Sharma P

References (50)

Title : N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation - Sharma_2023_Chem.Biol.Drug.Des__
Author(s) : Sharma P , Singh V , Singh M
Ref : Chemical Biology Drug Des , : , 2023
Abstract : The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC(50) = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.
ESTHER : Sharma_2023_Chem.Biol.Drug.Des__
PubMedSearch : Sharma_2023_Chem.Biol.Drug.Des__
PubMedID: 37599098

Title : Neuroprotective activity of novel phenanthrene derivative from Grewia tiliaefolia by in vitro and in silico studies - Rajput_2023_Sci.Rep_13_2444
Author(s) : Rajput A , Sharma P , Kumar N , Kaur S , Arora S
Ref : Sci Rep , 13 :2444 , 2023
Abstract : Medicinal plants possess range of phytochemicals accountable for their diverse biological activities. Presently, such compounds have been isolated from medicinal plants, characterized and evaluated for their pharmacological potential. In the present study, the efforts have been made to isolate the compound(s) from Grewia tiliaefolia Vahl., plant known for its ameliorative effect on brain related diseases such as anxiety, depression, cognitive disorders and Parkinson's disease. Plant extract was subjected to isolation of compound(s) using column chromatography and isolated compound was characterized by NMR FTIR and LCMS. The isolated compound was novel with the IUPAC name of the compound is propyl 3-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylate, designated as A-1 and has not been reported before. A-1 was further evaluated for its antioxidant potential using in vitro antioxidant assays (2,2-diphenyl-1-picryl-hydrazyl-hydrate, DPPH assay and reducing power assay, RPA). Also, Acetylcholinesterase (AChE) inhibitory potential of A-1 and extract was analysed. Results showed that A-1 exhibited significantly higher antioxidant activity in both DPPH and RPA assay as compared to plant extract. In case of AChE inhibitory activity again, A-1 has shown significantly higher activity as compared to plant extract. In silico study was conducted to predict its action on proteins playing crucial role in neurological and neurodegenerative disorders such as gamma amino butyric acid (GABA) receptor and glutamate alpha amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu AMPA) receptor in epilepsy and AChE enzyme in Alzheimer's diseases. The compound has shown interaction in following order: AChE > GABA receptor > Glu AMPA receptor. Further, molecular dynamic simulations and ADME studies of A-1 and AChE enzyme revealed that A-1 yielded good results in all parameters and hence can relieve Alzheimer's like symptoms.
ESTHER : Rajput_2023_Sci.Rep_13_2444
PubMedSearch : Rajput_2023_Sci.Rep_13_2444
PubMedID: 36765125

Title : Beyond molecular recognition: Perylene bisimide derivative as functional mimic of chlorpyrifos - Devi_2023_Chem.Asian.J__e202300406
Author(s) : Devi M , Sharma P , Sharma N , Kaur S , Sharma K , Raghav N , Singh L , Bhatti R , Kumar M , Bhalla V
Ref : Chem Asian J , :e202300406 , 2023
Abstract : Supramolecular assemblies of perylene bisimide derivative (PBI-SAH) have been developed which show 'turn-on' detection of chlorpyrifos in aqueous media, apple residue and blood serum. Differently from the already reported fluorescent probes for the detection of CPF, PBI-SAH assemblies also show affinity for acetylcholinesterase (AChE) which endow the PBI-SAH molecules with mixed inhibitory potential to restrict the AChE catalysed hydrolysis of acetylthiocholine (ATCh) in MG-63 cell lines (in vitro) and in mice (in vivo). The molecular docking studies support the inhibitory activity of PBI-SAH assemblies and their potential to act as safe insecticide with high benefit to harm ratio. The insecticidal potential of PBI-SAH derivative has been examined against Spodoptera litura (S. litura) and these studies demonstrate its excellent insecticidal activity (100% mortality in nineteen days). To the best of our knowledge, this is the first report regarding development of PBI-SAH assemblies which not only detect chlorpyrifos but also mimic AChE inhibitory activity of CPF to show promising aptitude as safe insecticide.
ESTHER : Devi_2023_Chem.Asian.J__e202300406
PubMedSearch : Devi_2023_Chem.Asian.J__e202300406
PubMedID: 37602577

Title : An ongoing journey of chalcone analogues as single and multi-target ligands in the field of Alzheimer's disease: A review with structural aspects - Sharma_2023_Life.Sci__121568
Author(s) : Sharma P , Singh M
Ref : Life Sciences , :121568 , 2023
Abstract : Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder with progressive dementia and cognitive impairment. AD poses severe health challenge in elderly people and become one of the leading causes of death worldwide. It possesses complex pathophysiology with several hypotheses (cholinergic hypothesis, amyloid hypothesis, tau hypothesis, oxidative stress, mitochondrial dysfunction etc.). Several attempts have been made for the management of multifactorial AD. Acetylcholinesterase is the only target has been widely explored in the management of AD to the date. The current review set forth the chalcone based natural, semi-synthetic and synthetic compounds in the search of potential anti-Alzheimer's agents. The main highlights of current review emphasizes on chalcone target different enzymes and pathways like Acetylcholinesterase, beta-secretase (BACE1), tau proteins, MAO, free radicals, Advanced glycation end Products (AGEs) etc. and their structure activity relationships contributing in the inhibition of above mentioned various targets of AD.
ESTHER : Sharma_2023_Life.Sci__121568
PubMedSearch : Sharma_2023_Life.Sci__121568
PubMedID: 36925061

Title : Impact of Chronic Sodium Fluoride Toxicity on Antioxidant Capacity, Biochemical Parameters, and Histomorphology in Cardiac, Hepatic, and Renal Tissues of Wistar Rats - Sharma_2022_Biol.Trace.Elem.Res__
Author(s) : Sharma P , Verma PK , Sood S , Singh M , Verma D
Ref : Biol Trace Elem Res , : , 2022
Abstract : The study was designed to determine the fluoride distribution after its oral exposure in drinking water and its associated impact on biochemical, antioxidant markers and histology in the liver, kidney, and heart of male Wistar rats. On 100 ppm exposure, the highest accretion of fluoride occurred in the liver followed by the kidney and heart. Fluoride exposure significantly (p0.05) increased the plasma levels of dehydrogenase, aminotransferases, kidney injury molecule-1 (KIM-1), and other plasma renal biomarkers but decreased the levels of total plasma proteins and albumin in a dose-dependent manner. Reduction (p0.05) in the activities of antioxidant enzymes viz. acetylcholinesterase, arylesterase, superoxide dismutase, catalase, glutathione peroxidase, and reductase with increased levels of protein and lipid peroxidation was recorded in the liver, kidney, and heart of fluoride-administered rats. Fluoride exposure (100 ppm) induced lipid peroxidation was highest in kidney (4.4 times) followed by liver (2.6 times) and heart (2.5 times) and as compared to their respective control. The percent rise in protein oxidation at 30% was almost equal in the kidney and liver but was 21.5% in the heart as compared to control. The histopathological alterations observed included congestion and hemorrhage along with degeneration and necrosis of parenchymal cells in hepato-renal tissues and myocardium, severity of which varied in a dose-dependent manner. Taken together, fluoride distribution in the liver, heart, and kidney after chronic fluoride intake correlated well with fluoride-induced hepatic and cardio-renal toxicity in a concentration-dependent manner. These results draw attention that chronic fluoride intake pose a significant health risk for human and animal residents of fluoride endemic areas.
ESTHER : Sharma_2022_Biol.Trace.Elem.Res__
PubMedSearch : Sharma_2022_Biol.Trace.Elem.Res__
PubMedID: 35023047

Title : Salubrious effects of ulinastatin and quercetin alone or in combination in endothelial dysfunction and vascular dementia - Sharma_2022_Pharmacol.Rep__
Author(s) : Sharma P , Gaur N , Jayant S , Sharma BM , Singh B , Kharkwal H , Sharma B
Ref : Pharmacol Rep , : , 2022
Abstract : BACKGROUND: Vascular dementia is the second most prevalent form of dementia. Hypertension is the leading risk factor for endothelial dysfunction and the progression of dementia that is of vascular origin. This study investigates the role of ulinastatin (UTI) and quercetin alone as well as in combination in hypertension-induced endothelial dysfunction and vascular dementia (VaD). METHOD: Two-kidney one-clip (2K1C) renovascular model was set up to induce hypertension in the Albino Wistar rats (males). Rats were assessed for mean arterial blood pressure, behavioral function (Morris water maze, attention set-shifting tests), vascular endothelial function, and biochemical levels (aortic superoxide anion and serum nitrite/nitrate), as well as brains' thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, interleukin-6, 10, tumor necrosis factor-TNF-alpha and acetylcholinesterase-AChE). UTI (10,000 U/kg, ip) and quercetin (60 mg/kg) were used alone and in combination for treatment. Donepezil (0.5 mg/kg) was used as a positive control. RESULTS: 2K1C rats showed impairment in learning, memory, executive functioning, and reversal learning. These rats further showed endothelial dysfunction as well as an increase in mean arterial blood pressure, brains' oxidative stress, inflammation, and AChE-activity. Treatment with UTI and quercetin alone as well in combination significantly attenuated the 2K1C model induced impairments in the behavioural, biochemical, and endothelial parameters. CONCLUSION: 2K1C renovascular hypertension-induced impairment in behavioural, biochemical, and endothelial parameters were attenuated by the treatment with UTI and quercetin alone as well as in combination. Therefore, the utility of these agents might be studied further to understand their full potential in hypertension-induced VaD.
ESTHER : Sharma_2022_Pharmacol.Rep__
PubMedSearch : Sharma_2022_Pharmacol.Rep__
PubMedID: 35396697

Title : Mechano-chemical and biological energetics of immobilized enzymes onto functionalized polymers and their applications - Sharma_2022_Bioengineered_13_10518
Author(s) : Sharma T , Xia C , Sharma A , Raizada P , Singh P , Sharma S , Sharma P , Kumar S , Lam S , Nadda AK
Ref : Bioengineered , 13 :10518 , 2022
Abstract : Enzymes of commercial importance, such as lipase, amylase, laccase, phytase, carbonic anhydrase, pectinase, maltase, glucose oxidase etc., show multifunctional features and have been extensively used in several fields including fine chemicals, environmental, pharmaceutical, cosmetics, energy, food industry, agriculture and nutraceutical etc. The deployment of biocatalyst in harsh industrial conditions has some limitations, such as poor stability. These drawbacks can be overcome by immobilizing the enzyme in order to boost the operational stability, catalytic activity along with facilitating the reuse of biocatalyst. Nowadays, functionalized polymers and composites have gained increasing attention as an innovative material for immobilizing the industrially important enzyme. The different types of polymeric materials and composites are pectin, agarose, cellulose, nanofibers, gelatin, and chitosan. The functionalization of these materials enhances the loading capacity of the enzyme by providing more functional groups to the polymeric material and hence enhancing the enzyme immobilization efficiency. However, appropriate coordination among the functionalized polymeric materials and enzymes of interest plays an important role in producing emerging biocatalysts with improved properties. The optimal coordination at a biological, physical, and chemical level is requisite to develop an industrial biocatalyst. Bio-catalysis has become vital aspect in pharmaceutical and chemical industries for synthesis of value-added chemicals. The present review describes the current advances in enzyme immobilization on functionalized polymers and composites. Furthermore, the applications of immobilized enzymes in various sectors including bioremediation, biosensor and biodiesel are also discussed.
ESTHER : Sharma_2022_Bioengineered_13_10518
PubMedSearch : Sharma_2022_Bioengineered_13_10518
PubMedID: 35443858

Title : Neurobehavioral and neurobiochemical effect of atomoxetine and N-acetylcysteine in streptozotocin diabetes induced endothelial dysfunction and related dementia - Aggarwal_2022_Physiol.Behav__113767
Author(s) : Aggarwal H , Gupta S , Sharma P , Sharma BM , Sharma B
Ref : Physiol Behav , :113767 , 2022
Abstract : Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50mg/kg i.p) was administered to Albino Wistar rats (male, 200-250g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-alpha, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mgkg(-1)/ 4 mgkg(-1)) and N-acetylcysteine- NAC (250 mgkg(-1)/ 500 mgkg(-1)) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5mg kg-(1)) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.
ESTHER : Aggarwal_2022_Physiol.Behav__113767
PubMedSearch : Aggarwal_2022_Physiol.Behav__113767
PubMedID: 35245527

Title : Urinary Incontinence and Alzheimer's Disease: Insights From Patients and Preclinical Models - Bartolone_2021_Front.Aging.Neurosci_13_777819
Author(s) : Bartolone SN , Sharma P , Chancellor MB , Lamb LE
Ref : Front Aging Neurosci , 13 :777819 , 2021
Abstract : Alzheimer's disease effects a large percentage of elderly dementia patients and is diagnosed on the basis of amyloid plaques and neurofibrillary tangles (NFTs) present in the brain. Urinary incontinence (UI) is often found in the elderly populations and multiple studies have shown that it is more common in Alzheimer's disease patients than those with normal cognitive function. However, the link between increased UI and Alzheimer's disease is still unclear. Amyloid plaques and NFTs present in micturition centers of the brain could cause a loss of signal to the bladder, resulting in the inability to properly void. Additionally, as Alzheimer's disease progresses, patients become less likely to recognize the need or understand the appropriate time and place to void. There are several treatments for UI targeting the muscarinic and beta3 adrenergic receptors, which are present in the bladder and the brain. While these treatments may aid in UI, they often have effects on the brain with cognitive impairment side-effects. Acetylcholine esterase inhibitors are often used in treatment of Alzheimer's disease and directly oppose effects of anti-muscarinics used for UI, making UI management in Alzheimer's disease patients difficult. There are currently over 200 pre-clinical models of Alzheimer's disease, however, little research has been done on voiding disfunction in these models. There is preliminary data suggesting these models have similar voiding behavior to Alzheimer's disease patients but much more research is needed to understand the link between UI and Alzheimer's disease and discover better treatment options for managing both simultaneously.
ESTHER : Bartolone_2021_Front.Aging.Neurosci_13_777819
PubMedSearch : Bartolone_2021_Front.Aging.Neurosci_13_777819
PubMedID: 34975457

Title : Efficacy of Ulinastatin and Sulforaphane Alone or in Combination in Rat Model of Streptozotocin Diabetes Induced Vascular Dementia - Sharma_2021_Clin.Psychopharmacol.Neurosci_19_470
Author(s) : Sharma P , Kaushik P , Jain S , Sharma BM , Awasthi R , Kulkarni GT , Sharma B
Ref : Clin Psychopharmacol Neurosci , 19 :470 , 2021
Abstract : OBJECTIVE: Vascular Dementia (VaD), is associated with metabolic conditions. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of ulinastatin (UTI) and sulforaphane (SUL) in streptozotocin (STZ)-diabetes induced vascular endothelium dysfunction and related dementia. METHODS: Single dose STZ (50 mg/kg i.p.) was administered to Albino Wistar rats (male, 200-250 g). Morris water maze and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-alpha, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE, blood brain barrier (BBB) permeability and histopathological changes were also assessed. UTI (10,000 U/kg) and SUL (25 mg/kg) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg/kg) was used as a positive control. RESULTS: STZ-administered rats showed reduction in body weight, learning, memory, reversal learning, executive functioning, impairment in endothelial function, BBB permeability, increase in serum glucose, brains' oxidative stress, inflammation, AChE-activity, BBB permeability and histopathological changes. Administration of UTI and SUL alone as well as in combination, significantly and dose dependently attenuated the STZ-diabetes-induced impairments in the behavioral, endothelial, and biochemical parameters. CONCLUSION: STZ administration caused diabetes and VaD which was attenuated by the administration of UTI and SUL. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD.
ESTHER : Sharma_2021_Clin.Psychopharmacol.Neurosci_19_470
PubMedSearch : Sharma_2021_Clin.Psychopharmacol.Neurosci_19_470
PubMedID: 34294616

Title : Neuroprotective potential of hydroethanolic hull extract of Juglans regia L. on isoprenaline induced oxidative damage in brain of Wistar rats - Sharma_2021_Toxicol.Rep_8_223
Author(s) : Sharma P , Verma PK , Sood S , Pankaj NK , Agarwal S , Raina R
Ref : Toxicol Rep , 8 :223 , 2021
Abstract : The study was aimed at assessing isoprenaline (ISO) induced oxidative damage in brain of Wistar rats and its protection by hydroethanolic hull extract of Juglans regia. Administration of ISO significantly increases catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), malondialdehyde (MDA) and advanced oxidation protein product (AOPP) levels and significantly reduced activities of antioxidant status (TAS), total thiols (TTH), acetylcholinesterase (AChE), arylesterase (AE), and glutathione peroxidase (GPx) in rat brain. Histopathologically, neuronal degeneration, spongiosis and gliosis were seen in cerebral cortex after ISO administration. Pretreatment with hull extract restored TAS, TTH, AChE, CAT and SOD values. Additionally, significant reductions were noted in levels of MDA, AOPP, and severity of histomorphological changes in cerebral cortex following hull extract treatment. Altered antioxidant biomarkers along with histopathological changes indicate oxidative injury in rat brain following ISO administration. Repeated administration of J. regia hull extract demonstrating presence of neuroprotective properties against ISO induced oxidative damage in rat brain.
ESTHER : Sharma_2021_Toxicol.Rep_8_223
PubMedSearch : Sharma_2021_Toxicol.Rep_8_223
PubMedID: 33520664

Title : Distribution of Fluoride in Plasma, Brain, and Bones and Associated Oxidative Damage After Induced Chronic Fluorosis in Wistar Rats - Sharma_2021_Biol.Trace.Elem.Res__
Author(s) : Sharma P , Verma PK , Sood S , Singh R , Gupta A , Rastogi A
Ref : Biol Trace Elem Res , : , 2021
Abstract : The study was aimed to determine fluoride levels in plasma, brain, and bones of Wistar rats following chronic administration of fluoride at different dose levels and the consequent oxidative damage inflicted in these tissues. Brain histomorphology and bone radiographs were also evaluated to assess the extent of damage in these organs. Eighteen rats were randomly divided into three groups with six animals in each group. Group I served as control and groups II and III received 50 and 100 ppm fluoride in tap water, respectively for 180 days. A dose-dependent rise in the levels of fluoride in plasma, brain, and bones was observed in rats. Significant (P < 0.05) alterations in levels of total thiols, glutathione peroxidase, glutathione reductase, acetylcholinesterase, catalase, superoxide dismutase, lipids, as well as protein peroxidation in blood and brain were observed as compared to control in a dose-dependent manner. Radiological examination of bone revealed thinning of bone cortex with haphazard ossification, reduced bone density, and widening of marrow cavity indicating occurrence of flawed bone remodeling upon chronic fluoride exposure. Improper mineralization in bones of intoxicated rats indirectly reflected reduced bone tensile strength. Moreover, alterations in plasma Ca:P ratio and high levels of fluoride in bone ash indicated that chronic fluoride exposure leads to alterations in the bone matrix further corroborating the radio-graphical findings. Additionally, severe microscopic alterations were recorded in the cerebrum and cerebellum of treated rats which included neuronal necrosis, gliosis, spongiosis, perivascular cuffing, congestion, and hemorrhage which correlated well with oxidative changes induced by fluoride intoxication in the brain tissue of rats.
ESTHER : Sharma_2021_Biol.Trace.Elem.Res__
PubMedSearch : Sharma_2021_Biol.Trace.Elem.Res__
PubMedID: 34128210

Title : Behavioral and biochemical investigations to explore the efficacy of quercetin and folacin in experimental diabetes induced vascular endothelium dysfunction and associated dementia in rats - Sharma_2021_J.Basic.Clin.Physiol.Pharmacol__
Author(s) : Sharma P , Aggarwal K , Awasthi R , Kulkarni GT , Sharma B
Ref : J Basic Clin Physiol Pharmacol , : , 2021
Abstract : OBJECTIVES: Vascular dementia (VaD), being strongly associated with metabolic conditions is a major health concern around the world. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of quercetin and folacin in diabetes induced vascular endothelium dysfunction and related dementia. METHODS: Single dose streptozotocin (STZ) (50 mg/kg i.p) was administered to albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), mitochondrial enzyme complex (I, II, and IV), inflammatory markers (interleukin-IL-6, IL-10, tumor necrosis factor-TNF-alpha, and myeloperoxidase-MPO), and acetylcholinesterase activity-AChE were also assessed. Quercetin (30 mg kg(-1)/60 mg kg(-1)) and folacin (30 mg kg(-1)/60 mg kg(-1)) were used as the treatment drugs. Donepezil (0.5 mg kg(-1)) was used as a positive control. RESULTS: STZ administered rats showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress; inflammation; AChE activity, and decrease in mitochondrial complex (I, II, and IV) activity. Administration of quercetin and folacin in two different doses, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, and biochemical parameters. CONCLUSIONS: STZ administration caused diabetes and VaD which was attenuated by the administration of quercetin and folacin. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD conditions.
ESTHER : Sharma_2021_J.Basic.Clin.Physiol.Pharmacol__
PubMedSearch : Sharma_2021_J.Basic.Clin.Physiol.Pharmacol__
PubMedID: 34161695

Title : Role of Genetic Variants and Gene Expression in the Susceptibility and Severity of COVID-19 - Choudhary_2021_Ann.Lab.Med_41_129
Author(s) : Choudhary S , Sreenivasulu K , Mitra P , Misra S , Sharma P
Ref : Ann Lab Med , 41 :129 , 2021
Abstract : Since its first report in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged as a pandemic affecting nearly all countries worldwide. As the COVID-19 pandemic progresses, the need to identify genetic risk factors for susceptibility to this serious illness has emerged. Host genetic factors, along with other risk factors may help determine susceptibility to respiratory tract infections. It is hypothesized that the ACE2 gene, encoding angiotensin-converting enzyme 2 (ACE2), is a genetic risk factor for SARS-CoV-2 infection and is required by the virus to enter cells. Together with ACE2, transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-4 (DPP4) also play an important role in disease severity. Evaluating the role of genetic variants in determining the direction of respiratory infections will help identify potential drug target candidates for further study in COVID-19 patients. We have summarized the latest reports demonstrating that ACE2 variants, their expression, and epigenetic factors may influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome.
ESTHER : Choudhary_2021_Ann.Lab.Med_41_129
PubMedSearch : Choudhary_2021_Ann.Lab.Med_41_129
PubMedID: 33063674

Title : Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer's disease - Tripathi_2020_J.Comput.Aided.Mol.Des__
Author(s) : Tripathi MK , Sharma P , Tripathi A , Tripathi PN , Srivastava P , Seth A , Shrivastava SK
Ref : J Comput Aided Mol Des , : , 2020
Abstract : The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 microM; BChE, IC50 = 1.482 microM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Abeta aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.
ESTHER : Tripathi_2020_J.Comput.Aided.Mol.Des__
PubMedSearch : Tripathi_2020_J.Comput.Aided.Mol.Des__
PubMedID: 32488355

Title : Possible involvement of D2\/D3 receptor activation in ischemic preconditioning mediated protection of the brain - Sharma_2020_Brain.Res__147116
Author(s) : Sharma P , Kulkarni GT , Sharma B
Ref : Brain Research , :147116 , 2020
Abstract : Ischemic stroke is a medical condition that arises because of poor blood supply to the brain. Reperfusion being salvage to the brain further causes, exacerbation of tissue injury, known as reperfusion injury. Ischemic preconditioning (IPC) has been known to provide benefits against ischemia reperfusion (I/R) injury. Dopamine D2/D3 receptor mediated several pathways are also reported as mediators in the IPC mediated neuroprotection. This study investigates the possible involvement of D2/D3 receptor activation in IPC mediated neuroprotection in the I/R brain. Global cerebral ischemia/reperfusion (GCI/R) injury in swiss albino mice was induced by occluding the common carotid arteries for 17 minutes, followed by 24hrs reperfusion. IPC was provided by giving 3 episodes of I/R prior to Ischemia (17 min). Morris water maze (MWM) was used to assess the spatial learning, memory and Rota rod, lateral push test as well as inclined beam test were conducted to assess the motor functions in animals. Cerebral oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-alpha, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE, infarct size (% weight and % volume), and histopathological changes were also assessed. Haloperidol (0.05 mg/kg, i.p) was used to antagonize the effects of D2/D3 receptor activation. I/R animals showed reduction in memory, motor function, increase in cerebral oxidative stress, inflammation, AChE activity, infarct size and histopathological changes. Episodes of IPC prior to ischemia, attenuated the deleterious effects of I/R injury. Administration of haloperidol abolished the protective effects of IPC. Hence, it may be concluded that IPC mediated neuroprotection may involves dopamine D2/D3 receptor activation in mice.
ESTHER : Sharma_2020_Brain.Res__147116
PubMedSearch : Sharma_2020_Brain.Res__147116
PubMedID: 32919985

Title : Flexibility of the petunia strigolactone receptor DAD2 promotes its interaction with signaling partners - Lee_2020_J.Biol.Chem_295_4181
Author(s) : Lee HW , Sharma P , Janssen BJ , Drummond RSM , Luo Z , Hamiaux C , Collier T , Allison JR , Newcomb RD , Snowden KC
Ref : Journal of Biological Chemistry , 295 :4181 , 2020
Abstract : Strigolactones (SLs) are terpenoid-derived plant hormones that regulate various developmental processes, particularly shoot branching, root development, and leaf senescence. The SL receptor has an unusual mode of action. Upon binding SL, it hydrolyses the hormone, and then covalently binds one of the hydrolytic products. These initial events enable the SL receptor DAD2 (in petunia) to interact with the F-box protein PhMAX2A of the Skp-Cullin-F-box (SCF) complex and/or a repressor of SL signaling, PhD53A. However, it remains unclear how binding and hydrolysis structurally alters the SL receptor to enable its engagement with signaling partners. Here, we used mutagenesis to alter DAD2 and affect SL hydrolysis or DAD2's ability to interact with its signaling partners. We identified three DAD2 variants whose hydrolytic activity had been separated from the receptor's interactions with PhMAX2A or PhD53A. Two variants, DAD2(N242I) and DAD2(F135A), having substitutions in the core alpha/beta hydrolase fold domain and the hairpin, exhibited hormone-independent interactions with PhMAX2A and PhD53A respectively. Conversely, the DAD2(D166A) variant could not interact with PhMAX2A in the presence of SL, but its interaction with PhD53A remained unaffected. Structural analyses of DAD2N242I and DAD2D166A revealed only small differences compared with the structure of the wild-type receptor. Results of molecular dynamics simulations of the DAD2(N242I) structure suggested that increased flexibility is a likely cause for its SL-independent interaction with PhMAX2A. Our results suggest that PhMAX2A and PhD53A have distinct binding sites on the SL receptor and that its flexibility is a major determinant of its interactions with these two downstream regulators.
ESTHER : Lee_2020_J.Biol.Chem_295_4181
PubMedSearch : Lee_2020_J.Biol.Chem_295_4181
PubMedID: 32071083
Gene_locus related to this paper: pethy-dad2

Title : Fibroblast Activation Protein Inhibitor PET\/CT: A Promising Molecular Imaging Tool - Sharma_2020_Clin.Nucl.Med_Publish Ahead of Print_
Author(s) : Sharma P , Singh SS , Gayana S
Ref : Clin Nucl Med , Publish Ahead of Print : , 2020
Abstract : PURPOSE: Fibroblast activation protein (FAP) is a cell membrane-bound serine peptidase, overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Recently, molecular PET/CT imaging with radiolabeled FAP inhibitor (FAPI) has been evaluated in different diseases. We aimed to assess its potential role based on the available literature. PATIENTS AND METHODS: We conducted a comprehensive review of the available preclinical and clinical data on FAPI PET/CT in an attempt to summarize its current status and potential future role. Based on that, we have discussed the pathophysiology behind FAP-based imaging, followed by a discussion of FAPI radiopharmaceuticals including their synthesis, biodistribution, and dosimetry. Next, we have discussed studies evaluating FAPI PET/CT in different oncological and nononcological pathologies. The potential of FAPI PET/CT in theranostics has also been addressed. RESULTS: Based on the early scientific evidence available, including preclinical and clinical studies, FAPI PET/CT seems to be a promising molecular imaging tool, especially in oncology. It can be used for imaging different types of cancers and outperforms 18F-FDG PET/CT in some of these. Its potential as a theranostic tool warrants special attention. CONCLUSIONS: Fibroblast activation protein inhibitor PET/CT has the potential to emerge as a powerful molecular imaging tool in the future. However, as of yet, the available evidence is limited, warranting further research and trials in this field.
ESTHER : Sharma_2020_Clin.Nucl.Med_Publish Ahead of Print_
PubMedSearch : Sharma_2020_Clin.Nucl.Med_Publish Ahead of Print_
PubMedID: 33351507

Title : Design, synthesis, and multitargeted profiling of N-benzylpyrrolidine derivatives for the treatment of Alzheimer's disease - Choubey_2020_Bioorg.Med.Chem_28_115721
Author(s) : Choubey PK , Tripathi A , Sharma P , Shrivastava SK
Ref : Bioorganic & Medicinal Chemistry , 28 :115721 , 2020
Abstract : Multitarget molecular hybrids of N-benzyl pyrrolidine derivatives were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease (AD). Among the synthesized compounds, 4k and 4o showed balanced enzyme inhibitions against cholinesterases (AChE and BChE) and BACE-1. Both leads showed considerable PAS-AChE binding capability, excellent brain permeation, potential disassembly of Abeta aggregates, and neuroprotective activity against Abeta-induced stress. Compounds 4k and 4o also ameliorated cognitive dysfunction against the scopolamine-induced amnesia model in the Y-maze test. The ex vivo study signified attenuated brain AChE activity and antioxidant potential of compounds 4k and 4o. Furthermore, compound 4o also showed improvement in Abeta-induced cognitive dysfunction by the Morris water maze test with excellent oral absorption characteristics ascertained by the pharmacokinetic study. In silico molecular docking and dynamics simulation studies of leads suggested their consensual binding affinity toward PAS-AChE in addition to aspartate dyad of BACE-1.
ESTHER : Choubey_2020_Bioorg.Med.Chem_28_115721
PubMedSearch : Choubey_2020_Bioorg.Med.Chem_28_115721
PubMedID: 33007563

Title : Maximum contaminant level of arsenic in drinking water potentiates quinalphos-induced renal damage on co-administration of both arsenic and quinalphos in Wistar rats - Singh_2020_Environ.Sci.Pollut.Res.Int__
Author(s) : Singh P , Verma PK , Raina R , Sood S , Sharma P
Ref : Environ Sci Pollut Res Int , : , 2020
Abstract : This study was designed to determine alterations in renal biomarkers, antioxidant profile, and histomorphology of renal tissue following subacute exposure to quinalphos alone or in conjunction with arsenic in rats. A total of 54 adult Wistar rats were randomly divided into nine groups of six rats each and were administered sub-lethal concentrations of quinalphos (1/100(th) and 1/10(th) of LD50) orally daily and arsenic (50 and 100 ppb) in drinking water for 28 days. Significantly (p < 0.05) decreased levels of antioxidant biomarkers in renal tissue, viz., total thiols, catalase, superoxide dismutase, glutathione peroxidase, glutathione-s-transferase, and glutathione reductase along with increased (p < 0.05) thiobarbituric acid reacting substance (TBRAS) levels indicated that significant oxidative damage to renal tissue occurred following repeated administrations of quinalphos at either dose levels or arsenic at the concentration of 100 ppb when compared with the control rats. The alterations in the antioxidant parameters were observed to be more pronounced in co-administered groups as compared with either toxicant administered group. Similarly, activity of renal acetylcholinesterase was decreased after repeated exposure to quinalphos or arsenic, but inhibition was higher (up to 48%) in rat renal tissue co-exposed with quinalphos and arsenic at the higher concentration. These findings corroborated with the histopathological alterations in renal tissue of toxicant exposed rats. The altered plasma and tissue antioxidant biomarkers along with histopathological changes in the kidney at higher dose level of either toxicant indicate that renal tissue is significantly impacted by these toxicants, and these effects become more pronounced after their co-administration.
ESTHER : Singh_2020_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Singh_2020_Environ.Sci.Pollut.Res.Int__
PubMedID: 32270456

Title : Cholinesterase as a Target for Drug Development in Alzheimer's Disease - Sharma_2020_Methods.Mol.Biol_2089_257
Author(s) : Sharma P , Tripathi MK , Shrivastava SK
Ref : Methods Mol Biol , 2089 :257 , 2020
Abstract : Alzheimer's disease (AD) is an enormous healthcare challenge, and 50 million people are currently suffering from it. There are several pathophysiological mechanisms involved, but cholinesterase inhibitors remained the major target from the last 2-3 decades. Among four available therapeutics (donepezil, rivastigmine, galantamine, and memantine), three of them are cholinesterase inhibitors. Herein, we describe the role of acetylcholine sterase (AChE) and related hypothesis in AD along with the pharmacological and chemical aspects of the available cholinesterase inhibitors. This chapter discusses the development of several congeners and hybrids of available cholinesterase inhibitors along with their binding patterns in enzyme active sites.
ESTHER : Sharma_2020_Methods.Mol.Biol_2089_257
PubMedSearch : Sharma_2020_Methods.Mol.Biol_2089_257
PubMedID: 31773661

Title : Metal-Free Fluorescent Supramolecular Assemblies for Distinct Detection of Organophosphate\/Organochlorine Pesticides - Sharma_2020_ACS.Omega_5_19654
Author(s) : Sharma P , Kumar M , Bhalla V
Ref : ACS Omega , 5 :19654 , 2020
Abstract : The "metal-free", easy-to-prepare fluorescent supramolecular assemblies based on anthracene/perylene bisamide (PBI) derivatives have been developed for the distinct detection of organophosphate (CPF) and organochlorine (DCN) pesticides in aqueous media. The supramolecular assemblies of anthracene derivative show rapid and highly selective "on-on" response toward organophosphate (CPF), which is attributed to the formation of CPF-induced formation of "closely packed" assemblies. A detection limit in the nanomolar range is observed for CPF. On the other hand, the inner filter effect is proposed as the mechanism for the "on-off" detection of DCN using supramolecular assemblies of the anthracene derivative. This is the first report on the development of fluorescent materials having the potential to differentiate between organophosphate and organochlorine pesticides. The assemblies of anthracene derivative 2 also act as "enzyme mimic" as organophosphate pesticide show a preferential affinity for assemblies of derivative 2 over acetylcholinesterase enzyme. Further, the real-time applications of supramolecular assemblies have also been explored for the detection of CPF and DCN in spiked water and in agricultural products such as grapes and apples.
ESTHER : Sharma_2020_ACS.Omega_5_19654
PubMedSearch : Sharma_2020_ACS.Omega_5_19654
PubMedID: 32803060

Title : Design, synthesis, and biological evaluation of ferulic acid based 1,3,4-oxadiazole hybrids as multifunctional therapeutics for the treatment of Alzheimer's disease - Tripathi_2019_Bioorg.Chem_95_103506
Author(s) : Tripathi A , Choubey PK , Sharma P , Seth A , Saraf P , Shrivastava SK
Ref : Bioorg Chem , 95 :103506 , 2019
Abstract : Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC50 = 0.068 microM). It also showed equipotent inhibition of BChE and BACE-1 with IC50 values of 0.218 microM and 0.255 microM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC50 values, 0.163 microM and 0.211 microM, respectively. Compounds 6j and 6k elicited significant displacement of propidium iodide from PAS-AChE, excellent BBB permeability in PAMPA assay, and anti-Abeta aggregatory activity in self- and AChE-induced experiments with neuroprotective activity towards neuroblastoma SH-SY5Y cells. The in vivo behavioral studies suggested amelioration of cognitive dysfunction by 6j and 6k in the Y maze test. The ex vivo study signified brain AChE inhibition and antioxidant activity from these compounds. Moreover, 6j showed improvement in learning and memory behavior in the Abeta-induced ICV rat model by Morris water maze test with excellent oral absorption characteristics ascertained by pharmacokinetic studies.
ESTHER : Tripathi_2019_Bioorg.Chem_95_103506
PubMedSearch : Tripathi_2019_Bioorg.Chem_95_103506
PubMedID: 31887472

Title : Design and development of novel N-(pyrimidin-2-yl)-1,3,4-oxadiazole hybrids to treat cognitive dysfunctions - Tripathi_2019_Bioorg.Med.Chem_27_1327
Author(s) : Tripathi PN , Srivastava P , Sharma P , Seth A , Shrivastava SK
Ref : Bioorganic & Medicinal Chemistry , 27 :1327 , 2019
Abstract : Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC50=6.52; Ki=0.17microM) and showed potential in vitro antioxidant activity (60.0%) when evaluated using the Ellman's and DPPH assays, respectively. Compound 28 competitively displaced propidium iodide (PI) from the peripheral anionic site (PAS) of hAChE (17.6%) and showed high blood-brain barrier (BBB) permeability, as observed in the PAMPA-BBB assay. Additionally, compound 28 inhibited hAChE-induced Abeta aggregation in a concentration-dependent manner according to the thioflavin T assay and was devoid of neurotoxic liability towards SH-SY5Y cell lines, as demonstrated by the MTT assay. The behavioral studies of compound 28 in mice showed a significant reversal of scopolamine-induced amnesia, as observed in Y-maze and passive avoidance tests. Furthermore, compound 28 exhibited significant AChE inhibition in the brain in ex vivo studies. An evaluation of oxidative stress biomarkers revealed the antioxidant potential of 28. Moreover, in silico molecular docking and dynamics simulation studies were used as a computational tool to evaluate the interactions of compound 28 with the active site residues of hAChE.
ESTHER : Tripathi_2019_Bioorg.Med.Chem_27_1327
PubMedSearch : Tripathi_2019_Bioorg.Med.Chem_27_1327
PubMedID: 30795991

Title : Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease - Tripathi_2019_Eur.J.Med.Chem_183_111707
Author(s) : Tripathi A , Choubey PK , Sharma P , Seth A , Tripathi PN , Tripathi MK , Prajapati SK , Krishnamurthy S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 183 :111707 , 2019
Abstract : The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50=0.054muM), butyrylcholinesterase (hBChE, IC50=0.787muM) and beta-secretase-1 (hBACE-1, IC50=0.098muM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki=0.030muM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Abeta aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Abeta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.
ESTHER : Tripathi_2019_Eur.J.Med.Chem_183_111707
PubMedSearch : Tripathi_2019_Eur.J.Med.Chem_183_111707
PubMedID: 31561043

Title : Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions - Mishra_2019_Bioorg.Chem_89_103025
Author(s) : Mishra P , Sharma P , Tripathi PN , Gupta SK , Srivastava P , Seth A , Tripathi A , Krishnamurthy S , Shrivastava SK
Ref : Bioorg Chem , 89 :103025 , 2019
Abstract : The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50=1.098microM; Ki=0.960microM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Abeta aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.
ESTHER : Mishra_2019_Bioorg.Chem_89_103025
PubMedSearch : Mishra_2019_Bioorg.Chem_89_103025
PubMedID: 31176239

Title : Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies - Sharma_2019_Prog.Neurobiol_174_53
Author(s) : Sharma P , Srivastava P , Seth A , Tripathi PN , Banerjee AG , Shrivastava SK
Ref : Prog Neurobiol , 174 :53 , 2019
Abstract : AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Abeta, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.
ESTHER : Sharma_2019_Prog.Neurobiol_174_53
PubMedSearch : Sharma_2019_Prog.Neurobiol_174_53
PubMedID: 30599179

Title : Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode - Hamiaux_2019_Biochem.J_476_1843
Author(s) : Hamiaux C , Larsen L , Lee HW , Luo Z , Sharma P , Hawkins BC , Perry NB , Snowden KC
Ref : Biochemical Journal , 476 :1843 , 2019
Abstract : Strigolactones (SLs) are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, SLs are recognized by alpha/beta hydrolase-fold proteins from the D14/DAD2 (Dwarf14/Decreased Apical Dominance 2) family in the initial step of the signaling pathway. We have previously discovered that N-phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of SL receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial in silico docking studies suggested that these compounds would bind to DAD2, the petunia SL receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in in vitro assays acted as a competitive antagonist of SL receptors, with reduced affinity and potency compared with its N-phenylanthranilic acid 'parent'. X-ray crystal structure analysis revealed that the binding mode of the active QADD inside DAD2's cavity was not that predicted in silico, highlighting a novel inhibition mechanism for SL receptors. Despite a approximately 10-fold difference in potency in vitro, the QADD and tolfenamic acid had comparable activity in planta, suggesting that the QADD compensates for lower potency with increased bioavailability. Altogether, our results establish this QADD as a novel lead compound towards the development of potent and bioavailable antagonists of SL receptors.
ESTHER : Hamiaux_2019_Biochem.J_476_1843
PubMedSearch : Hamiaux_2019_Biochem.J_476_1843
PubMedID: 31186286
Gene_locus related to this paper: pethy-dad2

Title : Design and development of multitarget-directed N-Benzylpiperidine analogs as potential candidates for the treatment of Alzheimer's disease - Sharma_2019_Eur.J.Med.Chem_167_510
Author(s) : Sharma P , Tripathi A , Tripathi PN , Prajapati SK , Seth A , Tripathi MK , Srivastava P , Tiwari V , Krishnamurthy S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 167 :510 , 2019
Abstract : The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and beta-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80muM. Meanwhile, both these compounds inhibited self- and AChE-induced Abeta aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Abeta aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Abeta1-42-induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies.
ESTHER : Sharma_2019_Eur.J.Med.Chem_167_510
PubMedSearch : Sharma_2019_Eur.J.Med.Chem_167_510
PubMedID: 30784883

Title : Novel Molecular Hybrids of N-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer's Disease - Sharma_2019_ACS.Chem.Neurosci_10_4361
Author(s) : Sharma P , Tripathi A , Tripathi PN , Singh SS , Singh SP , Shrivastava SK
Ref : ACS Chem Neurosci , 10 :4361 , 2019
Abstract : Multitargeted hybrids of N-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, and evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition against human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), and beta-secretase-1 (hBACE-1). The potential leads 6g and 10f exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids 6g and 10f also elicited favorable permeation across the blood-brain barrier and were devoid of neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both leads remarkably disassembled Abeta aggregation in thioflavin T-based self- and AChE-induced experiments. Compounds 6g and 10f ameliorated scopolamine-induced cognitive dysfunctions in the Y-maze test. The ex vivo studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound 6g also elicited noteworthy improvement in Abeta-induced cognitive dysfunctions in the Morris water maze test with downregulation in the expression of Abeta and BACE-1 proteins corroborated by Western blot and immunohistochemical analysis. The pharmacokinetic study showed excellent oral absorption characteristics of compound 6g. The in silico molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1.
ESTHER : Sharma_2019_ACS.Chem.Neurosci_10_4361
PubMedSearch : Sharma_2019_ACS.Chem.Neurosci_10_4361
PubMedID: 31491074

Title : Design, synthesis, and evaluation of novel N-(4-phenoxybenzyl)aniline derivatives targeting acetylcholinesterase, beta-amyloid aggregation and oxidative stress to treat Alzheimer's disease - Srivastava_2019_Bioorg.Med.Chem_27_3650
Author(s) : Srivastava P , Tripathi PN , Sharma P , Shrivastava SK
Ref : Bioorganic & Medicinal Chemistry , 27 :3650 , 2019
Abstract : Novel hybrids N-(4-phenoxybenzyl)aniline were designed, synthesized, and evaluated for their potential AChE inhibitory activity along with antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the tested compounds, 42 with trimethoxybenzene substituent showed maximum hAChE inhibition with the competitive type of enzyme inhibition (IC50=1.32microM; Ki=0.879microM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed favorable BBB permeability by most of the synthesized compounds. Meanwhile, compound 42 also inhibited AChE-induced Abeta aggregation (39.5-66.9%) in thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 42. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 42 in brain homogenates.
ESTHER : Srivastava_2019_Bioorg.Med.Chem_27_3650
PubMedSearch : Srivastava_2019_Bioorg.Med.Chem_27_3650
PubMedID: 31288978

Title : Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease - Shrivastava_2018_Bioorg.Chem_82_211
Author(s) : Shrivastava SK , Sinha SK , Srivastava P , Tripathi PN , Sharma P , Tripathi MK , Tripathi A , Choubey PK , Waiker DK , Aggarwal LM , Dixit M , Kheruka SC , Gambhir S , Shankar S , Srivastava RK
Ref : Bioorg Chem , 82 :211 , 2018
Abstract : Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.
ESTHER : Shrivastava_2018_Bioorg.Chem_82_211
PubMedSearch : Shrivastava_2018_Bioorg.Chem_82_211
PubMedID: 30326403

Title : Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory - Tripathi_2018_Bioorg.Chem_85_82
Author(s) : Tripathi PN , Srivastava P , Sharma P , Tripathi MK , Seth A , Tripathi A , Rai SN , Singh SP , Shrivastava SK
Ref : Bioorg Chem , 85 :82 , 2018
Abstract : A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2+/-0.01muM) compared to standard donepezil (AChE, IC50: 0.1+/-0.002muM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22+/-1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93+/-0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.
ESTHER : Tripathi_2018_Bioorg.Chem_85_82
PubMedSearch : Tripathi_2018_Bioorg.Chem_85_82
PubMedID: 30605887

Title : Inhibition of strigolactone receptors by N-phenylanthranilic acid derivatives: Structural and functional insights - Hamiaux_2018_J.Biol.Chem_293_6530
Author(s) : Hamiaux C , Drummond RSM , Luo Z , Lee HW , Sharma P , Janssen BJ , Perry NB , Denny WA , Snowden KC
Ref : Journal of Biological Chemistry , 293 :6530 , 2018
Abstract : The strigolactone (SL) family of plant hormones regulates a broad range of physiological processes affecting plant growth and development and also plays essential roles in controlling interactions with parasitic weeds and symbiotic fungi. Recent progress elucidating details of SL biosynthesis, signaling, and transport offers many opportunities for discovering new plant-growth regulators via chemical interference. Here, using high-throughput screening and downstream biochemical assays, we identified N-phenylanthranilic acid derivatives as potent inhibitors of the SL receptors from petunia (DAD2), rice (OsD14), and Arabidopsis (AtD14). Crystal structures of DAD2 and OsD14 in complex with inhibitors further provided detailed insights into the inhibition mechanism, and in silico modeling of 19 other plant strigolactone receptors suggested that these compounds are active across a large range of plant species. Altogether, these results provide chemical tools for investigating SL signaling and further define a framework for structure-based approaches to design and validate optimized inhibitors of SL receptors for specific plant targets.
ESTHER : Hamiaux_2018_J.Biol.Chem_293_6530
PubMedSearch : Hamiaux_2018_J.Biol.Chem_293_6530
PubMedID: 29523686
Gene_locus related to this paper: pethy-dad2

Title : Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory - Srivastava_2018_Eur.J.Med.Chem_163_116
Author(s) : Srivastava P , Tripathi PN , Sharma P , Rai SN , Singh SP , Srivastava RK , Shankar S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 163 :116 , 2018
Abstract : Based on the Gaussian-based quantitative structure-activity relationship (QSAR) and virtual screening (VS) processes, some promising acetylcholinesterase inhibitors (AChEIs) having antioxidant potential were designed synthesized, characterized, and evaluated for their ability to enhance learning and memory. The synthesized phenyl benzoxazole derivatives exhibited significant antioxidant potential and AChE inhibitory activity, whereas the antioxidant potential of compound 34 (49.6%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Enzyme kinetics study of most potent compound 34 (AChE IC50=0.363+/-0.017muM; Ki=0.19+/-0.03muM) revealed the true nature and competitive type of inhibition on AChE. The compound 34 was further assessed for in vivo and ex vivo studies and the results showed the significant reversal of cognitive deficits and antioxidant potential at the dose of 5mg/kg comparable to standard drug donepezil.
ESTHER : Srivastava_2018_Eur.J.Med.Chem_163_116
PubMedSearch : Srivastava_2018_Eur.J.Med.Chem_163_116
PubMedID: 30503937

Title : The Claudin-like Protein HPO-30 Is Required to Maintain LAChRs at the C. elegans Neuromuscular Junction - Sharma_2018_J.Neurosci_38_7072
Author(s) : Sharma P , Li L , Liu H , Tikiyani V , Hu Z , Babu K
Ref : Journal of Neuroscience , 38 :7072 , 2018
Abstract : Communications across chemical synapses are primarily mediated by neurotransmitters and their postsynaptic receptors. There are diverse molecular systems to localize and regulate the receptors at the synapse. Here, we identify HPO-30, a member of the claudin superfamily of membrane proteins, as a positive regulator for synaptic localization of levamisole-dependent AChRs (LAChRs) at the Caenorhabditis elegans neuromuscular junction (NMJ). The HPO-30 protein localizes at the NMJ and shows genetic and physical association with the LAChR subunits LEV-8, UNC-29, and UNC-38. Using genetic and electrophysiological assays in the hermaphrodite C. elegans, we demonstrate that HPO-30 functions through Neuroligin at the NMJ to maintain postsynaptic LAChR levels at the synapse. Together, this work suggests a novel function for a tight junction protein in maintaining normal receptor levels at the NMJ.SIGNIFICANCE STATEMENT Claudins are a large superfamily of membrane proteins. Their role in maintaining the functional integrity of tight junctions has been widely explored. Our experiments suggest a critical role for the claudin-like protein, HPO-30, in maintaining synaptic levamisole-dependent AChR (LAChR) levels. LAChRs contribute to <20% of the acetylcholine-mediated conductance in adult Caenorhabditis elegans; however, they play a significant functional role in worm locomotion. This study provides a new perspective in the study of LAChR physiology.
ESTHER : Sharma_2018_J.Neurosci_38_7072
PubMedSearch : Sharma_2018_J.Neurosci_38_7072
PubMedID: 29950505

Title : Purification and characterization of lipase by Bacillus methylotrophicus PS3 under submerged fermentation and its application in detergent industry - Sharma_2017_J.Genet.Eng.Biotechnol_15_369
Author(s) : Sharma P , Sharma N , Pathania S , Handa S
Ref : J Genet Eng Biotechnol , 15 :369 , 2017
Abstract : Lipase production bacterial isolate was isolated from soil of service station and identified as Bacillus methylotrophicus PS3 by 16SrRNA with accession number |LN999829.1|. Lipase enzyme was purified by sequential methods of ammonium sulfate precipitation and Sephadex G-100 gel column chromatography. The molecular weight of purified enzyme was 31.40 kDa on SDS-PAGE. This purification procedure resulted in 2.90-fold purification of lipase with a 24.10% final yield. The purified lipase presented maximal hydrolytic activity at a temperature of 55 ( degrees )C, and pH of 7.0. Lipase activity was stimulated by Triton X-100 and SDS with Mg(2+) and Ca(2+) metals employ a positive effect and outlast its stable in organic solvent i.e. methanol and ethanol.
ESTHER : Sharma_2017_J.Genet.Eng.Biotechnol_15_369
PubMedSearch : Sharma_2017_J.Genet.Eng.Biotechnol_15_369
PubMedID: 30647675

Title : Bacterial diversity and real-time PCR based assessment of linA and linB gene distribution at hexachlorocyclohexane contaminated sites - Lal_2015_J.Basic.Microbiol_55_363
Author(s) : Lal D , Jindal S , Kumari H , Jit S , Nigam A , Sharma P , Kumari K , Lal R
Ref : J Basic Microbiol , 55 :363 , 2015
Abstract : The disposal of hexachlorocyclohexane (HCH) muck has created large number of HCH dumpsites all over the world from where the harmful HCH isomers are leaking into the environment. Bacteria have evolved at such contaminated sites that have the ability to degrade HCH. Degradation of various HCH isomers in bacterial strains is mediated primarily by two genes: linA and linB which encode dehydrochlorinase and haloalkane dehalogenase respectively. In this study we explored one such highly contaminated HCH dumpsite located in Lucknow, Uttar Pradesh, India. To assess the biostimulation potential of the contaminated site, microbial diversity study and real-time PCR based quantification of lin genes was carried out. The soil samples from dumpsite and surrounding areas were found to be highly contaminated with HCH residue levels as high as 1.8 x 10(5) mg kg(-1) . The residues were detected in areas upto 13 km from the dumpsite. Sphingomonads, Chromohalobacter, and Marinobacter were the dominant genera present at the dump-site. Role of Sphingomonads in HCH degradation has been well documented. The highest copy numbers of linA and linB genes as determined using real-time PCR were 6.2 x 10(4) and 5.3 x 10(5) , respectively, were found in sample from the dump site. The presence of Sphingomonads, linA, and linB genes from HCH contaminated soil indicates the presence of indigenous bacterial communities capable of HCH degradation.
ESTHER : Lal_2015_J.Basic.Microbiol_55_363
PubMedSearch : Lal_2015_J.Basic.Microbiol_55_363
PubMedID: 24002962

Title : Functional screening of enzymes and bacteria for the dechlorination of hexachlorocyclohexane by a high-throughput colorimetric assay - Sharma_2014_Biodegradation_25_179
Author(s) : Sharma P , Jindal S , Bala K , Kumari K , Niharika N , Kaur J , Pandey G , Pandey R , Russell RJ , Oakeshott JG , Lal R
Ref : Biodegradation , 25 :179 , 2014
Abstract : Two distinct microbial dehalogenases are involved in the first steps of degradation of hexachlorocyclohexane (HCH) isomers. The enzymes, LinA and LinB, catalyze dehydrochlorination and dechlorination reactions of HCH respectively, each with distinct isomer specificities. The two enzymes hold great promise for use in the bioremediation of HCH residues in contaminated soils, although their kinetics and isomer specificities are currently limiting. Here we report the functional screening of a library of 700 LinA and LinB clones generated from soil DNA for improved dechlorination activity by means of a high throughput colorimetric assay. The assay relies upon visual colour change of phenol red in an aqueous medium, due to the pH drop associated with the dechlorination reactions. The assay is performed in a microplate format using intact cells, making it quick and simple to perform and it has high sensitivity, dynamic range and reproducibility. The method has been validated with quantitative gas chromatographic analysis of promising clones, revealing some novel variants of both enzymes with superior HCH degrading activities. Some sphingomonad isolates with potentially superior activities were also identified.
ESTHER : Sharma_2014_Biodegradation_25_179
PubMedSearch : Sharma_2014_Biodegradation_25_179
PubMedID: 23740574

Title : Kinetic and Sequence-Structure-Function Analysis of LinB Enzyme Variants with beta- and delta-Hexachlorocyclohexane - Pandey_2014_PLoS.One_9_e103632
Author(s) : Pandey R , Lucent D , Kumari K , Sharma P , Lal R , Oakeshott JG , Pandey G
Ref : PLoS ONE , 9 :e103632 , 2014
Abstract : Organochlorine insecticide hexachlorocyclohexane (HCH) has recently been classified as a 'Persistent Organic pollutant' by the Stockholm Convention. The LinB haloalkane dehalogenase is a key upstream enzyme in the recently evolved Lin pathway for the catabolism of HCH in bacteria. Here we report a sequence-structure-function analysis of ten naturally occurring and thirteen synthetic mutants of LinB. One of the synthetic mutants was found to have approximately 80 fold more activity for beta- and delta-hexachlorocyclohexane. Based on detailed biophysical calculations, molecular dynamics and ensemble docking calculations, we propose that the latter variant is more active because of alterations to the shape of its active site and increased conformational plasticity.
ESTHER : Pandey_2014_PLoS.One_9_e103632
PubMedSearch : Pandey_2014_PLoS.One_9_e103632
PubMedID: 25076214

Title : A new esterase, belonging to hormone-sensitive lipase family, cloned from Rheinheimera sp. isolated from industrial effluent - Virk_2011_J.Microbiol.Biotechnol_21_667
Author(s) : Virk AP , Sharma P , Capalash N
Ref : J Microbiol Biotechnol , 21 :667 , 2011
Abstract : The gene for esterase (rEst1) was isolated from a new species of genus Rheinheimera by functional screening of E. coli cells transformed with the pSMART/HaeIII genomic library. E. coli cells harboring the esterase gene insert could grow and produce clear halo zones on tributyrin agar. The rEst1 ORF consisted of 1,029 bp, corresponding to 342 amino acid residues with a molecular mass of 37 kDa. The signal P program 3.0 revealed the presence of a signal peptide of 25 amino acids. Esterase activity, however, was associated with a homotrimeric form of molecular mass 95 kDa and not with the monomeric form. The deduced amino acid sequence showed only 54% sequence identity with the closest lipase from Cellvibrio japonicus strain Ueda 107. Conserved domain search and multiple sequence alignment revealed the presence of an esterase/ lipase conserved domain consisting of a GXSXG motif, HGGG motif (oxyanion hole) and HGF motif, typical of the class IV hormone sensitive lipase family. On the basis of the sequence comparison with known esterases/ lipases, REst1 represents a new esterase belonging to class IV family. The purified enzyme worked optimally at 50 degrees C and pH 8, utilized pNP esters of short chain lengths, and showed best catalytic activity with p-nitrophenyl butyrate (C(4)), indicating that it was an esterase. The enzyme was completely inhibited by PMSF and DEPC and showed moderate organotolerance.
ESTHER : Virk_2011_J.Microbiol.Biotechnol_21_667
PubMedSearch : Virk_2011_J.Microbiol.Biotechnol_21_667
PubMedID: 21791951

Title : Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum - Solyakov_2011_Nat.Commun_2_565
Author(s) : Solyakov L , Halbert J , Alam MM , Semblat JP , Dorin-Semblat D , Reininger L , Bottrill AR , Mistry S , Abdi A , Fennell C , Holland Z , Demarta C , Bouza Y , Sicard A , Nivez MP , Eschenlauer S , Lama T , Thomas DC , Sharma P , Agarwal S , Kern S , Pradel G , Graciotti M , Tobin AB , Doerig C
Ref : Nat Commun , 2 :565 , 2011
Abstract : The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.
ESTHER : Solyakov_2011_Nat.Commun_2_565
PubMedSearch : Solyakov_2011_Nat.Commun_2_565
PubMedID: 22127061

Title : New metabolites in the degradation of alpha- and gamma-hexachlorocyclohexane (HCH): pentachlorocyclohexenes are hydroxylated to cyclohexenols and cyclohexenediols by the haloalkane dehalogenase LinB from Sphingobium indicum B90A - Raina_2008_J.Agric.Food.Chem_56_6594
Author(s) : Raina V , Rentsch D , Geiger T , Sharma P , Buser HR , Holliger C , Lal R , Kohler HP
Ref : Journal of Agricultural and Food Chemistry , 56 :6594 , 2008
Abstract : Technical hexachlorocyclohexane (HCH) and lindane are obsolete pesticides whose former production and use led to widespread contaminations posing serious and lasting health and environmental risks. Out of nine possible stereoisomers, alpha-, beta-, gamma-, and delta-HCH are usually present at contaminated sites, and research for a better understanding of their biodegradation has become essential for the development of appropriate remediation technologies. Because haloalkane dehalogenase LinB was recently found responsible for the hydroxylation of beta-HCH, delta-HCH, and delta-pentachlorocyclohexene (delta-PCCH), we decided to examine whether beta- and gamma-PCCH, which can be formed by LinA from alpha- and gamma-HCH, respectively, were also converted by LinB. Incubation of such substrates with Escherichia coli BL21 expressing functional LinB originating from Sphingobium indicum B90A showed that both beta-PCCH and gamma-PCCH were direct substrates of LinB. Furthermore, we identified the main metabolites as 3,4,5,6-tetrachloro-2-cyclohexene-1-ols and 2,5,6-trichloro-2-cyclohexene-1,4-diols by nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. In contrast to alpha-HCH, gamma-HCH was not a substrate for LinB. On the basis of our data, we propose a modified gamma-HCH degradation pathway in which gamma-PCCH is converted to 2,5-cyclohexadiene-1,4-diol via 3,4,5,6-tetrachloro-2-cyclohexene-1-ol and 2,5,6-trichloro-2-cyclohexene-1,4-diol.
ESTHER : Raina_2008_J.Agric.Food.Chem_56_6594
PubMedSearch : Raina_2008_J.Agric.Food.Chem_56_6594
PubMedID: 18598034

Title : Protein kinases of malaria parasites: an update - Doerig_2008_Trends.Parasitol_24_570
Author(s) : Doerig C , Billker O , Haystead T , Sharma P , Tobin AB , Waters NC
Ref : Trends Parasitol , 24 :570 , 2008
Abstract : Protein kinases (PKs) play crucial roles in the control of proliferation and differentiation in eukaryotic cells. Research on protein phosphorylation has expanded tremendously in the past few years, in part as a consequence of the realization that PKs represent attractive drug targets in a variety of diseases. Activity in Plasmodium PK research has followed this trend, and several reports on various aspects of this subject were delivered at the Molecular Approaches to Malaria 2008 meeting (MAM2008), a sharp increase from the previous meeting. Here, the authors of most of these communications join to propose an integrated update of the development of the rapidly expanding field of Plasmodium kinomics.
ESTHER : Doerig_2008_Trends.Parasitol_24_570
PubMedSearch : Doerig_2008_Trends.Parasitol_24_570
PubMedID: 18845480

Title : Hydroxylated metabolites of beta- and delta-hexachlorocyclohexane: bacterial formation, stereochemical configuration, and occurrence in groundwater at a former production site - Raina_2007_Environ.Sci.Technol_41_4292
Author(s) : Raina V , Hauser A , Buser HR , Rentsch D , Sharma P , Lal R , Holliger C , Poiger JT , Muller MD , Kohler HP
Ref : Environ Sci Technol , 41 :4292 , 2007
Abstract : Although the use of hexachlorocyclohexane (HCH), one of the most popular insecticides after the Second World War, has been discontinued in many countries, problems remain from former production and waste sites. Despite the widespread occurrence of HCHs, the environmental fate of these compounds is not fully understood. In particular, environmental metabolites of the more persistent beta-HCH and delta-HCH have not been fully identified. Such knowledge, however, is important to follow degradation and environmental fate of the HCHs. In the present study, several hydroxy metabolites that formed during incubation of beta- and delta-HCH with the common soil microorganism Sphingobium indicum B90A were isolated, characterized, and stereochemically identified by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). The metabolites were identified as isomeric pentachlorocyclohexanols (B1, D1) and tetrachlorocyclohexane-1,4-diols (B2, D2); delta-HCH additionally formed a tetrachloro-2-cyclohexen-1-ol (D3) and a trichloro-2-cyclohexene-1,4-diol (D4), most likely by hydroxylation of delta-pentachlorocyclohexene (delta-PCCH), initially formed by dehydrochlorination. The dehydrochlorinase LinA was responsible for conversion of delta-HCH into delta-PCCH, and the haloalkane dehalogenase LinB was responsible for the transformation of beta-HCH and delta-HCH into B1 and D1, respectively, and subsequently into B2 and D2, respectively. LinB was also responsible for transforming delta-PCCH into D3 and subsequently into D4. These hydroxylations proceeded in accordance with SN2 type reactions with initial substitution of equatorial Cls and formation of axially hydroxylated stereoisomers. The apparently high reactivity of equatorial Cls in beta- and delta-HCH toward initial hydroxylation by LinB of Sphingobium indicum B90A is remarkable when considering the otherwise usually higher reactivity of axial Cls. Several of these metabolites were detected in groundwater from a former HCH production site in Switzerland. Their presence indicates that these reactions proceed under natural environmental conditions and that the metabolites are of environmental relevance.
ESTHER : Raina_2007_Environ.Sci.Technol_41_4292
PubMedSearch : Raina_2007_Environ.Sci.Technol_41_4292
PubMedID: 17626427

Title : Analycys: a database for conservation and conformation of disulphide bonds in homologous protein domains - Thangudu_2007_Proteins_67_255
Author(s) : Thangudu RR , Sharma P , Srinivasan N , Offmann B
Ref : Proteins , 67 :255 , 2007
Abstract : Disulphide bonds in proteins are known to play diverse roles ranging from folding to structure to function. Thorough knowledge of the conservation status and structural state of the disulphide bonds will help in understanding of the differences in homologous proteins. Here we present a database for the analysis of conservation and conformation of disulphide bonds in SCOP structural families. This database has a wide range of applications including mapping of disulphide bond mutation patterns, identification of disulphide bonds important for folding and stabilization, modeling of protein tertiary structures and in protein engineering. The database can be accessed at: http://bioinformatics.univ-reunion.fr/analycys/.
ESTHER : Thangudu_2007_Proteins_67_255
PubMedSearch : Thangudu_2007_Proteins_67_255
PubMedID: 17285632

Title : Role of combined administration of Tiron and glutathione against aluminum-induced oxidative stress in rat brain - Sharma_2007_J.Trace.Elem.Med.Biol_21_63
Author(s) : Sharma P , Ahmad Shah Z , Kumar A , Islam F , Mishra KP
Ref : J Trace Elem Med Biol , 21 :63 , 2007
Abstract : The current study was carried out to investigate the potential role of 4,5 dihydroxy benzene 1,3 disulfonic acid di sodium salt (Tiron) and glutathione (GSH) either individually or in combination against aluminum (Al)-induced toxicity in Wistar rats. Animals were exposed to aluminum chloride at a dose of 172.5mg/kg/d orally for 10 weeks. Tiron and GSH were administered at a dose of 471-mg/kg/d i.p. and 100mg/kg/d orally, respectively, for 7 consecutive days. Tiron is a diphenolic chelating compound which forms water soluble complexes with a large number of metal ions. Induction of oxidative stress was recorded in brain and serum after Al exposure. Significant decrease was recorded in reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GP(x)), catalase (CAT), superoxide dismutase (SOD), acetyl cholinesterase (AChE) and an increase was observed in thiobarbituric acid reacting substance (TBARS) and glutathione-S-transferase (GST) in brain and serum. Most of the above parameters responded positively to individual therapy with Tiron, but more pronounced beneficial effects on the above-described parameters were observed when Tiron was administered in combination with GSH. Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) studies also showed significantly high concentration of Al in brain and blood. Tiron was slightly more effective then GSH in reducing the concentration of Al from the brain and blood, however, no further improvement was recorded when Tiron was administered in combination with GSH in reducing the concentration of Al.
ESTHER : Sharma_2007_J.Trace.Elem.Med.Biol_21_63
PubMedSearch : Sharma_2007_J.Trace.Elem.Med.Biol_21_63
PubMedID: 17317527

Title : Haloalkane dehalogenase LinB is responsible for beta- and delta-hexachlorocyclohexane transformation in Sphingobium indicum B90A - Sharma_2006_Appl.Environ.Microbiol_72_5720
Author(s) : Sharma P , Raina V , Kumari R , Malhotra S , Dogra C , Kumari H , Kohler HP , Buser HR , Holliger C , Lal R
Ref : Applied Environmental Microbiology , 72 :5720 , 2006
Abstract : Incubation of resting cells of Sphingobium indicum B90A, Sphingobium japonicum UT26, and Sphingobium francense Sp+ showed that they were able to transform beta- and delta-hexachlorocyclohexane (beta- and delta-HCH, respectively), the most recalcitrant hexachlorocyclohexane isomers, to pentachlorocyclohexanols, but only resting cells of strain B90A could further transform the pentachlorocyclohexanol intermediates to the corresponding tetrachlorocyclohexanediols. Moreover, experiments with resting cells of Escherichia coli expressing the LinB proteins of strains B90A, UT26, and Sp+ indicated that LinB was responsible for these transformations. Purified LinB proteins from all three strains also effected the formation of the respective pentachlorocyclohexanols. Although the three LinB enzymes differ only marginally with respect to amino acid sequence, they showed interesting differences with respect to substrate specificity. When LinB from strain B90A was incubated with beta- and delta-HCH, the pentachlorocyclohexanol products were further transformed and eventually disappeared from the incubation mixtures. In contrast, the LinB proteins from strains UT26 and Sp+ could not catalyze transformation of the pentachlorocyclohexanols, and these products accumulated in the incubation mixture. A mutant of strain Sp+ lacking linA and linB did not degrade any of the HCH isomers, including beta-HCH, and complementation of this mutant by linB from strain B90A restored the ability to degrade beta- and delta-HCH.
ESTHER : Sharma_2006_Appl.Environ.Microbiol_72_5720
PubMedSearch : Sharma_2006_Appl.Environ.Microbiol_72_5720
PubMedID: 16957186

Title : Aluminum-induced maternal and developmental toxicity and oxidative stress in rat brain: response to combined administration of Tiron and glutathione - Sharma_2006_Reprod.Toxicol_21_313
Author(s) : Sharma P , Mishra KP
Ref : Reprod Toxicol , 21 :313 , 2006
Abstract : The current study was performed to assess the potential of 4,5-dihydroxy 1,3-benzene disulfonic acid di sodium salt (Tiron) and glutathione (GSH) either individually or in combination against aluminum (Al)-induced developmental toxicity in fetuses and sucklings of Wistar rats. Female rats were exposed to aluminum chloride at a dose of 345 mg/(kg day) oral from days 0 to 16 of gestation and 0 to 16 of post-partum (P.P.). Tiron and GSH were administered at a dose of 471 mg/(kg day) i.p. and 100 mg/(kg day) oral, respectively, on days 5, 7, 9, 11, 13, 15 and 17 of gestation and post-partum. Al caused reduction in number of corpora lutea, number of implantation sites, placental and fetal weight and stunted growth. Skeletal malformations were also observed in fetuses. Maternal toxicity was demonstrated by reduction in body weight gain. Induction of oxidative stress was also recorded in the brain of mother as well as in fetuses and sucklings after Al exposure. Significant decrease was recorded in reduced glutathione, glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), acetyl cholinesterase (AChE) and increase was observed in TBARS and glutathione-S-transferase (GST) in brain of pregnant mothers, fetuses and sucklings. Most of the above parameters responded positively with individual therapy with Tiron, but more pronounced beneficial effects on the above-described parameters were observed when Tiron was administered in combination with GSH. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) studies also showed significantly high concentration of Al in suckling's brain and maternal blood, brain, placenta and fetal brain. Treatment with Tiron individually or in combination with glutathione, reduced the accumulation of the Al in almost all the organs studied. It is concluded that chelating agents reduced the Al-induced toxicity and Tiron was more effective in reducing blood Al concentration than glutathione when given individually.
ESTHER : Sharma_2006_Reprod.Toxicol_21_313
PubMedSearch : Sharma_2006_Reprod.Toxicol_21_313
PubMedID: 16040227

Title : GABA agonists and neurotransmitters metabolizing enzymes in steroid-primed OVX rats - Kaur_1997_Mol.Cell.Biochem_167_107
Author(s) : Kaur G , Sharma P , Bhardwaj S
Ref : Molecular & Cellular Biochemistry , 167 :107 , 1997
Abstract : The effect of intraventricular (IVT) administration of GABAA receptor agonist muscimol and GABAB receptor agonist, baclofen was examined on the activity of acetylcholinesterase (AChE), monoamine oxidase (MAO) and Na+, K(+)-ATPase in discrete areas of brain from estrogen-progesterone primed ovariectomized rats. AChE enzyme activity was increased in two subcellular fractions (soluble and total particulate) studied, with statistically significant changes in cerebral hemispheres (CH), cerebellum (CB), thalamus (TH) and hypothalamus (HT), Na+, K(+)-ATPase enzyme activity was decreased in both these fractions. MAO activity increased significantly in CH, TH and HT. The presented results suggest a functional relationship between GABAergic (inhibitory), cholinergic and monoaminergic (excitatory) systems by affecting the rate of degradation of the excitatory neurotransmitters and Na+, K(+)-ATPase.
ESTHER : Kaur_1997_Mol.Cell.Biochem_167_107
PubMedSearch : Kaur_1997_Mol.Cell.Biochem_167_107
PubMedID: 9059987