Kumar P

References (50)

Title : Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy - Waiker_2024_Eur.J.Med.Chem_271_116409
Author(s) : Waiker DK , Verma A , Gajendra TA , Namrata , Roy A , Kumar P , Trigun SK , Srikrishna S , Krishnamurthy S , Davisson VJ , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116409 , 2024
Abstract : Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), beta secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Abeta aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC(50) value = 0.486 +/- 0.047 microM), BACE-1 inhibition (IC(50) value = 0.542 +/- 0.099 microM) along with good anti-Abeta aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC(50) value = 2.000 +/- 0.360 microM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Abeta-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.
ESTHER : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedSearch : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedID: 38663285

Title : Identification of a novel drug molecule for neurodegenerative disease from marine algae through in-silico analysis - Dhanabalan_2024_J.Biomol.Struct.Dyn__1
Author(s) : Dhanabalan AK , Kumar P , Vasudevan S , Chworos A , Velmurugan D
Ref : J Biomol Struct Dyn , :1 , 2024
Abstract : Cognitive functions are lost due to the rapid hydrolysis of acetylcholine including Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE). Marine algae-derived compounds were reported for their neuroprotective activities and hence they can be utilised for treating neurodegenerative ailments like Alzheimer's Disease and Parkinson's Disease which are due to the loss of cognitive functions. Major attention is currently paid to seaweeds due to their health benefits and high nutritional values. Sea weeds are of a rich sense of natural bioactive compounds which antioxidants, pharmaceutical compounds, flavonoids and alkaloids. They also contain a high amount of vitamins A, D, E, C and Ca, K, Mg and Fe. Regular consumption of a marine algae-based diet may boost immunities. In searching for natural cholinesterase inhibitors, the present study is focussed on some marine bioactive compounds reported from brown, red and green algae. Molecular docking studies have been carried out along with molecular dynamics simulations studies and binding energy calculations resulting in three best bioactive compounds when AChE is used as the target. The results are compared with cocrystal studies. Two best compounds, namely, Diphlorethohydroxycarmalol and Phlorofucofuroeckol from the brown seaweeds are identified as the potential lead compounds for neurodegenerative diseases, Alzheimer's and Parkinson's.Communicated by Ramaswamy H. Sarma.
ESTHER : Dhanabalan_2024_J.Biomol.Struct.Dyn__1
PubMedSearch : Dhanabalan_2024_J.Biomol.Struct.Dyn__1
PubMedID: 38456260

Title : Pyrano[2,3-c]pyrazole fused spirooxindole-linked 1,2,3-triazoles as antioxidant agents: Exploring their utility in the development of antidiabetic drugs via inhibition of alpha-amylase and DPP4 activity - Chahal_2024_Bioorg.Chem_147_107363
Author(s) : Chahal S , Rani P , Shweta , Goel KK , Joshi G , Singh R , Kumar P , Singh D , Sindhu J
Ref : Bioorg Chem , 147 :107363 , 2024
Abstract : Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate alpha-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential alpha-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and alpha-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics.
ESTHER : Chahal_2024_Bioorg.Chem_147_107363
PubMedSearch : Chahal_2024_Bioorg.Chem_147_107363
PubMedID: 38657527

Title : Lipase domain effector AGLIP1 in Rhizoctonia solani triggers necrotic killing in plants - Kumar_2024_Plant.Cell.Rep_43_145
Author(s) : Kumar P , Kumari P
Ref : Plant Cell Rep , 43 :145 , 2024
Abstract : We highlight the emerging role of the R. solani novel lipase domain effector AGLIP1 in suppressing pattern-triggered immunity and inducing plant cell death. The dynamic interplay between plants and Rhizoctonia solani constitutes a multifaceted struggle for survival and dominance. Within this complex dynamic, R. solani has evolved virulence mechanisms by secreting effectors that disrupt plants' first line of defense. A newly discovered effector, AGLIP1 in R. solani, plays a pivotal role in inducing plant cell death and subverting immune responses. AGLIP1, a protein containing a signal peptide and a lipase domain, involves complex formation in the intercellular space, followed by translocation to the plant cytoplasm, where it induces cell death (CD) and suppresses defense gene regulation. This study provides valuable insights into the intricate molecular interactions between plants and necrotrophic fungi, underscoring the imperative for further exploration in this field.
ESTHER : Kumar_2024_Plant.Cell.Rep_43_145
PubMedSearch : Kumar_2024_Plant.Cell.Rep_43_145
PubMedID: 38761220
Gene_locus related to this paper: 9agam-a0a8h2wbw6

Title : A comprehensive in silico analysis of putative outer membrane and secretory hydrolases from the pathogenic Leptospira: Possible implications in pathogenesis - Shankar_2024_Biotechnol.Appl.Biochem__
Author(s) : Shankar UN , Shiraz M , Kumar P , Akif M
Ref : Biotechnol Appl Biochem , : , 2024
Abstract : Outer surface/membrane and virulent secretory proteins are primarily crucial for pathogenesis. Secreted and outer membrane hydrolases of many pathogens play an important role in attenuating the host immune system. Leptospira expresses many such proteins, and few have been characterized to display various roles, including host immune evasion. However, identification, classification, characterization, and elucidation of the possible role of Leptospira's outer membrane and secretory hydrolases have yet to be explored. In the present study, we used bioinformatics tools to predict exported proteins from the pathogenic Leptospira proteome. Moreover, we focused on secretory and outer membrane putative hydrolases from the exported proteins to generate a deeper understanding. Our analysis yielded four putative outer/secretory hydrolases, LIC_10995, LIC_11183, LIC_11463, and LIC_12988, containing alpha/beta hydrolase fold and displayed similarity with lipase motif. Moreover, their conservation analysis of the predicted hydrolases across the spectrum of different Leptospira species showed high clustering with the pathogenic species. Outer membrane and secretory proteins with lipolytic activity may have a role in pathogenesis. This is the first bioinformatics analysis of secretory and outer membrane alpha/beta hydrolases from leptospiral species. However, experimental studies are indeed required to unravel this possibility.
ESTHER : Shankar_2024_Biotechnol.Appl.Biochem__
PubMedSearch : Shankar_2024_Biotechnol.Appl.Biochem__
PubMedID: 38733098

Title : Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment - Verma_2024_Eur.J.Med.Chem_271_116450
Author(s) : Verma A , Waiker DK , Singh N , Singh A , Saraf P , Bhardwaj B , Kumar P , Krishnamurthy S , Srikrishna S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116450 , 2024
Abstract : The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and beta-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Abeta aggregation inhibition in a self- and AChE-induced Abeta aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Abeta-induced cognitive deficits in the Abeta-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the A-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Abeta and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.
ESTHER : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedSearch : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedID: 38701714

Title : Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo - Mugnaini_2024_ACS.Chem.Neurosci__
Author(s) : Mugnaini C , Brizzi A , Paolino M , Scarselli E , Castelli R , de Candia M , Gambacorta N , Nicolotti O , Kostrzewa M , Kumar P , Mahmoud AM , Borgonetti V , Iannotta M , Morace A , Galeotti N , Maione S , Altomare CD , Ligresti A , Corelli F
Ref : ACS Chem Neurosci , : , 2024
Abstract : Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC(50) values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with K(i) of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.
ESTHER : Mugnaini_2024_ACS.Chem.Neurosci__
PubMedSearch : Mugnaini_2024_ACS.Chem.Neurosci__
PubMedID: 38372253

Title : Exploring the Therapeutic Potential of Alkaloids in Alzheimer's Disease Management - Dahiya_2024_Cent.Nerv.Syst.Agents.Med.Chem__
Author(s) : Dahiya R , Rani N , Kaur R , Chahal G , Kumar P , Kaur G
Ref : Cent Nerv Syst Agents Med Chem , : , 2024
Abstract : BACKGROUND: Alkaloids are important phytoconstituents obtained from various plant sources. The study's primary goal is to assess the anti-Alzheimer potential of alkaloids using a molecular docking study. Alzheimer's disease (AD) is considered a gradual decline in memory, reasoning, decision-making, orientation to one's physical surroundings, and language. METHOD AND MATERIAL: The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. RESULT: The structures of various alkaloids were drawn using Chem Draw Software, PDB was retrieved from the RCSB PDB database, and molecular docking study was performed on Molergo Virtual Docker. The potential alkaloids were identified with anti-Alzheimer potency. CONCLUSION: Reserpine, vinblastine, ergotamine, and tubocurarine were found to exhibit potential anti-Alzheimer potency.
ESTHER : Dahiya_2024_Cent.Nerv.Syst.Agents.Med.Chem__
PubMedSearch : Dahiya_2024_Cent.Nerv.Syst.Agents.Med.Chem__
PubMedID: 38213138

Title : Influence of elevated pressure and pressurized fluids on microenvironment and activity of enzymes - Kumar_2023_Biotechnol.Adv__108219
Author(s) : Kumar P , Kermanshahi-Pour A , Brar SK , He QS , Rainey JK
Ref : Biotechnol Adv , :108219 , 2023
Abstract : Enzymes have great potential in bioprocess engineering due to their green and mild reaction conditions. However, there are challenges to their application, such as enzyme extraction and purification costs, enzyme recovery, and long reaction time. Enzymatic reaction rate enhancement and enzyme immobilization have the potential to overcome some of these challenges. Application of high pressure (e.g., hydrostatic pressure, supercritical carbon dioxide) has been shown to increase the activity of some enzymes, such as lipases and cellulases. Under high pressure, enzymes undergo multiple alterations simultaneously. High pressure reduces the bond lengths of molecules of reaction components and causes a reduction in the activation volume of enzyme-substrate complex. Supercritical CO(2) interacts with enzyme molecules, catalyzes structural changes, and removes some water molecules from the enzyme's hydration layer. Interaction of scCO(2) with the enzyme also leads to an overall change in secondary structure content. In the extreme, such changes may lead to enzyme denaturation, but enzyme activation and stabilization have also been observed. Immobilization of enzymes onto silica and zeolite-based supports has been shown to further stabilize the enzyme and provide resistance towards perturbation under subjection to high pressure and scCO(2).
ESTHER : Kumar_2023_Biotechnol.Adv__108219
PubMedSearch : Kumar_2023_Biotechnol.Adv__108219
PubMedID: 37488056

Title : Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease - Kiran_2023_Bioorg.Chem_139_106749
Author(s) : Kiran PVR , Waiker DK , Verma A , Saraf P , Bhardwaj B , Kumar H , Singh A , Kumar P , Singh N , Srikrishna S , Trigun SK , Shrivastava SK
Ref : Bioorg Chem , 139 :106749 , 2023
Abstract : Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Abeta-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 microM concentration which was comparable to donepezil and also demonstrated anti-Abeta aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 microM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Abeta-phenotypic drosophila AD model and amelioration of behavioral deficits in the Abeta-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.
ESTHER : Kiran_2023_Bioorg.Chem_139_106749
PubMedSearch : Kiran_2023_Bioorg.Chem_139_106749
PubMedID: 37517157

Title : Effect of Curcumin and Coenzyme Q10 Alone and in Combination on Learning and Memory in an Animal Model of Alzheimer's Disease - Kumar_2023_Biomedicines_11_
Author(s) : Kumar P , Singh A , Kumar A , Kumar R , Pal R , Sachan AK , Dixit RK , Nath R
Ref : Biomedicines , 11 : , 2023
Abstract : The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer's disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study's goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer's disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer's disease and can be utilised alone or as an add-on therapy for the condition.
ESTHER : Kumar_2023_Biomedicines_11_
PubMedSearch : Kumar_2023_Biomedicines_11_
PubMedID: 37239093

Title : Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs - Thakral_2023_Ageing.Res.Rev__101960
Author(s) : Thakral S , Yadav A , Singh V , Kumar M , Kumar P , Narang R , Sudhakar K , Verma A , Khalilullah H , Jaremko M , Emwas AH
Ref : Ageing Res Rev , :101960 , 2023
Abstract : Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid beta deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid beta deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca(2+) influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid beta plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid beta therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.
ESTHER : Thakral_2023_Ageing.Res.Rev__101960
PubMedSearch : Thakral_2023_Ageing.Res.Rev__101960
PubMedID: 37224884

Title : Vision on Synthetic and Medicinal Facets of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazine Scaffold - Aggarwal_2022_Top.Curr.Chem.(Cham)_380_10
Author(s) : Aggarwal R , Hooda M , Kumar P , Sumran G
Ref : Top Curr Chem (Cham) , 380 :10 , 2022
Abstract : The present review article strives to compile the latest synthetic approaches for the synthesis of triazolothiadiazine and its derivatives, along with their diverse pharmacological activities, viz. anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors (carbonic anhydrase inhibitors, cholinesterase inhibitors, alkaline phosphatase inhibitors, anti-lipase activity, and aromatase inhibitors) and antitubercular agents. The review focuses particularly on the structure-activity relationship of biologically important 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines, which have profound importance in drug design, discovery and development. In silico pharmacokinetic and molecular modeling studies have also been summarized. It is hoped that this review article will be of help to researchers engaged in the development of new biologically active entities for the rational design and development of new target-oriented 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine-based drugs for the treatment of multifunctional diseases.
ESTHER : Aggarwal_2022_Top.Curr.Chem.(Cham)_380_10
PubMedSearch : Aggarwal_2022_Top.Curr.Chem.(Cham)_380_10
PubMedID: 35122161

Title : Identification of natural inhibitors to inhibit C. acnes lipase through docking and simulation studies - Singh_2022_J.Mol.Model_28_281
Author(s) : Singh AP , Arya H , Singh V , Kumar P , Gautam HK
Ref : J Mol Model , 28 :281 , 2022
Abstract : Acne vulgaris is a common skin disease affecting 80-90% of teenagers worldwide. C. acnes producing lipases are the main virulence factor that catalyzes sebum lipid into free fatty acid that is used for C. acnes growth. Recently, computational biology and bioinformatics play a significant role in drug discovery programs and the identification of novel lead(s). In this study, potential inhibitors against the C. acnes lipase have been identified via cost-effective computational investigations. Molecular docking, MD simulations, and binding affinity analysis have been performed between the active site of C. acnes lipase protein and selected natural plant constituents. First, C. acnes lipase protein was downloaded from PDB and defined the catalytically active site. Next, 16 active natural plant constituents were shortlisted from the PubChem library (based on their pharmacokinetics, pharmacodynamics, and antibacterial activity). Docking studies identified the best five active compounds that showed significantly strong binding affinity interacted through hydrogen bonding, hydrophobic interactions, and Pi-stacking with the active site residues of the target protein. Furthermore, a 100 ns MD simulation run showed a stable RMSD and less fluctuating RMSF graph for luteolin and neryl acetate. In silico investigation suggested that luteolin, neryl acetate, and isotretinoin were involved in stable interactions which were maintained throughout the MD run with the C. acnes lipase enzyme, virtually. The results advocated that these could potentially inhibit lipase activity and be used in the clinical management of acne.
ESTHER : Singh_2022_J.Mol.Model_28_281
PubMedSearch : Singh_2022_J.Mol.Model_28_281
PubMedID: 36040538

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 : Recent Updates in Development of Small Molecules as Potential Clinical Candidates for Alzheimer's Disease: A Review - Umar_2022_Chem.Biol.Drug.Des__
Author(s) : Umar T , Meena RP , Mustehasan , Kumar P , Khan AA
Ref : Chemical Biology Drug Des , : , 2022
Abstract : Alzheimer's disease (AD) is one of the prominent causes for disability and lowered quality of life worldwide in elderly population. It has fostered immense burden to AD patients, families and society. Burgeoning progress in the field of pathogenesis over last two decades has persuaded the investigation of novel pharmacological therapeutics that focuses towards the pathophysiological events of AD. Miscellaneous clinical trials, development and testing of interventions aimed at various targets, such as anti-tau and anti-amyloid interventions, neurotransmitter modification, neuroprotection and anti-neuroinflammation interventions, cognitive enhancement, and interventions to palliate behavioral symptoms have been carried out. Despite massive efforts to find disease modifying therapies there lingers a vital need for continuing the advancement in progress of the AD research. This review features the new developments of small molecule compounds that will be beneficial in evolution of new AD therapies. In particular, this review briefly describes summary of mechanistic causes chiefly associated with AD and focuses on medicinal approach via small molecule inhibitors that can manage cognitive impairment and dysfunction and may combat Alzheimer's development.
ESTHER : Umar_2022_Chem.Biol.Drug.Des__
PubMedSearch : Umar_2022_Chem.Biol.Drug.Des__
PubMedID: 35996229

Title : Metal determination and biochemical status of marine fishes facilitate the biomonitoring of marine pollution - Kumar_2021_Mar.Pollut.Bull_170_112682
Author(s) : Kumar N , Bhushan S , Gupta SK , Kumar P , Chandan NK , Singh DK
Ref : Mar Pollut Bull , 170 :112682 , 2021
Abstract : In the present study, the bioaccumulation of chromium, manganese, cobalt, copper, zinc, selenium, arsenic, strontium, cadmium, tin, antimony and lead in tissues of thirty marine fish species collected from New Ferry Whorf, Sassoon dock and Versova fishing harbour in Mumbai, India, were analysed. The bioaccumulation patterns of these twelve elements were determined to assess pollution biomarkers based on cellular and oxidative stresses. Catalase, superoxide dismutase and glutathione-s-transferase, glycolytic enzymes viz. lactate dehydrogenase and malate dehydrogenase, protein metabolism enzymes viz. aspartate transferase and alanine transferase, and lipid peroxidation were significantly higher in muscle and gill tissues. The activities of the neurotransmitter enzyme acetylcholine esterase in muscle and brain tissues was inhibited due to pollution. This study suggested that biochemical attributes such as oxidative stress enzymes, cellular biomarkers, neurotransmitter enzymes and metal and metalloid contamination could be successfully employed, even at low concentrations, as reliable biomarkers for biomonitoring of contaminated marine ecosystems.
ESTHER : Kumar_2021_Mar.Pollut.Bull_170_112682
PubMedSearch : Kumar_2021_Mar.Pollut.Bull_170_112682
PubMedID: 34218033

Title : Neuroprotective effect of nerolidol in traumatic brain injury associated behavioural comorbidities in rats - Kaur_2021_Toxicol.Res.(Camb)_10_40
Author(s) : Kaur A , Jaiswal G , Brar J , Kumar P
Ref : Toxicol Res (Camb) , 10 :40 , 2021
Abstract : Traumatic brain injury (TBI) is an insult to the brain from an external mechanical force, leading to temporary/permanent secondary injuries, i.e. impairment of cognitive, physical, and psycho-social functions with altered consciousness. The leading mechanism responsible for neuronal damage following TBI is an increase in oxidative reactions initiated by free radicals generated by the injury along with various other mechanisms. Nerolidol is reported to have potent antioxidant and anti-neuroinflammatory properties. The present study was designed to explore the neuroprotective effect of nerolidol in weight-drop-induced TBI in rats. Animals were injured on the 1st day by dropping a free-falling weight of 200 gm from a height of 1 m through a guide pipe onto the exposed skull. After 14 days of injury, nerolidol (25, 50, and 100 mg/kg, i.p.) treatment was given for the next 14 days. Locomotor activity and motor coordination were evaluated using an actophotometer and rotarod, respectively. Cognitive impairment was observed through the Morris Water Maze and Object Recognition Test. On the 29th day, animals were sacrificed, and their brains were collected for the biochemical estimation. The weight drop model significantly decreased locomotor activity, motor coordination, increased Acetylcholinesterase (AChE) activity, oxidative stress, and induced cognitive deficits in TBI rats. Nerolidol significantly improved locomotor activity, reversed motor incoordination and cognitive impairment, and reduced the AChE activity and oxidative/nitrosative stress. The present study demonstrates the promising neuroprotective effects of nerolidol, which might improve the quality of life of TBI patients.
ESTHER : Kaur_2021_Toxicol.Res.(Camb)_10_40
PubMedSearch : Kaur_2021_Toxicol.Res.(Camb)_10_40
PubMedID: 33613971

Title : Computational Studies on Acetylcholinesterase Inhibitors: From Biochemistry to Chemistry - Bagri_2020_Mini.Rev.Med.Chem_20_1403
Author(s) : Bagri K , Kumar A , Manisha , Kumar P
Ref : Mini Rev Med Chem , 20 :1403 , 2020
Abstract : Acetylcholinesterase inhibitors are the most promising therapeutics for Alzheimer's disease treatment as these prevent the loss of acetylcholine and slows the progression of the disease. The drugs approved for the management of Alzheimer's disease by the FDA are acetylcholinesterase inhibitors but are associated with side effects. Consistent and stringent efforts by the researchers with the help of computational methods opened new ways of developing novel molecules with good acetylcholinesterase inhibitory activity. In this manuscript, we reviewed the studies that identified the essential structural features of acetylcholinesterase inhibitors at the molecular level as well as the techniques like molecular docking, molecular dynamics, quantitative structure-activity relationship, virtual screening, and pharmacophore modelling that were used in designing these inhibitors.
ESTHER : Bagri_2020_Mini.Rev.Med.Chem_20_1403
PubMedSearch : Bagri_2020_Mini.Rev.Med.Chem_20_1403
PubMedID: 31884928

Title : Probing simple structural modification of alpha-mangostin on its cholinesterase inhibition and cytotoxicity - Khaw_2020_Arch.Pharm.(Weinheim)__e2000156
Author(s) : Khaw KY , Kumar P , Yusof SR , Ramanathan S , Murugaiyah V
Ref : Arch Pharm (Weinheim) , :e2000156 , 2020
Abstract : alpha-Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of alpha-mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of alpha-mangostin on its cholinesterase inhibitory activities and toxicity toward neuroblastoma and liver cancer cells. The dialkylated derivatives retained good acetylcholinesterase (AChE) inhibitory activities with IC(50) values between 4.15 and 6.73 muM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with alpha-mangostin, a dual inhibitor (IC(50) : AChE, 2.48 muM; BChE, 5.87 muM). Dialkylation of alpha-mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of alpha-mangostin showed much lower cytotoxicity, being 6.4- to 9.0-fold and 3.8- to 5.5-fold less toxic than their parent compound on neuroblastoma and liver cancer cells, respectively. Likewise, their selectivity index was higher by 1.9- to 4.4-fold; in particular, A2 and A4 showed improved selectivity index compared with alpha-mangostin. Taken together, modification of the hydroxyl groups of alpha-mangostin at positions C-3 and C-6 greatly influenced its BChE inhibitory and cytotoxic but not its AChE inhibitory activities. These dialkylated derivatives are viable candidates for further structural modification and refinement, worthy in the search of new AChE inhibitors with higher safety margins.
ESTHER : Khaw_2020_Arch.Pharm.(Weinheim)__e2000156
PubMedSearch : Khaw_2020_Arch.Pharm.(Weinheim)__e2000156
PubMedID: 32716578

Title : Cloning, Characterization, and Structural Modeling of an Extremophilic Bacterial Lipase Isolated from Saline Habitats of the Thar Desert - Verma_2020_Appl.Biochem.Biotechnol__
Author(s) : Verma S , Kumar R , Kumar P , Sharma D , Gahlot H , Sharma PK , Meghwanshi GK
Ref : Appl Biochem Biotechnol , : , 2020
Abstract : Lipases have a characteristic folding pattern of alpha/beta-hydrolase with mostly parallel beta-sheets, flanked on both sides by alpha-helixes in the structure. The active site is formed by a catalytic triad (serine, aspartic/glutamic acid, and histidine), which is highly conserved. In this study, we have used an integrated experimental and computational approach to identify the extremophilic microbial lipases from the saline habitats of the Thar Desert of Rajasthan. Lipase-producing bacteria were screened and a few samples showed significant lipase activity in both quantitative and qualitative experiments. 16S rRNA sequence analysis of the isolate F1 showed that its sequence is quite similar to that of Bacillus licheniformis and Bacillus haynesii, indicating that this isolate belongs to a new subspecies of Bacillus. The isolate F7 showed maximum sequence identity with Bacillus tequilensis strain 10b. The isolate F7 sequence analysis provided a clear testimony that it can be a new strain of Bacillus tequilensis. The F7 lipase exhibited optimal activity at 60 degrees C and pH 9. Structural modeling of the F7 lipase revealed that it has a highly conserved alpha/beta hydrolase fold at the sequence and structural level except for the N-terminal region. Interestingly, residue Glu128 was different from the template structure and showed the hydrogen bonding between the side chain of Glu128 and side chains of Asn35 and Gln152 amino acids. Besides, this amino acid also showed salt bridge interaction between Glu128--Lys101. These interactions may be assisting in preserving the stability and activity of lipase at high temperatures and in alkaline pH conditions. The information gathered from this investigation will guide in the rational designing of new more potential extremophilic lipase.
ESTHER : Verma_2020_Appl.Biochem.Biotechnol__
PubMedSearch : Verma_2020_Appl.Biochem.Biotechnol__
PubMedID: 32424739
Gene_locus related to this paper: 9baci-F7lip

Title : A hydrolase with esterase activity expressed from a fosmid gene bank prepared from DNA of a North West Himalayan glacier frozen soil sample - Gupta_2019_3.Biotech_9_107
Author(s) : Gupta V , Singh I , Kumar P , Rasool S , Verma V
Ref : 3 Biotech , 9 :107 , 2019
Abstract : Screening of 20,000 clones of a fosmid gene bank, constructed from DNA extracted from North West Himalaya (NWH) glacier soil sample, using functional approach identified 10 esterase/lipase-producing clones. Of these, a clone designated pFG43 with an insert size of 45 kb which produced the highest concentration of enzyme (467.43 U/mg) was sequenced. Clone pFG43 contained 61 open reading frames (ORF) and of these an ORF of 1155 bp designated ME-003, was found to be closely related to a hydrolase from Acidobacteria sps (77% sequence identity and E value = 1e-164) and subsequently identified as a putative cocaine esterase. ORF ME-003 was amplified and sub-cloned using a TA vector system into E. coli (DH5alpha). The purified recombinant enzyme with a molecular weight of 43 kDa had optimal activity at 40 degrees C, pH 6 and the highest activity with shorter chain fatty acids than with higher chain length fatty acids. There is insignificant effect of inhibitors on the enzyme activity of ME-003, except PMSF which completely inhibited its activity. ME-003 activity was also inhibited in the presence of copper oxide but remained stable in presence of other metal ions. The enzyme activity was also inhibited in the presence of organic solvents; however, in the presence of 10% isopropanol, 12% of enzymatic activity was retained. Among various detergents, SDS completely inhibited enzymatic activity. The recombinant enzyme also shows enantio-specific activity against the racemic drug intermediates/precursors and exhibited 90% ee against racemic 1-phenyl ethanol and fluoxetine.
ESTHER : Gupta_2019_3.Biotech_9_107
PubMedSearch : Gupta_2019_3.Biotech_9_107
PubMedID: 30863691

Title : Dual Inhibition of DPP-4 and Cholinesterase Enzymes by the Phytoconstituents of the Ethanolic Extract of Prosopis cineraria Pods: Therapeutic Implications for the Treatment of Diabetes-associated Neurological Impairments - Ram_2019_Curr.Alzheimer.Res_16_1230
Author(s) : Ram H , Jaipal N , Kumar P , Deka P , Kumar S , Kashyap P , Singh BP , Alqarawi AA , Hashem A , Tabassum B , Abd Allah EF
Ref : Curr Alzheimer Res , 16 :1230 , 2019
Abstract : BACKGROUND: Insulin resistance causes decreased uptake of glucose which promotes the susceptibility of type 2 associated neurological impairments. METHODS: The study was aimed to evaluate the inhibition potential of the ethanolic extract of Prosopis cineraria (EPC) pods against DPP-4 and cholinesterase enzymes by in-vitro, in-vivo and in-silico assessments. The present study consists of in vivo studies on a diabetes-induced rat model by HOMA (Homeostasis model assessment) and related parameters, in vitro studies through the DPP-4 enzyme assay and cholinesterase assays using Ellman's reaction. The in-silico studies were conducted by the molecular docking of Cinerin C with targeted enzymes. The phytochemical characterization of the extract was demonstrated through LCMS studies. The antioxidant studies on the extract were performed by FRAP and TEAC assays. RESULTS: The extract showed 64.8% maximum inhibition of DPP-4, 34.91% inhibition of AChE and 74.35% inhibition of BuChE. The antioxidant capacity of the extract was observed to be 847.81+/-16.25muM Fe2+ equivalent in the FRAP assay and 0.40 +/- 0.08 mmol/l of Trolox equivalent in the TEAC assay. The in vivo study showed competent glycaemic control against significant HOMA IR (1.5), HOMA % beta (26.5) and HOMA % S (68.8) as well as pancreatic cell mass proliferation. The insilico analysis also revealed positive interactions of Cinerin C with targeted enzymes (DPP4 and cholinesterase). CONCLUSION: It can be concluded that the phytoconstituents of Prosopis cineraria pod extract can be significantly considered in neuropharmacology to resolve insulin resistance-induced neurological complications as it showed inhibition against DPP-4, AChE and BuChE target enzymes.
ESTHER : Ram_2019_Curr.Alzheimer.Res_16_1230
PubMedSearch : Ram_2019_Curr.Alzheimer.Res_16_1230
PubMedID: 31797759

Title : Repurposing an Ancient Protein Core Structure: Structural Studies on FmtA, a Novel Esterase of Staphylococcus aureus - Dalal_2019_J.Mol.Biol_431_3107
Author(s) : Dalal V , Kumar P , Rakhaminov G , Qamar A , Fan X , Hunter H , Tomar S , Golemi-Kotra D
Ref : Journal of Molecular Biology , 431 :3107 , 2019
Abstract : FmtA is a penicillin-recognizing protein (PRP) with novel hydrolytic activity toward the ester bond between d-Ala and the backbone of teichoic acids. Teichoic acids are polyol-phosphate polymers found in the Staphylococcus aureus cell wall, and they play important roles in antibiotic resistance and pathogenesis. Two of the PRPs conserved motifs, namely, SXXK and Y(S)XN, are involved in the hydrolysis by FmtA, but the catalytic mechanism remains elusive. Here we determined the crystal structure of FmtA. FmtA shares the core structure of PRPs: an all alpha-helical domain and alpha/beta domain sandwiched together. However, it does not have the typical PRPs active-site cleft. Its active site is shallow, solvent-exposed, and enlarged. Furthermore, our mutagenesis and kinetic studies suggest that the SXXK and Y(S)XN motifs of FmtA offer all that is necessary for catalysis, and more: the active-site nucleophile (serine), the general base (lysine) required for the acylation step and the deacylation step, and an anchor (tyrosine) to hold the active-site serine, and possibly the substrate, in an optimum conformation for catalysis. Our study establishes that the FmtA esterase activity represents an expansion of the catalytic activity repertoire of the PRPs core structure, which typically displays peptidase activity. This finding points toward a novel mechanism of ester bond hydrolysis by a PRP. The structure of FmtA provides insights to the design of inhibitor molecules with the potential to serve as leads in the development of novel antibacterial chemotherapeutic agents.
ESTHER : Dalal_2019_J.Mol.Biol_431_3107
PubMedSearch : Dalal_2019_J.Mol.Biol_431_3107
PubMedID: 31260692

Title : Comparative evaluation of antidotal efficacy of 2-PAM and HNK-102 oximes during inhalation of sarin vapor in Swiss albino mice - Swami_2018_Inhal.Toxicol__1
Author(s) : Swami D , Yadav R , Bhaskar ASB , Soni A , Nagar DP , Acharya J , Karade HN , Singh KP , Kumar P
Ref : Inhal Toxicol , :1 , 2018
Abstract : Efficacy of two oximes treatments evaluated during inhalation of sarin vapor (LCt50, 755.9 mg/min/m(3)) in simulated real scenario in vivo. Majority of mice either became moribund or died within 1-2 min during exposure to multifold-lethal concentrations of sarin vapor. Protection indices were determined by exposing to sarin vapor in two sessions, 1 min exposure followed by treatments with or without HNK-102 (56.56 mg/kg, im) or 2-PAM (30 mg/kg, im) and atropine (10 mg/kg, ip), and again exposed for remaining 14 min. Protection offered by HNK-102 was found to be four folds higher compared to 2-PAM in the same toxic environment. Secondly, sub-lethal concentration of sarin vapor (0.8 x LCt50 or 605 mg/min/m(3)), 24 h post investigations revealed that the oximes could not reactivate brain and serum acetylcholinesterase (AChE) activity. The treatments prevented increase in protein concentration (p < .05) and macrophages infiltration compared to sarin alone group in broncho-alveolar lavage fluid. Lung histopathology showed intense peribronchial infiltration and edema with desquamating epithelial lining and mild to moderate alveolar septal infiltration in sarin and atropine groups, respectively. Noticeable peeling-off observed in epithelial lining and sporadic mild infiltration of epithelial cells at bronchiolar region in 2-PAM and HNK-102 groups, respectively. The oximes failed to reactivate AChE activity; however, the mice survived up to 6.0 x LCt50, proved involvement of non-AChE targets in sarin toxicity. Atropine alone treatment was found to be either ineffective or increased the toxicity. HNK-102, exhibited better survivability with lung protection, can be considered as a better replacement for 2-PAM to treat sarin inhalation induced poisoning.
ESTHER : Swami_2018_Inhal.Toxicol__1
PubMedSearch : Swami_2018_Inhal.Toxicol__1
PubMedID: 30375901

Title : In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice - Swami_2017_Hum.Exp.Toxicol_36_23
Author(s) : Swami D , Karade HN , Acharya J , Kumar P
Ref : Hum Exp Toxicol , 36 :23 , 2017
Abstract : In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)- N-(pyridin-3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 microg/kg) and 0.48 LD50 (77.23 microg/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE ( p < 0.05) at 2x IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo.
ESTHER : Swami_2017_Hum.Exp.Toxicol_36_23
PubMedSearch : Swami_2017_Hum.Exp.Toxicol_36_23
PubMedID: 26962110

Title : Appendicular Biopsy in Total Colonic Aganglionosis: A Histologically Challenging and Inadvisable Practice - Mohanty_2017_Pediatr.Dev.Pathol_20_277
Author(s) : Mohanty S , Kini U , Das K , Puttegowda D , Yadav L , Babu MK , Mahadevappa K , Kumar P , Mahadevaiah SA , Deb M
Ref : Pediatr Dev Pathol , 20 :277 , 2017
Abstract : Background The reliability of intraoperative evaluation of ganglion cells in the appendix as a guide to a diagnosis of total colonic aganglionosis is unclear. Objective To evaluate the diagnostic utility of appendicular innervation in colonic Hirschsprung disease (HD) and TCA. Methods Prospective, systematic study of ganglion cells and the neural plexii in appendices from cases (HD and TCA) and age matched controls with frozen and paraffin sections, rapid acetylcholinesterase (AChE) and immunohistochemistry. Results A total of 48 appendices (28 controls, 20 cases; 19 frozen) were evaluated. Of these 48, 30 were neonates. Ganglion cell clusters were smaller in controls (28) and HD (6) than those in the rectum, distorted at places and mimicked lymphocytes and endothelial cells, especially in neonates. Complete study of 13 appendices in TCA showed absence of ganglion cells, hypertrophic nerves, AChE activity, and calretinin staining. In 2/13 TCA, an erroneous frozen section identification of ganglia was later corrected based on AChE histochemistry and a panel of IHC stains. Ileal biopsies guided the placement of a ganglionic ileostomy in all. One case each of skip segment aganglionosis in a TCA and variable hypoganglionosis in long segment colonic HD is reported. Conclusion Intraoperative characterization of appendicular innervation as a guide to the diagnosis of TCA is unreliable, in part because of the possibility of skip segment disease/variable hypoganglionosis. We propose terminal ileal biopsies for diagnosis and leveling of aganglionosis. AChE on frozen/calretinin on paraffin tissue is the best approach to avoid diagnostic errors.
ESTHER : Mohanty_2017_Pediatr.Dev.Pathol_20_277
PubMedSearch : Mohanty_2017_Pediatr.Dev.Pathol_20_277
PubMedID: 28727975

Title : In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives (HNK oximes) against tabun and soman poisoning in Swiss albino mice - Kumar_2017_Hum.Exp.Toxicol_36_1270
Author(s) : Kumar P , Swami D , Nagar DP , Singh KP , Acharya J , Karade HN , Yadav R
Ref : Hum Exp Toxicol , 36 :1270 , 2017
Abstract : The study reports antidotal efficacy of three HNK [ bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives] and pralidoxime (2-PAM), against soman and tabun poisoning in Swiss albino mice. Protection index (PI) was determined (treatment doses: HNK oximes, x0.20 of their median lethal dose (LD50) and 2-PAM, 30 mg/kg, intramuscularly (im)) together with atropine (10 mg/kg, intraperitoneally). Probit log doses with difference of 0.301 log of LD50 of the nerve agents administered and inhibition of acetylcholinesterase (AChE) activity by 50% (IC50) was calculated at optimized time in brain and serum. Using various doses of tabun and soman (subcutaneously (sc)), in multiples of their IC50, AChE reactivation ability of the oximes was studied. Besides, acute toxicity (0.8x LD50, im, 24 h postexposure) of HNK-102 and 2-PAM was also compared by determining biochemical, hematological variables and making histopathological observations. Protection offered by HNK-102 against tabun poisoning was found to be four times higher compared to 2-PAM. However, nearly equal protection was noted with all the four oximes against soman poisoning. HNK-102 reactivated brain AChE activity by 1.5 times more than 2-PAM at IC50 dose of soman and tabun. Acute toxicity studies of HNK-102 and 2-PAM showed sporadic changes in urea, uric acid, aspartate aminotransferase, and so on compared to control group, however, not supported by histopathological investigations. The present investigation showed superiority of newly synthesized HNK-102 oxime over standard 2-PAM, as a better antidote, against acute poisoning of tabun (4.00 times) and soman (1.04 times), in Swiss albino mice.
ESTHER : Kumar_2017_Hum.Exp.Toxicol_36_1270
PubMedSearch : Kumar_2017_Hum.Exp.Toxicol_36_1270
PubMedID: 28078916

Title : Biodegradation of phthalic acid esters (PAEs) and in silico structural characterization of mono-2-ethylhexyl phthalate (MEHP) hydrolase on the basis of close structural homolog - Singh_2017_J.Hazard.Mater_338_11
Author(s) : Singh N , Dalal V , Mahto JK , Kumar P
Ref : J Hazard Mater , 338 :11 , 2017
Abstract : Three bacterial strains capable of degrading phthalates namely Pseudomonas sp. PKDM2, Pseudomonas sp. PKDE1 and Pseudomonas sp. PKDE2 were isolated and characterized for their degradative potential. These strains efficiently degraded 77.4%-84.4% of DMP, 75.0%-75.7% of DEP and 71.7%-74.7% of DEHP, initial amount of each phthalate is 500mgL(-1) of each phthalate, after 44h of incubation. GC-MS results reveal the tentative DEHP degradation pathway, where hydrolases mediate the breakdown of DEHP to phthalic acid (PA) via an intermediate MEHP. MEHP hydrolase is a serine hydrolase which is involved in the reduction of the MEHP to PA. The predicted 3D model of MEHP hydrolase from Pseudomonas mosselii was docked with phthalate monoesters (PMEs) such as MEHP, mono-n-hexyl phthalate (MHP), mono-n-butyl phthalate (MBP) and mono-n-ethyl phthalate (MEP), respectively. Docking results show the distance between the carbonyl carbon of respective phthalate monoester and the hydroxyl group of catalytic serine lies in the range of 2.9 to 3.3A, which is similar to the ES complex of other serine hydrolases. This structural study highlights the interaction and the role of catalytic residues of MEHP hydrolase involved in the biodegradation of PMEs to phthalate.
ESTHER : Singh_2017_J.Hazard.Mater_338_11
PubMedSearch : Singh_2017_J.Hazard.Mater_338_11
PubMedID: 28531656
Gene_locus related to this paper: 9psed-a0a1h9kym9

Title : Small chromosomal regions position themselves autonomously according to their chromatin class - van de Werken_2017_Genome.Res_27_922
Author(s) : van de Werken HJG , Haan JC , Feodorova Y , Bijos D , Weuts A , Theunis K , Holwerda SJB , Meuleman W , Pagie L , Thanisch K , Kumar P , Leonhardt H , Marynen P , van Steensel B , Voet T , de Laat W , Solovei I , Joffe B
Ref : Genome Res , 27 :922 , 2017
Abstract : The spatial arrangement of chromatin is linked to the regulation of nuclear processes. One striking aspect of nuclear organization is the spatial segregation of heterochromatic and euchromatic domains. The mechanisms of this chromatin segregation are still poorly understood. In this work, we investigated the link between the primary genomic sequence and chromatin domains. We analyzed the spatial intranuclear arrangement of a human artificial chromosome (HAC) in a xenospecific mouse background in comparison to an orthologous region of native mouse chromosome. The two orthologous regions include segments that can be assigned to three major chromatin classes according to their gene abundance and repeat repertoire: (1) gene-rich and SINE-rich euchromatin; (2) gene-poor and LINE/LTR-rich heterochromatin; and (3) gene-depleted and satellite DNA-containing constitutive heterochromatin. We show, using fluorescence in situ hybridization (FISH) and 4C-seq technologies, that chromatin segments ranging from 0.6 to 3 Mb cluster with segments of the same chromatin class. As a consequence, the chromatin segments acquire corresponding positions in the nucleus irrespective of their chromosomal context, thereby strongly suggesting that this is their autonomous property. Interactions with the nuclear lamina, although largely retained in the HAC, reveal less autonomy. Taken together, our results suggest that building of a functional nucleus is largely a self-organizing process based on mutual recognition of chromosome segments belonging to the major chromatin classes.
ESTHER : van de Werken_2017_Genome.Res_27_922
PubMedSearch : van de Werken_2017_Genome.Res_27_922
PubMedID: 28341771

Title : Protection studies of new bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives (HNK-series) oximes against acute poisoning by dichlorvos (DDVP) in Swiss albino mice - Kumar_2016_Interdiscip.Toxicol_9_101
Author(s) : Kumar P , Swami D , Karade HN , Singh M , Tiwari A , Singh KP
Ref : Interdiscip Toxicol , 9 :101 , 2016
Abstract : The available antidotal therapy against acute poisoning by organophosphates involves the use of atropine alone or in combination with one of the oximes, e.g. 2-PAM, Obidoxime, TMB-4(Trimedoxime) or HI-6. Each of these oximes has some limitation, raising the question of the universal antidotal efficacy against poisoning by all OPs/nerve agents. In the present study, newly synthesized bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives (HNK-series) oximes were evaluated for their antidotal efficacy against DDVP intoxicated Swiss mice, in terms of the Protection Index (PI) and AChE reactivation in brain and serum. The inhibition concentration (IC50) was determined in brain and serum after optimizing the time point for maximum inhibition (60 min post DDVP exposure). AChE reactivation efficacy of the HNK series was evaluated at IC50 and compared with 2-PAM. HNK-102 showed a ~2 times better Protection Index (PI) as compared to 2-PAM against DDVP toxicity. IC50 at 60 min DDVP post exposure was found to be approximately one fifth and one half of the LD50 dose for brain and serum AChE, respectively. Out of three HNK oximes, HNK-102 & 106 at 0.20 LD50 dose significantly reactivated DDVP intoxicated brain AChE (p<0.05) as compared to 2-PAM at double IC50 dose of DDVP. In light of double PI and higher AChE reactivation, HNK 102 was found to be a better oxime than 2-PAM in the treatment of acute poisoning by DDVP.
ESTHER : Kumar_2016_Interdiscip.Toxicol_9_101
PubMedSearch : Kumar_2016_Interdiscip.Toxicol_9_101
PubMedID: 28652853

Title : Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against beta-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats - Kalra_2016_Pharmacol.Biochem.Behav_146-147_1
Author(s) : Kalra J , Kumar P , Majeed AB , Prakash A
Ref : Pharmacol Biochem Behav , 146-147 :1 , 2016
Abstract : Several lines of evidence indicate that beta amyloid (beta-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced beta-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in beta-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-alpha, IL-1beta and PGE2), beta-A1-42 levels and histopathological analysis. ICV administration of beta-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, beta-A1-42 level, neuronal cell death and neuroinflammation are more profound in beta-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in beta-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.
ESTHER : Kalra_2016_Pharmacol.Biochem.Behav_146-147_1
PubMedSearch : Kalra_2016_Pharmacol.Biochem.Behav_146-147_1
PubMedID: 27106205

Title : Modulation of fatty acid metabolism and tricarboxylic acid cycle to enhance the lipstatin production through medium engineering in Streptomyces toxytricini - Kumar_2016_Bioresour.Technol_213_64
Author(s) : Kumar P , Dubey KK
Ref : Bioresour Technol , 213 :64 , 2016
Abstract : This work investigated the potential of medium engineering to obtain maximum biomass, non-conventional carbon sources for lipstatin production and modulation of tricarboxylic acid (TCA) cycle to promote lipstatin synthesis. It was found that 2:3 carbon and nitrogen ratio, produced maximum biomass of 7.9g/L in growth medium and 6.6g/L in pre-seed medium. Among the studied non-conventional carbon sources i.e., soya flour 40g/L and sesame oil 30mL/L were found producing 1109.37mg/L (1.24-fold of control) and 1196.75mg/L (1.34-fold of control) lipstatin respectively. Supplementation of TCA cycle intermediates revealed that NADH and succinic acid showed lipstatin production to 1132.99mg/L and 1171.10mg/L respectively. Experimental outcome was validated in 7L bioreactor and produced 2242.63mg/L lipstatin which was approximately 14% higher than shake flask.
ESTHER : Kumar_2016_Bioresour.Technol_213_64
PubMedSearch : Kumar_2016_Bioresour.Technol_213_64
PubMedID: 26897471

Title : A novel bile salts-lipase polymeric film-infused minitablet system for enhanced oral delivery of cholecalciferol - Braithwaite_2015_Pharm.Dev.Technol__1
Author(s) : Braithwaite MC , Choonara YE , Kumar P , Tomar LK , Du Toit LC , Pillay V
Ref : Pharm Dev Technol , :1 , 2015
Abstract : Few researchers have investigated the use of multiple physiological enhancers combined with synthetic carriers to augment delivery of nutraceuticals. The current work describes the development of an oral delivery system termed a bioactive association platform (BAP) capable of delivering nutraceutical actives from a formulation framework specifically for enhancing the in vitro and in vivo performance of model vitamin, cholecalciferol (Vitamin D3). Synthesis of a novel triple vitamin minitablet and an optimized bile salt/lipase alginate-glycerin film provided unique oral components for inclusion in a BAP capsule. Component validation and physicochemical characterizations included comparative ex vivo permeability, chemical structure mapping, thermodynamic analysis and magnetic resonance imaging. In vitro dissolution studies of the BAP produced an area under the dissolution curve (AUC) for cholecalciferol release that was 28% greater than a conventional comparator product. A total of 84.01% of cholecalciferol was released from the BAP within 3 h versus only 59% from a comparator. Ex vivo permeation studies revealed superior cholecalciferol membrane diffusion from the triple vitamin minitablet BAP component. In vivo performance showed a greater mean change from baseline cholecalciferol to peak plasma levels (Cmax) from the BAP compared to the comparator (55.66 versus 46.05 ng/mL). Cholecalciferol bioavailability was improved in vivo with an AUC0-inf from the BAP that was 3.2x greater than the conventional product. The BAP was also superior at improving and maintaining serum levels of the main metabolite, 25-hydroxyvitamin D3, compared to the conventional system. In vitro and in vivo results thus confirmed improvements in cholecalciferol dissolution, membrane permeability and plasma drug levels. The study results position the BAP as an ideal oral vehicle for enhanced delivery of cholecalciferol.
ESTHER : Braithwaite_2015_Pharm.Dev.Technol__1
PubMedSearch : Braithwaite_2015_Pharm.Dev.Technol__1
PubMedID: 26333524

Title : Diagnosing bacterial peritonitis made easy by use of leukocyte esterase dipsticks - Chugh_2015_Int.J.Crit.Illn.Inj.Sci_5_32
Author(s) : Chugh K , Agrawal Y , Goyal V , Khatri V , Kumar P
Ref : Int J Crit Illn Inj Sci , 5 :32 , 2015
Abstract : INTRODUCTION: Spontaneous bacterial peritonitis (SBP) requires rapid diagnosis for the initiation of antibiotics. Its diagnosis is usually based on manual examination of ascitic fluid (AF) having long reporting time. AF infection is diagnosed when the fluid polymorphonuclear leukocyte (PMNL) concentration >/=250 cells/mm(3). AIMS AND OBJECTIVES: Aim was to evaluate the diagnostic utility of leukocyte esterase (LE) reagent strip for rapid diagnosis of SBP in patients who underwent abdominal paracentesis and to calculate the sensitivity, specificity, positive, and negative predictive values. MATERIALS AND
METHODS: The study was carried out on 103 patients with ascites. Cell count of AF as determined by colorimetric scale of Multistix 10 SG reagent strip was compared with counting chamber method (PMNL count >/=250 cells/mm(3) was considered positive). RESULTS AND OBSERVATIONS: Of the 103 patients SBP was diagnosed in 20 patients, 83 patients were negative for SBP by manual cell count. The sensitivity and specificity of the LE test for detecting neutrocytic SBP taking grade 2 as cut off were 95% and 96.4% respectively, with a positive predictive value of 86.4% and a negative predictive value of 98.8%. Diagnostic accuracy of LE test was 96.1%. DISCUSSION: There was a good correlation between the reagent strip result and PMNL count. The LE strip test is based on the esterase activity of activated granulocytes which reacts with an ester-releasing hydroxyphenylpyrrole causing a colour change in the azo dye of reagent strip. It is a very sensitive and specific method for the prompt detection of elevated PMNL count, and represents a convenient, inexpensive, simple, and bedside method for diagnosis of SBP. A negative LE test result excludes SBP with a high degree of certainty.
ESTHER : Chugh_2015_Int.J.Crit.Illn.Inj.Sci_5_32
PubMedSearch : Chugh_2015_Int.J.Crit.Illn.Inj.Sci_5_32
PubMedID: 25810962

Title : Effect of GLT-1 modulator and P antagonists alone and in combination in the kindling model of epilepsy in rats - Soni_2015_Epilepsy.Behav_48_4
Author(s) : Soni N , Koushal P , Reddy BV , Deshmukh R , Kumar P
Ref : Epilepsy Behav , 48 :4 , 2015
Abstract : INTRODUCTION: Multiple lines of investigation have explored the role of glutamatergic and purinergic systems in epilepsy, related cognitive impairment, and oxidative stress. Glutamate transporters, particularly GLT-1 expression, were found to be decreased, and purinergic receptor, P2X7 expression, was found to be increased in brain tissue associated with epilepsy. The present study was carried out to investigate the effect of ceftriaxone (GLT-1 upregulator) and Brilliant Blue G (P2X7 antagonist) against PTZ-induced kindling in rats. The study was further extended to elucidate the cross-link between glutamatergic and purinergic pathways in epilepsy. MATERIAL AND
METHODS: Systemic administration of subconvulsant dose of PTZ (30mg/kg) every other day for 27days (14 injections) significantly increased the mean kindling, and developed generalized tonic-clonic seizures, and reduced motor co-ordination, cognitive skills, oxidative defense (increases lipid peroxidation, nitrite levels and decreases GSH level) and acetylcholinesterase enzyme activities in the cortex and subcortical region. Treatments with CEF (100 and 200mg/kg) and BBG (15 and 30mg/kg) alone and in combination (CEF 100mg/kg and BBG 15mg/kg) significantly decreased the mean kindling score and restored behavioral and oxidative defense activities compared with treatment with PTZ.
CONCLUSIONS: The combination of both the drugs was shown to have better effect in preventing kindled seizures and a significantly synergistic effect compared with their effect alone in PTZ-kindled rats. The present study elucidated the mechanistic role of GLT-1 modulator and selective P2X7 antagonist and their combination against PTZ-induced kindling. The study for the first time demonstrated the cross-link between glutamatergic and purinergic pathways in epilepsy treatment.
ESTHER : Soni_2015_Epilepsy.Behav_48_4
PubMedSearch : Soni_2015_Epilepsy.Behav_48_4
PubMedID: 26037843

Title : Inhibition of acetylcholinesterase and cytochrome oxidase activity in Fasciola gigantica cercaria by phytoconstituents - Sunita_2015_Acta.Trop_154_19
Author(s) : Sunita K , Habib M , Kumar P , Singh VK , Husain SA , Singh DK
Ref : Acta Trop , 154 :19 , 2015
Abstract : Fasciolosis is an important cattle and human disease caused by Fasciola hepatica and Fasciola gigantica. One of the possible methods to control this problem is to interrupt the life cycle of Fasciola by killing its larva (redia and cercaria) in host snail. Molecular identification of cercaria larva of F. gigantica was done by comparing the nucleotide sequencing with adult F. gigantica. It was noted that nucleotide sequencing of cercaria larva and adult F. gigantica were 99% same. Every month during the year 2011-2012, in vivo treatment with 60% of 4h LC50 of phyto cercaricides citral, ferulic acid, umbelliferone, azadirachtin and allicin caused significant inhibition of acetylcholinesterase (AChE) and cytochrome oxidase activity in the treated cercaria larva of F. gigantica. Whereas, activity of both enzymes were not significantly altered in the nervous tissues of vector snail Lymnaea acuminata exposed to same treatments. Maximum reduction in AChE (1.35% of control in month of June) and cytochrome oxidase (3.71% of control in the month of July) activity were noted in the cercaria exposed to 60% of 4h LC50 of azadirachtin and allicin, respectively.
ESTHER : Sunita_2015_Acta.Trop_154_19
PubMedSearch : Sunita_2015_Acta.Trop_154_19
PubMedID: 26536397

Title : In vivo protection of diisopropylphosphorofluoridate (DFP) poisoning by three bis-quaternary 2 -(hydroxyimino) -N -(pyridin-3-yl) acetamide derivatives in Swiss mice - Kumar_2014_Cell.Mol.Biol.(Noisy-le-grand)_60-3_53
Author(s) : Kumar P , Swami D , Karade HN , Acharya J , Jatav PC , Kumar A , Meena MK
Ref : Cellular & Molecular Biology (Noisy-le-grand) , 60-3 :53 , 2014
Abstract : This study reports efficacy of three bis pyridinium derivatives of 2&mdash;(hydroxyimino)&mdash; N&mdash;(pyridine&mdash;3&mdash;yl) acetamide in terms of survival, reactivation of brain and serum acetylcholinesterase (AChE) activity in diisopropylphosphorofluoridate (DFP) intoxicated Swiss albino male mice. LD50 of DFP (3.9 mg/kg, s.c.) and new oximes, HNK&mdash;102, HNK&mdash;106, HNK&mdash;111, (282.8, 35.0 and 35.0 mg/kg respectively, i.m.) was determined. Various doses of DFP and oximes as treatment doses with atropine (10 mg/kg, i.p.) were used to determine protection index (PI). For time dependent maximum AChE inhibition, two doses of DFP (0.20 and 2.0 LD50) were chosen. At optimized time i.e. Sixty minutes, IC50 value was calculated as 0.249 and 0.017 LD50 of brain and serum AChE, respectively. Shift of DFP induced brain AChE IC50 curves to right was observed at 0.20 LD50 treatment dose of oximes with respect to 2&mdash;PAM. These findings propose that new HNK series of oximes are effective antidote, compared to that of 2&mdash;PAM in vivo.
ESTHER : Kumar_2014_Cell.Mol.Biol.(Noisy-le-grand)_60-3_53
PubMedSearch : Kumar_2014_Cell.Mol.Biol.(Noisy-le-grand)_60-3_53
PubMedID: 25346249

Title : Ameliorating effect of lyophilized extract of Butea frondosa leaves on scopolamine-induced amnesia in rats - Malik_2013_Pharm.Biol_51_233
Author(s) : Malik J , Kumar M , Deshmukh R , Kumar P
Ref : Pharm Biol , 51 :233 , 2013
Abstract : Context: Butea frondosa (BF) Roxb. & Koen. (syn. B. monosperma Lam.) (Fabaceae) leaves have been used in folklore medicine for the treatment of diabetes, conjunctivitis, gastrointestinal tract, and central nervous system disorders such as anxiety, amnesia, etc. Objective: To evaluate the effect of lyophilized hydroalcoholic extract of BF leaves (BFLE) at 100, 200 and 400 mg/kg, p.o., for its memory enhancing activity against scopolamine-induced amnesia in rats. Materials and methods: Antiamnesic effect of the BFLE was evaluated using Morris water maze and object recognition test models. The effect of BFLE on acetylcholinesterase activity and malondialdehyde and glutathione levels were also evaluated in brain homogenate. Result: BFLE ameliorates scopolamine-induced amnesia in both the models with maximum effect at 400 mg/kg. BFLE (400 mg/kg) decreased escape latency and increased time spent in target quadrant (24.2 and 42.5 s, respectively) in comparison to scopolamine (82 and 18.2 s, respectively) in the Morris water maze task. In the object recognition test, BFLE produced significant increase in ability to discriminate between novel and familiar objects. The highest investigated dose of BFLE (400 mg/kg), produced a significant decrease in acetylcholinesterase activity and malondialdehyde levels, and improves glutathione levels in comparison to scopolamine. Moreover, this effect of BFLE at 400 mg/kg was comparable to that of standard, donepezil. Conclusion: BFLE exhibited significant antiamnesic activity in rats thereby validating its folklore use.
ESTHER : Malik_2013_Pharm.Biol_51_233
PubMedSearch : Malik_2013_Pharm.Biol_51_233
PubMedID: 23127163

Title : Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis - Wilson_2013_Nat.Chem.Biol_9_499
Author(s) : Wilson R , Kumar P , Parashar V , Vilcheze C , Veyron-Churlet R , Freundlich JS , Barnes SW , Walker JR , Szymonifka MJ , Marchiano E , Shenai S , Colangeli R , Jacobs WR, Jr. , Neiditch MB , Kremer L , Alland D
Ref : Nat Chemical Biology , 9 :499 , 2013
Abstract : We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13(F79S) mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.
ESTHER : Wilson_2013_Nat.Chem.Biol_9_499
PubMedSearch : Wilson_2013_Nat.Chem.Biol_9_499
PubMedID: 23770708
Gene_locus related to this paper: myctu-PKS13

Title : Proteogenomic analysis of Mycobacterium tuberculosis by high resolution mass spectrometry - Kelkar_2011_Mol.Cell.Proteomics_10_M111.011627
Author(s) : Kelkar DS , Kumar D , Kumar P , Balakrishnan L , Muthusamy B , Yadav AK , Shrivastava P , Marimuthu A , Anand S , Sundaram H , Kingsbury R , Harsha HC , Nair B , Prasad TS , Chauhan DS , Katoch K , Katoch VM , Chaerkady R , Ramachandran S , Dash D , Pandey A
Ref : Mol Cell Proteomics , 10 :M111 011627 , 2011
Abstract : The genome sequencing of H37Rv strain of Mycobacterium tuberculosis was completed in 1998 followed by the whole genome sequencing of a clinical isolate, CDC1551 in 2002. Since then, the genomic sequences of a number of other strains have become available making it one of the better studied pathogenic bacterial species at the genomic level. However, annotation of its genome remains challenging because of high GC content and dissimilarity to other model prokaryotes. To this end, we carried out an in-depth proteogenomic analysis of the M. tuberculosis H37Rv strain using Fourier transform mass spectrometry with high resolution at both MS and tandem MS levels. In all, we identified 3176 proteins from Mycobacterium tuberculosis representing ~80% of its total predicted gene count. In addition to protein database search, we carried out a genome database search, which led to identification of ~250 novel peptides. Based on these novel genome search-specific peptides, we discovered 41 novel protein coding genes in the H37Rv genome. Using peptide evidence and alternative gene prediction tools, we also corrected 79 gene models. Finally, mass spectrometric data from N terminus-derived peptides confirmed 727 existing annotations for translational start sites while correcting those for 33 proteins. We report creation of a high confidence set of protein coding regions in Mycobacterium tuberculosis genome obtained by high resolution tandem mass-spectrometry at both precursor and fragment detection steps for the first time. This proteogenomic approach should be generally applicable to other organisms whose genomes have already been sequenced for obtaining a more accurate catalogue of protein-coding genes.
ESTHER : Kelkar_2011_Mol.Cell.Proteomics_10_M111.011627
PubMedSearch : Kelkar_2011_Mol.Cell.Proteomics_10_M111.011627
PubMedID: 21969609
Gene_locus related to this paper: myctu-ephA , myctu-ephB , myctu-ephd , myctu-linb , myctu-MBTB , myctu-PKS13 , myctu-Rv1833c , myctu-RV2296 , myctu-RV2695 , myctu-RV2765

Title : Enzyme Inhibition by Molluscicidal Components of Myristica fragrans Houtt. in the Nervous Tissue of Snail Lymnaea acuminata - Jaiswal_2010_Enzyme.Res_2010_478746
Author(s) : Jaiswal P , Kumar P , Singh VK , Singh DK
Ref : Enzyme Res , 2010 :478746 , 2010
Abstract : This study was designed to investigate the effects of molluscicidal components of Myristica fragrans Houtt. (Myristicaceae) on certain enzymes in the nervous tissue of freshwater snail Lymnaea acuminata Lamarck (Lymnaeidae). In vivo and in vitro treatments of trimyristin and myristicin (active molluscicidal components of Myristica fragrans Houtt.) significantly inhibited the acetylcholinesterase (AChE), acid and alkaline phosphatase (ACP/ALP) activities in the nervous tissue of Lymnaea acuminata. The inhibition kinetics of these enzymes indicates that both the trimyristin and myristicin caused competitive noncompetitive inhibition of AChE. Trimyristin caused uncompetitive and competitive/noncompetitive inhibitions of ACP and ALP, respectively whereas the myristicin caused competitive and uncompetitive inhibition of ACP and ALP, respectively. Thus results from the present study suggest that inhibition of AChE, ACP, and ALP by trimyristin and myristicin in the snail Lymnaea acuminata may be the cause of the molluscicidal activity of Myristica fragrans.
ESTHER : Jaiswal_2010_Enzyme.Res_2010_478746
PubMedSearch : Jaiswal_2010_Enzyme.Res_2010_478746
PubMedID: 21048864

Title : Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington's disease like symptoms: possible behavioural, biochemical and cellular alterations - Kumar_2009_Eur.J.Pharmacol_615_91
Author(s) : Kumar P , Kumar A
Ref : European Journal of Pharmacology , 615 :91 , 2009
Abstract : 3-Nitropropionic acid inhibits succinate dehydrogenase, complex II enzyme in the mitochondrial respiratory chain that leads to cellular energy deficit and oxidative stress. Huntington's disease is characterized by abnormal body movements (chorea) and cognitive dysfunctions. Rivastigmine, a well known cholinesterase inhibitor used in the management of Alzheimer's disease in a clinical practice. Recent clinical studies suggest the potential role of rivastigmine in the management of Huntington's disease. The present study has been designed to explore the possible role of rivastigmine against 3-nitropropionic acid induced behavioral, biochemical and cellular alterations. Intraperitoneal administration of 3-nitropropionic acid (10 mg/kg for 14 days) caused significant loss in body weight, motor in coordination (locomotor activity and rota rod performance) and poor memory retention in Morris water maze and elevated plus maze performance tasks as compared to vehicle treated animals. Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration and depleted superoxide dismutase, catalase levels and alterations in mitochondrial complex enzymes (I, II, IV and MTT assay) in the different regions (striatum, cortex and hippocampus) of rat brain. Rivastigmine (0.5, 1 and 2 mg/kg, orally) once daily treatment for a period of 14 days significantly improved motor performance and cognitive task in both Morris water maze and elevated plus maze tests. Further, rivastigmine treatment significantly attenuated oxidative damage and improved mitochondrial complexes enzyme activities in different regions (striatum, cortex and hippocampus) of rat brain. The results show that rivastigmine could be used as an effective therapeutic agent in the management of Huntington's disease and related conditions.
ESTHER : Kumar_2009_Eur.J.Pharmacol_615_91
PubMedSearch : Kumar_2009_Eur.J.Pharmacol_615_91
PubMedID: 19445928

Title : Protective role of sertraline against 3-nitropropionic acid-induced cognitive dysfunction and redox ratio in striatum, cortex and hippocampus of rat brain - Kumar_2009_Indian.J.Exp.Biol_47_715
Author(s) : Kumar P , Kumar A
Ref : Indian J Exp Biol , 47 :715 , 2009
Abstract : Huntington's disease (HD) is an inherited progressive neurodegenerative disorder in human characterized by progressive loss of movement and cognitive disturbances. 3-nitropropionic acid (3-NP; a mitochondrial toxin) produces age-dependent oxidative linked striatal damage, responsible for HD like symptoms. In the present study protective effect of sertraline in 3-NP induced HD like symptoms was evaluated in rats. Systemic administration of 3-NP (10 mg/kg for 14 days) resulted in impairment of memory as assessed in Morris water maze and elevated plus paradigm tasks. Biochemical analysis revealed that systemic 3-NP administration significantly impaired reduced glutathione, total glutathione, oxidized glutathione and glutathione-S-transferase levels, whereas the level of acetylcholinesterase enzyme increased in striatum, cortex and hippocampus regions of rat brain. Sertraline (5 and 10 mg/kg po) treatment once daily for 14 days significantly improved cognitive performance tasks and glutathione levels in 3-NP treated group. However, combination of yohimbine (2 mg/kg) (non selective serotonin receptors antagonist) with the higher dose of sertraline (10 mg/kg) did not influence the protective action of sertraline. Result shows that neuroprotective and antioxidant like effect of sertraline is independent of its conventional action on 5-HT receptor.
ESTHER : Kumar_2009_Indian.J.Exp.Biol_47_715
PubMedSearch : Kumar_2009_Indian.J.Exp.Biol_47_715
PubMedID: 19957883

Title : Protective effect of quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats - Kumar_2008_Phytother.Res_22_1563
Author(s) : Kumar A , Sehgal N , Kumar P , Padi SS , Naidu PS
Ref : Phytother Res , 22 :1563 , 2008
Abstract : Intracerebroventricular (i.c.v.) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction and oxidative stress. The present study was designed to investigate the protective effects of quercetin against colchicine-induced memory impairment and oxidative damage in rats. An i.c.v. cannula was implanted in the lateral ventricle of male Wistar rats. Colchicine was administered at dose of 15 microg/rat. Morris water maze and plus-maze performance tests were used to assess memory tasks. Various biochemical parameters such as lipid peroxidation, reduced glutathione, nitrite level, acetylcholinesterase and proteins were also assessed. Central administration of colchicine (15 microg/rat) showed poor retention of memory. Chronic treatment with quercetin (20 and 40 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemical analysis revealed that i.c.v. colchicine injection significantly increased lipid peroxidation, nitrite and depleted reduced glutathione activity in the brains of rats. Chronic administration of quercetin significantly attenuated elevated lipid peroxidation and restored the depleted reduced glutathione, acetylcholinesterase activity and nitrite activity. The results of the present study clearly indicated that quercetin has a neuroprotective effect against colchicine-induced cognitive dysfunctions and oxidative damage. This article was published online on 3 November 2008. An error was subsequently identified. This notice is included in the online and print version to indicate that both have been corrected.
ESTHER : Kumar_2008_Phytother.Res_22_1563
PubMedSearch : Kumar_2008_Phytother.Res_22_1563
PubMedID: 18980205

Title : A preliminary study of protein thiols and serum cholinesterase in assisted reproduction - Prabhu_2008_Indian.J.Clin.Biochem_23_98
Author(s) : Prabhu K , Kumar P , Pai M , Sinha I , Rao A
Ref : Indian J Clinical Biochemistry , 23 :98 , 2008
Abstract : In this study we sought to investigate the levels of serum protein thiols and cholinesterase levels before and after intrauterine insemination IUI).We observed 68 patients showed a decrease in protein thiols and 63 showed a decrease in serum cholinesterase levels after insemination as compared to their respective pre procedure levels The fall in thiols was statistically significant p=0.021 indicating there is increased oxidative stress after the procedure However we could not comment on any reason for the fall in cholinesterase Whether the changes in above parameters may have some implication on the overall success rate of IUI is yet to be ascertained.
ESTHER : Prabhu_2008_Indian.J.Clin.Biochem_23_98
PubMedSearch : Prabhu_2008_Indian.J.Clin.Biochem_23_98
PubMedID: 23105732

Title : The tautomeric half-reaction of BphD, a C-C bond hydrolase. Kinetic and structural evidence supporting a key role for histidine 265 of the catalytic triad - Horsman_2007_J.Biol.Chem_282_19894
Author(s) : Horsman GP , Bhowmik S , Seah SY , Kumar P , Bolin JT , Eltis LD
Ref : Journal of Biological Chemistry , 282 :19894 , 2007
Abstract : BphD of Burkholderia xenovorans LB400 catalyzes an unusual C-C bond hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) to afford benzoic acid and 2-hydroxy-2,4-pentadienoic acid (HPD). An enol-keto tautomerization has been proposed to precede hydrolysis via a gem-diol intermediate. The role of the canonical catalytic triad (Ser-112, His-265, Asp-237) in mediating these two half-reactions remains unclear. We previously reported that the BphD-catalyzed hydrolysis of HOPDA (lambda(max) is 434 nm for the free enolate) proceeds via an unidentified intermediate with a red-shifted absorption spectrum (lambda(max) is 492 nm) (Horsman, G. P., Ke, J., Dai, S., Seah, S. Y. K., Bolin, J. T., and Eltis, L. D. (2006) Biochemistry 45, 11071-11086). Here we demonstrate that the S112A variant generates and traps a similar intermediate (lambda(max) is 506 nm) with a similar rate, 1/tau approximately 500 s(-1). The crystal structure of the S112A:HOPDA complex at 1.8-A resolution identified this intermediate as the keto tautomer, (E)-2,6-dioxo-6-phenyl-hex-3-enoate. This keto tautomer did not accumulate in either the H265A or the S112A/H265A double variants, indicating that His-265 catalyzes tautomerization. Consistent with this role, the wild type and S112A enzymes catalyzed tautomerization of the product HPD, whereas H265A variants did not. This study thus identifies a keto intermediate, and demonstrates that the catalytic triad histidine catalyzes the tautomerization half-reaction, expanding the role of this residue from its purely hydrolytic function in other serine hydrolases. Finally, the S112A:HOPDA crystal structure is more consistent with hydrolysis occurring via an acyl-enzyme intermediate than a gem-diol intermediate as solvent molecules have poor access to C6, and the closest ordered water is 7 A away.
ESTHER : Horsman_2007_J.Biol.Chem_282_19894
PubMedSearch : Horsman_2007_J.Biol.Chem_282_19894
PubMedID: 17442675
Gene_locus related to this paper: burxl-bphD

Title : Clinical, biochemical and neurobehavioural studies of workers engaged in the manufacture of quinalphos - Srivastava_2000_Food.Chem.Toxicol_38_65
Author(s) : Srivastava AK , Gupta BN , Bihari V , Mathur N , Srivastava LP , Pangtey BS , Bharti RS , Kumar P
Ref : Food & Chemical Toxicology , 38 :65 , 2000
Abstract : 59 workers exposed to different chemicals during the manufacture of quinalphos, an organophosphate pesticide (OP) and 17 control subjects were studied. Despite similar blood acetylcholinestarase (AChE) levels in both the exposed and control subjects, a significant number of exposed subjects had altered plantar and ankle reflexes. Higher nervous functions such as memory, learning and vigilance were also found to be affected in these subjects. These findings were attributed to chronic low dose combined exposure to different chemicals used/formed in the manufacture of quinalphos. The study raises the doubt that monitoring of AChE alone among subjects engaged in the manufacture of OP pesticides may not be an adequate safeguard as regards to their health.
ESTHER : Srivastava_2000_Food.Chem.Toxicol_38_65
PubMedSearch : Srivastava_2000_Food.Chem.Toxicol_38_65
PubMedID: 10685015

Title : Protective Efficacy of Physostigmine and Pyridostigmine at Various Pretreatment Times against Inhaled Sarin in Rats -
Author(s) : Vijayaraghavan R , Husain K , Kumar P , Pandey KS , Das Gupta S
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :408 , 1995

Title : Toxicological evaluation of 1-chloroacetophenone and dibenz[b,f]-1,4-oxazepine after repeated inhalation exposure in mice - Kumar_1994_J.Appl.Toxicol_14_411
Author(s) : Kumar P , Flora SJ , Pant SC , Sachan AS , Saxena SP , Gupta SD
Ref : Journal of Applied Toxicology , 14 :411 , 1994
Abstract : Toxicological evaluation was made on the effects of two peripheral sensory irritants (tear gases): 1-chloroacetophenone (CN) and dibenz[b,f]-1,4-oxazepine (CR). Animals had a 15-min daily inhalation exposure to average vapour concentrations of 87.6 mg CN m-3 or 1008 mg CR m-3 (both equal to 0.05 LC50) for 5 or 10 days and were sacrificed 24 h after the last exposure, when biochemical and histopathological observations were made. Both chemicals caused a significant decrease in body weight gain. Histological changes in lung, liver and kidneys were more severe after 10 than after 5 days of exposure and were more severe in CN-exposed than in CR-exposed mice. Organ weight to body weight ratios remained normal except for the spleen to body weight ratio, which decreased in CN-exposed mice after both 5 and 10 days of exposure. Biochemical indicators showed a toxic response only in CN-exposed mice, but the only consistent change was an increase in blood glucose. Hepatic alkaline phosphatase was not influenced, malondialdehyde concentration and acid phosphatase activity were increased only after 5 days of exposure and liver GSH concentration decreased after 10 days of exposure. Results indicate that CN is not only more toxic than CR in absolute terms but is also more toxic at the 5% level of their LC50.
ESTHER : Kumar_1994_J.Appl.Toxicol_14_411
PubMedSearch : Kumar_1994_J.Appl.Toxicol_14_411
PubMedID: 7884145