episodes of MC. Mean age at presentation was 39.83 + 13.18 years with male predominance. Seven patients had undergone thymectomy previously; of which 2 had postoperative MC. Six patients had thymoma. Steroid or cholinesterase inhibitor withdrawal and infections were the commonest precipitating factors for MC. Patients required ventilatory support for median 14 days. They responded to low volume of plasma exchange (PE) (mean 854 ml / day with mean 6.5 cycles per patient).
CONCLUSIONS: This report highlights that the subset of Indian patients with MG who are at risk to develop MC belong to the 3rd and 4th decade, have bulbar symptoms at presentation and are associated with thymoma. Patients with MC should have judicious drug adjustments under supervision and should be treated aggressively during impending MC.
ESTHER : Panda_2004_Neurol.India_52_453
PubMedSearch : Panda_2004_Neurol.India_52_453
PubMedID: 15626832

Title : Enzyme inhibition by the molluscicidal agent Punica granatum Linn. bark and Canna indica Linn. root - Tripathi_2004_Phytother.Res_18_501
Author(s) : Tripathi SM , Singh VK , Singh S , Singh DK
Ref : Phytother Res , 18 :501 , 2004
Abstract : Sublethal in vivo 24 h exposure to (40% and 80% of 24 h LC(50)) active fractions of Punica granatum bark or Canna indica root or in combination with other plant-derived molluscicides significantly inhibited the activity of acetylcholinesterase, acid/alkaline phosphatase, Na(+)K(+)ATPase and lactic dehydrogenase in the nervous tissue of Lymnaea acuminata. The inhibition kinetics of these enzymes indicates that active fractions of both the plants caused a competitive inhibition of AChE, LDH, ALP, ACP and Na(+)K(+)ATPase.
ESTHER : Tripathi_2004_Phytother.Res_18_501
PubMedSearch : Tripathi_2004_Phytother.Res_18_501
PubMedID: 15305305

Title : Organophosphorus poisoning (acute) -
Author(s) : Eddleston M , Singh S , Buckley N
Ref : Clin Evid , :1941 , 2004
PubMedID: 15865762

Title : Acute pancreatitis following propoxyfur (Baygon) ingestion - Singh_2003_J.Assoc.Physicians.India_51_78
Author(s) : Singh S , Parthasarathy S , Sud A , Wanchu A , Bambery P
Ref : J Assoc Physicians India , 51 :78 , 2003
Abstract : Elevation of serum amylase and blood glucose is not uncommon following anticholinesterase poisoning. We report a young male who developed acute cholinergic crisis and acute pancreatitis following propoxyfur (Baygon) ingestion and recovered completely with conservative management.
ESTHER : Singh_2003_J.Assoc.Physicians.India_51_78
PubMedSearch : Singh_2003_J.Assoc.Physicians.India_51_78
PubMedID: 12693465

Title : A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba. Anticholinesterase and cognitive enhancing activities - Das_2002_Pharmacol.Biochem.Behav_73_893
Author(s) : Das A , Shanker G , Nath C , Pal R , Singh S , Singh H
Ref : Pharmacol Biochem Behav , 73 :893 , 2002
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.
ESTHER : Das_2002_Pharmacol.Biochem.Behav_73_893
PubMedSearch : Das_2002_Pharmacol.Biochem.Behav_73_893
PubMedID: 12213536

Title : Lewy body dementia: case report and discussion - Khotianov_2002_J.Am.Board.Fam.Pract_15_50
Author(s) : Khotianov N , Singh R , Singh S
Ref : J Am Board Fam Pract , 15 :50 , 2002
Abstract : BACKGROUND: Lewy body dementia is a common but frequently underdiagnosed cause of dementia often mistaken for the more familiar entity of Alzheimer disease. Clinically the distinction is important, because it can have profound implications for management. METHODS: The medical literature was searched using the keywords "Lewy bodies," "Lewy body dementia," "Alzheimer dementia," and "parkinsonian disorders." A case of Lewy body dementia is described. RESULTS: An elderly man had long-standing diagnoses of Alzheimer disease and Parkinson disease. After he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status. Evidence from the literature suggests that Lewy body dementia can be diagnosed in primary care settings based on clinical criteria. The physician should be alert to this diagnosis, and special attention should be paid to dementia patients who exhibit parkinsonism, hallucinations, fluctuating cognition, or prominent visuosperceptual deficits.
CONCLUSIONS: The diagnosis of Lewy body dementia has important implications. It is associated with a high incidence of neuroleptic sensitivity, necessitating great caution in the use of these common antipsychotic agents. Early studies indicate cholinesterase inhibitors can be beneficial for treating the hallucinations and behavior disturbances that afflict these patients and might also improve cognition.
ESTHER : Khotianov_2002_J.Am.Board.Fam.Pract_15_50
PubMedSearch : Khotianov_2002_J.Am.Board.Fam.Pract_15_50
PubMedID: 11841138

Title : Aggressive atropinisation and continuous pralidoxime (2-PAM) infusion in patients with severe organophosphate poisoning: experience of a northwest Indian hospital - Singh_2001_Hum.Exp.Toxicol_20_15
Author(s) : Singh S , Chaudhry D , Behera D , Gupta D , Jindal SK
Ref : Hum Exp Toxicol , 20 :15 , 2001
Abstract : OBJECTIVE: The aim of the study was to find whether continuous pralidoxime (2-PAM) infusion along with aggressive atropinisation improves the outcome in patients with severe organophosphate poisoning who require assisted ventilation.
METHODS: Sixteen patients admitted to the respiratory intensive care unit (RICU) with severe organophosphate poisoning and requiring assisted ventilation were included in the study. The compounds involved were phorate (six), dichlorvos (four), oxydimeton methyl (one), monocrotophos (one), methyl parathion (one) and in three it was unknown. After decontamination, they were given intravenous (iv) bolus atropine 5 mg at onset and then 2.5 mg every 5-10 min till atropinisation was achieved, and then maintained either by intermittent bolus doses or by continuous infusion if the required dose was large. They were also given continuous iv infusion of 2-PAM in dose of 7.5 mg/ kg body weight/h (maximum 500 mg/h) after an initial bolus dose of 2 g.
RESULTS: The mean (+/-S.D.) dose of atropine was 735.02 +/- 742.98 mg (range 85-3000 mg) with maximum dose on day 1. The mean (+/-S.D) duration of 2-PAM infusion was 96.4+/-49.4 h (range 10-216 h). The mean (+/-S.D) duration of mechanical ventilation (MV) was 131.5 +/- 95.65 h (range 4-336 h). Fourteen patients could be successfully extubated and two died of bronchopneumonia and sepsis (mortality 12.5%). CONCLUSION: Continuous 2-PAM infusion along with aggressive atropinisation after initial decontamination improved the outcome but not the duration of MV in severely intoxicated patients with organophosphate compounds who required assisted ventilation in this case series.
ESTHER : Singh_2001_Hum.Exp.Toxicol_20_15
PubMedSearch : Singh_2001_Hum.Exp.Toxicol_20_15
PubMedID: 11339619

Title : Factors influencing the low-frequency associated nicotinic ACh autoreceptor-mediated depression of ACh release from rat motor nerve terminals - Prior_2000_Br.J.Pharmacol_129_1067
Author(s) : Prior C , Singh S
Ref : British Journal of Pharmacology , 129 :1067 , 2000
Abstract : 1. We have studied the inhibitory autoreceptor control of acetylcholine (ACh) release from rat motor nerve endings using an electrophysiological technique to quantify evoked ACh release in isolated hemidiaphragm muscles. Quantal ACh release (m) was estimated from the ratio of amplitudes of nerve evoked endplate currents and spontaneously occurring miniature endplate currents. 2. The nicotinic ACh receptor agonist cytisine (1 microM) decreased m at 0.5 Hz by around 20% but had no effect on m at 50 Hz. Changing the extracellular Ca(2+) concentration from 1.8 mM to either 0.45 or 3.6 mM abolished the effect of cytisine on m at 0.5 Hz. The nicotinic ACh receptor antagonist hexamethonium (200 microM) increased m at 0.5 Hz by 15 - 20%. 3. The effects of cytisine and hexamethonium on m at 0.5 Hz were blocked by 10 microM verapamil, which itself significantly increased m. However, the effects of cytisine and hexamethonium on m at 0.5 Hz were not sensitive to 10 microM of the calmodulin antagonist, W-7. This concentration of W-7 attenuates effects on ACh release mediated by facilitatory prejunctional nicotinic ACh autoreceptors. 4. Our present observations are suggestive of actions of cytisine and hexamethonium to activate and inhibit respectively negative-feedback prejunctional nicotinic ACh autoreceptors. Further, they strengthen the case for the existence of two separate and independent autoregulatory mechanisms for the control of ACh release from motor nerve terminals and give a preliminary insight into the cellular mechanism involved in the autoinhibition of ACh release.
ESTHER : Prior_2000_Br.J.Pharmacol_129_1067
PubMedSearch : Prior_2000_Br.J.Pharmacol_129_1067
PubMedID: 10725254

Title : Aspirin esterases in North-West Indians: the influence of age and nutrition - Singh_2000_Int.J.Clin.Pharmacol.Ther_38_315
Author(s) : Singh S , Nain CK , Verma M , Leelamma CO , Goel RC
Ref : Int J Clinical Pharmacology & Therapeutics , 38 :315 , 2000
Abstract : OBJECTIVE: To determine the activity of aspirin esterases in North-West Indian population and to find the effect of age and nutrition on it. SUBJECTS, MATERIAL AND
METHODS: The serum albumin, plasma cholinesterase (PChE), aspirin esterase (ASPES) and phenyl acetate esterase (PAE) were determined in 175 subjects: young (< 40 years) and healthy (BMI > 19) = 74; elderly (> 50 years) and healthy (BMI > 19) = 32; young (< 40 years) and emaciated (BMI < 19) = 44; elderly (> 50 years) and emaciated (BMI < 19) = 25).
RESULTS: The serum albumin levels significantly decreased with increase in age (r = -0.384, p < 0.01) and with decrease in body mass index (r = 0.457, p < 0.01). When the activity of esterases in four groups was compared, the PAE activity was not found to be affected by age or nutrition and the ASPES and PChE activity were significantly lower only in elderly emaciated (p < 0.01). CONCLUSION: As elderly emaciated have decreased serum albumin, ASPES and PChE activity, they may need a lower dose of aspirin to achieve the desired antiplatelet and analgesic effect. The young emaciated subjects, in spite of their lower serum albumin levels, may not require a lower dose of aspirin.
ESTHER : Singh_2000_Int.J.Clin.Pharmacol.Ther_38_315
PubMedSearch : Singh_2000_Int.J.Clin.Pharmacol.Ther_38_315
PubMedID: 10890581

Title : Effect of active molluscicidal component of spices on different enzyme activities and biogenic amine levels in the nervous tissue of Lymnaea acuminata - Singh_1999_Phytother.Res_13_649
Author(s) : Singh VK , Singh S , Singh DK
Ref : Phytother Res , 13 :649 , 1999
Abstract : In vivo exposure of Lymnaea acuminata to thymol and [6]-gingerol (active molluscicidal components of Trachyspermum ammi and Zingiber officinale, respectively) indicates that they significantly alter acetylcholinesterase, lactic dehydrogenase, succinic dehydrogenase and cyto-oxidase activity in the nervous -tissue of snails. In vitro exposure showed that, except for acetylcholinesterase and lactic dehydrogenase, no significant changes were observed in cyto-oxidase and succinic dehydrogenase activity in the nervous tissue of L. acuminata. Sublethal exposure to thymol and [6]-gingerol reduced the levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the nervous tissue of L. acuminata. There was, however, no significant change in the level of 5-hydroxy indol acetic acid (5-HIAA). Thymol and [6]-gingerol thus affects all the known neurotransmission mechanisms in the snail either separately or through a complex interaction between the different neurotransmitters. This may account for their toxicity to snails.
ESTHER : Singh_1999_Phytother.Res_13_649
PubMedSearch : Singh_1999_Phytother.Res_13_649
PubMedID: 10594932

Title : Prejunctional effects of the nicotinic ACh receptor agonist dimethylphenylpiperazinium at the rat neuromuscular junction - Singh_1998_J.Physiol_511 ( Pt 2)_451
Author(s) : Singh S , Prior C
Ref : The Journal of Physiology , 511 ( Pt 2) :451 , 1998
Abstract : 1. We have studied the effects of the nicotinic acetylcholine (ACh) receptor agonist dimethylphenylpiperazinium (DMPP) on the evoked release of ACh from motor terminals in the rat isolated hemidiaphragm using an electrophysiological approach. 2. DMPP (1-4 microM) had no effect on the rate of spontaneous quantal ACh release but increased the number of quanta of ACh released per impulse during 50 Hz stimulation. The DMPP-induced increase in evoked ACh release was dependent on the frequency of stimulation, being absent when it was reduced to 0.5 Hz, but was not Ca2+ dependent, being unaffected at 50 Hz by a 4-fold decrease in the extracellular Ca2+ concentration. 3. The facilitation of evoked ACh release at 50 Hz by 2 microM DMPP was abolished by 10 microM of the calmodulin antagonist W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide hydrochloride) and, in the presence of W7, 2 microM DMPP depressed evoked ACh release at 0.5 Hz. The ability of the nicotinic ACh receptor antagonist vecuronium (1 microM) to depress evoked ACh release at 50 Hz was also abolished by 10 microM W7. 4. The present findings demonstrate, using an electrophysiological technique, that DMPP can produce changes in the evoked ACh release from rat motor nerve terminals that are consistent with the existence of facilitatory nicotinic ACh receptors on the motor nerve endings. Further, they indicate a role for calmodulin-dependent systems in this facilitatory effect of the compound.
ESTHER : Singh_1998_J.Physiol_511 ( Pt 2)_451
PubMedSearch : Singh_1998_J.Physiol_511 ( Pt 2)_451
PubMedID: 9706022

Title : Selective blockade of the delayed rectifier potassium current by tacrine in Drosophila - Kraliz_1997_J.Neurobiol_32_1
Author(s) : Kraliz D , Singh S
Ref : Journal of Neurobiology , 32 :1 , 1997
Abstract : Tetrahydroaminoacridine (tacrine) is an anticholinesterase agent used in the treatment of Alzheimer's disease. Its effectiveness against dementia is attributed to its inhibition of acetylcholine breakdown in the synaptic cleft. Tacrine has also been shown to block ionic currents, including many types of potassium (K+) currents, calcium currents, and sodium currents. However, the physiologic significance of this blockade, especially with respect to its effectiveness against Alzheimer's disease, is not clear because of relatively high (several hundred micromolar to millimolar) concentrations of tacrine employed in many studies of channel blockade, and because it blocks several types of currents. A complete mutational and pharmacologic resolution of ionic currents in the larval muscles of Drosophila allowed us to examine the selectivity of tacrine's effects at very low concentrations. At concentrations as low as 10 microM, tacrine selectively blocked the delayed rectifier K+ current without affecting the three other K+ currents or the calcium channel current in these cells. It also increased the duration of the action potentials significantly. An interesting aspect of tacrine's selectivity is that the current blocked by it is the quinidine-sensitive delayed rectifier K+ current rather than the 4-aminopyridine (4-AP)-sensitive transient K+ current. This is in contrast to the generally emphasized structural relationship between tacrine and 4-AP. Since tacrine is structurally related to quinidine as well, these observations suggest a structural basis for the selectivity of tacrine, 4-AP, and quinidine for specific K+ channels. Furthermore, the data are consistent with the possibility of increased neurotransmitter release, due to prolonged presynaptic action potentials, acting synergistically with the anticholinesterase activity of tacrine to increase its therapeutic effectiveness.
ESTHER : Kraliz_1997_J.Neurobiol_32_1
PubMedSearch : Kraliz_1997_J.Neurobiol_32_1
PubMedID: 8989658

Title : Some physicochemical properties of human milk bile-salt activated lipase - Singh_1991_Indian.J.Biochem.Biophys_28_155
Author(s) : Singh S , Gupta J
Ref : Indian J Biochem Biophys , 28 :155 , 1991
Abstract : Influence of pH, deoxycholate and denaturing reagents on human milk bile-salt activated lipase (EC has been studied. It appears that pH between 5.0-8.0 has no significant effect on the secondary structure of this lipase, but its higher order structures are affected. Lipase-dependent 8-anilino-1-naphthalene sulphonate fluorescence has revealed that the deoxycholate activated form of lipase has a surface rich in hydrophobic amino acid residues. Circular dichroism and second derivative electronic absorption spectroscopic observations have also provided an evidence for deoxycholate-induced alterations in the surface conformation of this lipase.
ESTHER : Singh_1991_Indian.J.Biochem.Biophys_28_155
PubMedSearch : Singh_1991_Indian.J.Biochem.Biophys_28_155
PubMedID: 1879872

Title : Thin-layer chromatographic examination of the degradation of centbucridine in aqueous solutions - Baveja_1987_J.Chromatogr_396_337
Author(s) : Baveja SK , Singh S
Ref : Journal of Chromatography , 396 :337 , 1987
Abstract : Centbucridine (9-n-butylamino-1,2,3,4-tetrahydroacridine) is a new potent local anaesthetic. Its degradation in aqueous solutions has been investigated with the help of thin-layer chromatography. Apart from the degradation products 9-amino-1,2,3,4-tetrahydroacridine and 1,2,3,4-tetrahydroacridone, acridone was also found to be present. It is shown that the acridone is produced not through a dehydrogenation reaction but some other unknown pathway.
ESTHER : Baveja_1987_J.Chromatogr_396_337
PubMedSearch : Baveja_1987_J.Chromatogr_396_337
PubMedID: 3624379

Title : Investigation of some biochemical genetic markers in four endogamous groups from Panjab (N. W. India). I. Protein and enzyme polymorphisms in serum -
Author(s) : Singh S , Sareen KN , Goedde HW
Ref : Humangenetik , 21 :341 , 1974
PubMedID: 4134629

Title : Pseudocholinesterase polymorphism among alanders (Finno-Swedes), maris (Cheremisses, USSR) and greenland eskimos, and the segregation of some E1 and E2 locus types in Finnish Lapp Families -
Author(s) : Singh S , Saternus K , Munsch H , Altland K , Goedde HW , Eriksson AW
Ref : Hum Hered , 24 :352 , 1974
PubMedID: 4461660

Title : Population genetic studies of serum protein polymorphisms in four Spanish populations. II -
Author(s) : Goedde HW , Hirth L , Benkmann HG , Pellicer A , Pellicer T , Stahn M , Singh S
Ref : Hum Hered , 23 :135 , 1973
PubMedID: 4756852

Title : Genetic survey in the population of Assam. II. Serum protein and erythrocyte enzyme polymorphisms -
Author(s) : Goedde HW , Benkmann HG , Singh S , Das BM , Chakravartti MR , Delbruck H , Flatz G
Ref : Hum Hered , 22 :331 , 1972
PubMedID: 4647198

Title : Family studies on the third component of complement (C3), 1-antitrypsin and pseudocholinesterase polymorphism (locus E 1 and E 2 ) in the area of Marburg (Germany) -
Author(s) : Goedde HW , Hirth L , Benkmann HG , Singh S , Wendt GG
Ref : Humangenetik , 17 :85 , 1972
PubMedID: 4647726

Title : A study of the pseudocholinesterase polymorphism among a panjabi population -
Author(s) : Singh S , Amma MK , Sareen KN , Goedde HW
Ref : Hum Hered , 21 :388 , 1971
PubMedID: 5139254

Title : Pseudocholinesterase polymorphism among Lapp populations in Finland - Singh_1971_Humangenetik_12_131
Author(s) : Singh S , Jensen M , Goedde HW , Lehmann W , Pyorala K , Eriksson AW
Ref : Humangenetik , 12 :131 , 1971
Abstract :
ESTHER : Singh_1971_Humangenetik_12_131
PubMedSearch : Singh_1971_Humangenetik_12_131
PubMedID: 5568731