Sharma M

References (28)

Author(s) : Sharma M , Pal P , Gupta SK
Ref : Neurochem Int , :105761 , 2024
Abstract : Alzheimer's disease (AD) remains one of the most formidable neurological disorders, affecting millions globally. This review provides a holistic overview of the therapeutic strategies, both conventional and novel, aimed at mitigating the impact of AD. Initially, we delve into the conventional approach, emphasizing the role of Acetylcholinesterase (AChE) inhibition, which has been a cornerstone in AD management. As our understanding of AD evolves, several novel potential approaches emerge. We discuss the promising roles of Butyrylcholinesterase (BChE) inhibition, Tau Protein inhibitors, COX-2 inhibition, PPAR-gamma agonism, and FAHH inhibition, among others. The potential of the endocannabinoids (eCB) system, cholesterol-lowering drugs, metal chelators, and MMPs inhibitors are also explored, culminating in the exploration of the pivotal role of microRNA in AD progression. Parallel to these therapeutic insights, we shed light on the novel tools and methodologies revolutionizing AD research. From the quantitative analysis of gene expression by qRTPCR to the evaluation of mitochondrial function using induced pluripotent stem cells (iPSCs), the advances in diagnostic and research tools offer renewed hope. Moreover, we explore the current landscape of clinical trials, highlighting the leading drug interventions and their respective stages of development. This comprehensive review concludes with a look into the future perspectives, capturing the potential breakthroughs and innovations on the horizon. Through a synthesis of current knowledge and emerging research, this article aims to provide a consolidated resource for clinicians, researchers, and academicians in the realm of Alzheimer's disease.
ESTHER : Sharma_2024_Neurochem.Int__105761
PubMedSearch : Sharma_2024_Neurochem.Int__105761
PubMedID: 38723902

Title : Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease - Nagori_2024_Curr.Alzheimer.Res__
Author(s) : Nagori K , Pradhan M , Sharma M , Ajazuddin , Badwaik HR , Nakhate KT
Ref : Curr Alzheimer Res , : , 2024
Abstract : Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-beta plaques and tau protein-rich neurofibrillary tangles. Amyloid-beta also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.
ESTHER : Nagori_2024_Curr.Alzheimer.Res__
PubMedSearch : Nagori_2024_Curr.Alzheimer.Res__
PubMedID: 38529600

Title : Cyclic carbamates in medicine: A clinical perspective - Prasher_2023_Drug.Dev.Res__
Author(s) : Prasher P , Mall T , Sharma M
Ref : Drug Dev Res , : , 2023
Abstract : Carbamate group is mainly used for designing prodrugs to achieve first-pass and systemic stability against enzyme hydrolysis as the carbamate functionality is recognized by esterase enzymes. As compared to the ester functionality, the carbamate group shows a lesser lability towards enzyme hydrolysis, but a higher susceptibility than amides. Cyclic carbamates present a unique motif in the contemporary drug discovery and development owing to the presence of a polar, and sterically small, constrained Hydrogen-bonding acceptor atom. The metabolic stability of 5/6-membered cyclic carbamates are higher as compared to their acyclic counterparts as the former do not undergo metabolic ring opening under physiological conditions. Besides, the metabolic lability of acyclic carbamates is determined by the degree of substitution at the endocyclic/exocyclic 'N' atom, which further enables the design and development of various carbamate drugs or prodrugs. As such, the metabolic stability of carbamates follows the order: Cyclic carbamates > Alkyl-OCO-NH(2) Alkyl-OCO-NHAcyl - Alkyl-OCO-NHAryl <= Aryl-OCO-N(endocyclic) - Aryl-OCO-N(Alkyl)(2) <= Alkyl-OCO-N(endocyclic) <= Alkyl-OCO-N(Alkyl)(2) - Alkyl-OCO-NHAlkyl Aryl-OCO-NHAlkyl.
ESTHER : Prasher_2023_Drug.Dev.Res__
PubMedSearch : Prasher_2023_Drug.Dev.Res__
PubMedID: 36651662

Title : Discovery of blood-brain barrier permeable and orally bioavailable caffeine-based amide derivatives as acetylcholinesterase inhibitors - Sharma_2023_Bioorg.Chem_139_106719
Author(s) : Sharma M , Sharma A , Thakur S , Nuthakki VK , Jamwal A , Nandi U , Jadhav HR , Bharate SB
Ref : Bioorg Chem , 139 :106719 , 2023
Abstract : Caffeine is one of the privileged natural products that shows numerous effects on the central nervous system. Herein, thirty-one caffeine-based amide derivatives were synthesized and evaluated in vitro for their anticholinesterase activity. The introduction of the amide group to the caffeine core augmented its anticholinesterase activity from an IC(50) value of 128 to 1.32 microM (derivative, 6i). The SAR study revealed that N7 substitution on caffeine core is favorable over N1, and the presence of amide 'carbonyl' as a part of the linker contributes to the biological activity. The caffeine core of 6i exhibits interactions with the peripheral anionic site, whereas the N-benzyl ring fits nicely inside the catalytic anionic site. Analog 6i inhibits AChE in a mixed-type mode (K(i) 4.58 microM) and crosses the BBB in an in-vitro PAMPA assay. Compound 6i has a descent metabolic stability in MLM (>70% remaining after 30 min) and favorable oral pharmacokinetics in Swiss albino mice.
ESTHER : Sharma_2023_Bioorg.Chem_139_106719
PubMedSearch : Sharma_2023_Bioorg.Chem_139_106719
PubMedID: 37473478

Title : Methoxy-naphthyl-Linked N-Benzyl Pyridinium Styryls as Dual Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Structure-Activity Relationship - Abdullaha_2023_ACS.Omega_8_17591
Author(s) : Abdullaha M , Banoo R , Nuthakki VK , Sharma M , Kaur S , Thakur S , Kumar A , Jadhav HR , Bharate SB
Ref : ACS Omega , 8 :17591 , 2023
Abstract : The multifaceted nature of Alzheimer's disease (AD) indicates the need for multitargeted agents as potential therapeutics. Both cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), play a vital role in disease progression. Thus, inhibiting both ChEs is more beneficial than only one for effectively managing AD. The present study provides a detailed lead optimization of the e-pharmacophore-generated pyridinium styryl scaffold to discover a dual ChE inhibitor. A structure-activity relationship analysis indicated the importance of three structural fragments, methoxy-naphthyl, vinyl-pyridinium, and substituted-benzyl, in a dual ChE inhibitor pharmacophore. The optimized 6-methoxy-naphthyl derivative, 7av (SB-1436), inhibits EeAChE and eqBChE with IC(50) values of 176 and 370 nM, respectively. The kinetic study has shown that 7av inhibits AChE and BChE in a non-competitive manner with k(i) values of 46 and 115 nM, respectively. The docking and molecular dynamics simulation demonstrated that 7av binds with the catalytic and peripheral anionic sites of AChE and BChE. Compound 7av also significantly stops the self-aggregation of Abeta. The data presented herein indicate the potential of 7av for further investigation in preclinical models of AD.
ESTHER : Abdullaha_2023_ACS.Omega_8_17591
PubMedSearch : Abdullaha_2023_ACS.Omega_8_17591
PubMedID: 37251153

Title : Studies on the interaction of 2,4-dibromophenol with human hemoglobin using multi-spectroscopic, molecular docking and molecular dynamics techniques - Sharma_2023_J.Biomol.Struct.Dyn__1
Author(s) : Sharma M , Farhat N , Khan AU , Khan FH , Mahmood R
Ref : J Biomol Struct Dyn , :1 , 2023
Abstract : 2,4-Dibromophenol (DBP) has several industrial applications, including as a wood preservative and flame retardant. This study investigated the interaction between DBP and human hemoglobin (Hb) using spectroscopic, molecular docking and molecular dynamic techniques. The UV-visible spectra showed ground-state complex formation between DBP and Hb. Fluorescence studies revealed that DBP binding caused significant quenching of Hb fluorescence by the static quenching mechanism. The binding of DBP to Hb is a spontaneous process that involves van der Waals forces and hydrogen bonds. There is one DBP binding site on each Hb molecule that is located at the alpha(1)beta(2) interface of Hb. DBP binding did not alter the microenvironment of tyrosine and tryptophan residues in Hb. Circular dichroism studies revealed that DBP increased the alpha-helical content of Hb. The intrinsic esterase activity of Hb was inhibited by DBP in a concentration-dependent manner. Molecular docking showed that DBP binds to Hb via hydrogen bonds, hydrophobic, van der Waals and Pi - Pi interactions. Molecular dynamics simulation confirmed that the Hb-DBP complex is stable. Overall, the results of this study clearly show that DBP induces structural changes and interferes with the function of Hb. This can have important implications for human health.Communicated by Ramaswamy H. Sarma.
ESTHER : Sharma_2023_J.Biomol.Struct.Dyn__1
PubMedSearch : Sharma_2023_J.Biomol.Struct.Dyn__1
PubMedID: 37811549

Title : Design, synthesis, and structure-activity relationship of caffeine-based triazoles as dual AChE and BACE-1 inhibitors - Sharma_2022_Drug.Dev.Res__
Author(s) : Sharma M , Sharma A , Nuthakki VK , Bhatt S , Nandi U , Bharate SB
Ref : Drug Dev Res , : , 2022
Abstract : Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well-known central nervous system(CNS)-active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory-enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine-based triazoles were synthesized and evaluated in vitro for cholinesterase and beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half-maximal inhibitory concentration (IC(50) ) of 129 microM to 0.49 microM (derivative, 6l). The caffeine core interacts with the peripheral anionic site, whereas the benzyl triazole occupies the catalytic anionic site located at the bottom of the active site gorge. The structure-activity relationship revealed that the four-atom ester linker is superior to shorter linkers for connecting the caffeine core to the triazole. The 2,6-difluorobenzyl triazole-linked caffeine derivative, 6d, exhibits dual inhibition of AChE and BACE-1 with IC(50) values of 1.43 and 10.9 microM, respectively. The derivative 6d inhibits AChE via a mixed-type mode with an inhibition rate constant (K(i) ) value of 2.35 microM, which was corroborated by docking studies. The triazole 6d has an acceptable stability profile in human liver microsomes (t(1/2) = 54 min) and was found to possess CNS permeability when evaluated using the parallel artificial membrane permeability blood-brain barrier assay. The results presented herein warrant investigating caffeine-based triazoles in preclinical models of Alzheimer's disease.
ESTHER : Sharma_2022_Drug.Dev.Res__
PubMedSearch : Sharma_2022_Drug.Dev.Res__
PubMedID: 36161804

Title : Influence of ligand geometry on cholinesterase enzyme - A comparison of 1-isoindolinone based structural analog with Donepezil - Upadhyay_2022_J.Mol.Struct_1247_
Author(s) : Upadhyay SP , Singh V , Sharma R , Zhou J , Thapa P , Johnson DK , Keightley A , Chen M , Suo W , Sharma M
Ref : J Mol Struct , 1247 : , 2022
Abstract : Donepezil (DNPZ) is one of the few FDA-approved widely used medication in the clinical care of Alzheimer's disease (AD) patients. To investigate the effect of geometry and to find the significance of an enol form if any in DNPZ on acetylcholinesterase (AChE) inhibition, we changed the tetrahedral geometry of DNPZ to planar trigonal pyramidal geometry by replacing the alpha-carbon atom next to ketone functionality with a nitrogen atom. To mimic 1-indanone in DNPZ, we selected 1-isoindolinone framework to synthesize 25 new DNPZ derivatives and characterized using (1)H NMR, (13)C NMR and ESI-MS spectroscopy methods. Drug likeliness profile for each compound was predicted using Molinspiration online software following Lipinski's rule. Commercially available assay kits were used to measure AChE and butyrylcholinesterase (BuChE) inhibitory effects. NIH/3T3 mouse embryonic fibroblast cell line was used to measure cytotoxic and proliferation effects using LDH and MTT assay, respectively. Compound #20 was selected for comparative computational docking, modelling and physicochemical studies. Our results show that DNPZ with tetrahedral geometry has 3-fold higher AChE inhibition as compared to compound #20 with planar trigonal pyramidal geometry. Our approach may be useful as a novel indirect method to study the significance of the enol form in DNPZ (or similar compounds), since constant interconversion between the keto and enol forms does not permit a direct determination of the effect of the enol form of DNPZ in vivo. Overall, we conclude that the tetrahedral is a better fit and any change in geometry significantly drives down the cholinesterase inhibitory effect of DNPZ.
ESTHER : Upadhyay_2022_J.Mol.Struct_1247_
PubMedSearch : Upadhyay_2022_J.Mol.Struct_1247_
PubMedID: 34776532

Title : Blood-brain barrier permeable benzylpiperidin-4-yl-linked benzylamino benzamides as dual cholinesterase inhibitors - Banoo_2022_Drug.Dev.Res__
Author(s) : Banoo R , Nuthakki VK , Abdullaha M , Sharma M , Bharate SB
Ref : Drug Dev Res , : , 2022
Abstract : Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder involving various pathological events. The existing options for managing the disease utterly rely on cholinesterase (ChE) inhibitors. In recent years, the dual inhibition of ChEs as a potential AD therapeutics has substantially attracted the attention of medicinal chemists. Recently, we reported benzyl piperidinyl-linked methoxy-naphthamides as dual ChE inhibitors. Herein, we investigated the peripheral anionic binding site-binding methoxy-naphthamide fragment that yielded benzyl piperidinyl-linked benzyl aminobenzamide as another class of dual ChE inhibitors. The 3,5-dimethoxy benzyl aminobenzamide, 8c1, exhibits inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with half-maximal inhibitory concentration values of 0.61 and 2.04 microM, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed-type mode of inhibition for AChE and BChE with k(i) values of 0.14 and 0.46 microM, respectively. The derivative 8c1 crosses the blood-brain barrier as indicated by the P(e) value of 14.34 x 10(-6) cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self-aggregation of amyloid-beta. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.
ESTHER : Banoo_2022_Drug.Dev.Res__
PubMedSearch : Banoo_2022_Drug.Dev.Res__
PubMedID: 36112736

Title : Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer's disease - Thapa_2021_Bioorg.Chem_108_104681
Author(s) : Thapa P , Upadhyay SP , Suo WZ , Singh V , Gurung P , Lee ES , Sharma R , Sharma M
Ref : Bioorg Chem , 108 :104681 , 2021
Abstract : Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with alpha, beta unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer's disease (AD). Small molecular size, convenient and cost-effective synthesis, and flexibility for modifications to modulate lipophilicity suitable for blood brain barrier (BBB) permeability make chalcones a preferred candidate for their therapeutic and diagnostic potential in AD. This review summarizes and highlights the importance of chalcone and its analogs as single target small therapeutic agents, multi-target directed ligands (MTDLs) as well as molecular imaging agents for AD. The information summarized here will guide many medicinal chemist and researchers involved in drug discovery to consider chalcone as a potential scaffold for the development of anti-AD agents including theranostics.
ESTHER : Thapa_2021_Bioorg.Chem_108_104681
PubMedSearch : Thapa_2021_Bioorg.Chem_108_104681
PubMedID: 33571811

Title : Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)5: Guidelines for management of vascular cognitive impairment - Smith_2020_Alzheimers.Dement.(N.Y)_6_e12056
Author(s) : Smith EE , Barber P , Field TS , Ganesh A , Hachinski V , Hogan DB , Lanctt KL , Lindsay MP , Sharma M , Swartz RH , Ismail Z , Gauthier S , Black SE
Ref : Alzheimers Dement (N Y) , 6 :e12056 , 2020
Abstract : INTRODUCTION: Vascular disease is a common cause of dementia, and often coexists with other brain pathologies such as Alzheimer's disease to cause mixed dementia. Many of the risk factors for vascular disease are treatable. Our objective was to review evidence for diagnosis and treatment of vascular cognitive impairment (VCI) to issue recommendations to clinicians. METHODS: A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed areas of emerging evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assign the quality of the evidence and strength of the recommendations. RESULTS: Using standardized diagnostic criteria, managing hypertension to conventional blood pressure targets, and reducing risk for stroke are strongly recommended. Intensive blood pressure lowering in middle-aged adults with vascular risk factors, using acetylsalicylic acid in persons with VCI and covert brain infarctions but not if only white matter lesions are present, and using cholinesterase inhibitors are weakly recommended. CONCLUSIONS: The CCCDTD has provided evidence-based recommendations for diagnosis and management of VCI for use nationally in Canada, that may also be of use worldwide.
ESTHER : Smith_2020_Alzheimers.Dement.(N.Y)_6_e12056
PubMedSearch : Smith_2020_Alzheimers.Dement.(N.Y)_6_e12056
PubMedID: 33209971

Title : Eugenol Attenuates Scopolamine-Induced Hippocampal Cholinergic, Glutamatergic, and Mitochondrial Toxicity in Experimental Rats - Garabadu_2019_Neurotox.Res_35_848
Author(s) : Garabadu D , Sharma M
Ref : Neurotox Res , 35 :848 , 2019
Abstract : Eugenol is one of the essential chemical constituents of several functional food plants including Eugenia caryophyllata Thunb. (Family: Myrtaceae). Eugenol exhibits neuroprotective and anti-stress activities through multimodal mechanisms of action. Further, eugenol exerts anti-amnesic activity in Alzheimer's disease (AD)-like animals perhaps through anti-oxidant mechanism to date. Hence, the present study was designed to elaborate the anti-amnesic activity of eugenol in scopolamine-challenged rodents. Scopolamine (3 mg/kg/day, i.p.) and eugenol (12.5, 25.0, and 50.0 mg/kg) were administered to male rats for 14 consecutive days of the experimental schedule at a time lag of 30 min. Eugenol (25.0 and 50.0 mg/kg) attenuated scopolamine-induced loss in learning ability in terms of increased escape latency at day-4 (D-4) and memory function in terms of decreased time spent in target quadrant at D-5 of Morris water maze test protocol. Moreover, eugenol attenuated scopolamine-induced loss in spatial memory in terms of decreased percentage of spontaneous alteration behavior in Y-maze test. Additionally, eugenol attenuated scopolamine-induced hippocampal cholinergic dysfunction (decrease in acetylcholine level, increase in acetylcholinesterase activity, and decrease in density and affinity of M1 and total muscarinic receptor), glutamate neurotoxicity (increase in levels of glutamate, calcium, calcium-dependent calpain-2, and brain-derived neurotropic factor), and mitochondrial dysfunction (decrease in formazan produced, membrane potential, and oxidative stress) in rats. Thus, it could be considered as an alternate candidate in the management of AD. Moreover, inclusion of functional foods containing eugenol could be a better option to manage memory formation in neurological disorders.
ESTHER : Garabadu_2019_Neurotox.Res_35_848
PubMedSearch : Garabadu_2019_Neurotox.Res_35_848
PubMedID: 30737653

Title : N-(4-Hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives as potential memory enhancers: Synthesis, biological evaluation and molecular simulation studies - Piplani_2017_J.Biomol.Struct.Dyn__1
Author(s) : Piplani P , Sharma M , Mehta P , Malik R
Ref : J Biomol Struct Dyn , :1 , 2017
Abstract : The present paper describes the synthesis, biological evaluation and molecular simulation studies of a series of N-(4-hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives with N,N-dialkylaminoethoxy/propoxy moiety as potential memory enhancers with acetylcholinesterase inhibiting activity having IC50 in low micromolar range (4.0-16.5 muM). All the compounds showed a good degree of agreement between in vivo and in vitro results as most of these derivatives showed dose dependent increase in percent retention. Compound 10a showed significant % retention of 84.73 +/- 4.51 as compared to piracetam (46.88 +/- 5.42) at 3 mg kg-1 and also exhibited a maximal percent inhibition of 97% at 50 muM. Molecular docking, MM-GBSA and molecular simulation studies were performed establishing a correlation between the experimental biology and in silico results. In silico results indicate that all the compounds have better docking scores and predicted binding free energies as compared to co-crystallized ligand with the best potent ligand retaining conserved hydrophobic interactions with residues of catalytic triad (HIS447), Catalytic anionic site (CAS) (TRP86, TYR337, PHE338) and peripheral anionic site (PAS) (TYR72, TYR124, TRP286 and TYR341). Root mean square deviation (RMSD=2.4 A) and root mean square fluctuations of 10a-AChE complex during simulation proved its stable nature in binding toward acetylcholinesterase. The docked conformation of 10a and other analogs at the binding site have also been simulated with polar and non polar interactions interlining the gorge residues from PAS to catalytic triad.
ESTHER : Piplani_2017_J.Biomol.Struct.Dyn__1
PubMedSearch : Piplani_2017_J.Biomol.Struct.Dyn__1
PubMedID: 28565938

Title : Thirty-degree shift in optimum temperature of a thermophilic lipase by a single-point mutation: effect of serine to threonine mutation on structural flexibility - Sharma_2017_Mol.Cell.Biochem_430_21
Author(s) : Sharma M , Kumar R , Singh R , Kaur J
Ref : Molecular & Cellular Biochemistry , 430 :21 , 2017
Abstract : In order to understand the molecular basis of cold adaptation, we have used directed evolution to transform a thermophilic lipase LipR1 into its psychrophilic counterpart. A single round of random mutagenesis followed by screening for improved variants yielded a mutant with single-point mutation LipR1M1 (S130T), with optimum activity at 20 degrees C. Its activity at 50 degrees C is only 20% as compared to wild type (100%). It showed catalytic rate constant (k cat) 3 times higher and a catalytic efficiency (k cat/K m) 4 times that of wild type. Circular dichroism and fluorescence studies also supported our observation of mutant structural flexibility. Structure analysis using homology models showed that Threonine 130 is exposed to solvent and has lost H-bond interaction with neighboring amino acid, thereby increasing flexibility of this lipase structure.
ESTHER : Sharma_2017_Mol.Cell.Biochem_430_21
PubMedSearch : Sharma_2017_Mol.Cell.Biochem_430_21
PubMedID: 28190170

Title : Emerging Roles of Strigolactones in Plant Responses to Stress and Development - Pandey_2016_Front.Plant.Sci_7_434
Author(s) : Pandey A , Sharma M , Pandey GK
Ref : Front Plant Sci , 7 :434 , 2016
Abstract : Our environment constantly undergoes changes either natural or manmade affecting growth and development of all the organisms including plants. Plants are sessile in nature and therefore to counter environmental changes such as light, temperature, nutrient and water availability, pathogen, and many others; plants have evolved intricate signaling mechanisms, composed of multiple components including several plant hormones. Research conducted in the last decade has placed Strigolactones (SLs) in the growing list of plant hormones involved in coping with environmental changes. SLs are carotenoid derivatives functioning as both endogenous and exogenous signaling molecules in response to various environmental cues. Initially, SLs were discovered as compounds that are harmful to plants due to their role as stimulants in seed germination of parasitic plants, a more beneficial role in plant growth and development was uncovered much later. SLs are required for maintaining plant architecture by regulating shoot and root growth in response to various external stimuli including arbuscular mycorrhizal fungi, light, nutrients, and temperature. Moreover, a role for SLs has also been recognized during various abiotic and biotic stress conditions making them suitable target for generating genetically engineered crop plants with improved yield. This review discusses the biosynthesis of SLs and their regulatory and physiological roles in various stress conditions. Understanding of detailed signaling mechanisms of SLs will be an important factor for designing genetically modified crops for overcoming the problem of crop loss under stressful conditions.
ESTHER : Pandey_2016_Front.Plant.Sci_7_434
PubMedSearch : Pandey_2016_Front.Plant.Sci_7_434
PubMedID: 27092155

Title : Design, synthesis and biological evaluation of selected 3-[3-(amino) propoxy] benzenamines as acetylcholinesterase inhibitors - Malik_2017_J.Biomol.Struct.Dyn_35_2382
Author(s) : Malik R , Gupta R , Srivastava S , Choudhary BS , Sharma M
Ref : J Biomol Struct Dyn , :1 , 2016
Abstract : The present paper describes design, synthesis, and biological evaluation of a series of some 3-[3-(amino)propoxy]benzenamines as acetylcholinesterase inhibitors using mice as a model and piracetam as a reference drug. The structures of these compounds were confirmed by spectral analysis and compounds were tested for memory enhancing activity using elevated plus maze test and acetylcholinesterase inhibitory assay. The inhibitory range of synthesized compounds was from 8.99 to 28.31 muM. The synthesized compounds possessed higher or equivalent percent retention as compared to piracetam at 1 mg/kg with no other CNS-related activities (locomotor and muscle relaxant, analgesic and anticonvulsant activities). Compound 3-[3-(imidazolo)propoxy]benzenamine has shown significant dose-dependent (1 and 3 mg/kg) memory enhancing activity, while 3-[3-(pyrrolidino)propoxy]benzenamine also showed activity equivalent to reference drug piracetam at 1 mg/kg. Both compounds 3-[3-(pyrrolidino)propoxy]benzenamine and 3-[3-(imidazolo)propoxy]benzenamine were also found to show AChE inhibition with IC50 value of 8.99 and 17.87 muM. The molecular docking, MM-GBSA and molecular dynamics simulation studies were performed in order to establish a relationship between the biological results. RMSD, root-mean-square fluctuations, and interaction patterns of 10a-AChE and Sck-AChE complexes proved that the binding affinity of 10a toward AChE was highly stable with the proposed binding orientations.
ESTHER : Malik_2017_J.Biomol.Struct.Dyn_35_2382
PubMedSearch : Malik_2017_J.Biomol.Struct.Dyn_35_2382
PubMedID: 27540770

Title : Identification of novel Acetylcholinesterase inhibitors through e-pharmacophore based virtual screening and molecular dynamics simulations - Malik_2017_J.Biomol.Struct.Dyn_35_3268
Author(s) : Malik R , Choudhary BS , Srivastava S , Mehta P , Sharma M
Ref : J Biomol Struct Dyn , :1 , 2016
Abstract : Alzheimer's disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value 0.71 and BEDROC value 0.028. Among eleven selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand-AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338 and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125 and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety.
ESTHER : Malik_2017_J.Biomol.Struct.Dyn_35_3268
PubMedSearch : Malik_2017_J.Biomol.Struct.Dyn_35_3268
PubMedID: 27782777

Title : Combined in silico and in vivo studies shed insights into the acute acetylcholinesterase response in rat and human brain - Nazam_2015_Biotechnol.Appl.Biochem_62_407
Author(s) : Nazam N , Shaikh S , Lone MI , Sharma M , Ahmad W
Ref : Biotechnol Appl Biochem , 62 :407 , 2015
Abstract : Combined in vivo and in silico studies were undertaken to gain insights into the change in mammalian brain acetylcholinesterase (AChE) activity under acute toxicity conditions in response to two representatives of organophosphates (OPs)-dichlorvos (DCV) and dimethoate (DM). In vivo experiments elucidated that DCV, at multiple sublethal doses for acute time periods, markedly reduced (10-25%) AChE activity, whereas with DM intoxication, a decrease in enzyme activity appeared to be lower, that is, (2-15%), in contrast to respective normal control (100%). Furthermore, a significant inhibition (P < 0.01) in the brain esterase activity was recorded for positive control animals treated with an alkylating agent-cyclophosphamide, with spontaneous reactivation at later time periods. In vivo results were further substantiated with in silico molecular docking analysis using "Autodock 4.2." The lowest binding energy obtained through the computational study strongly augment that DCV binds to brain AChE with greater affinity compared with DM with reference to G and Ki values. Thus, the animal biochemical assay and computational assessment suggest that DM is better to be used over DCV. The precautionary antidote for exposed humans can be developed prior to dealing with OPs. The study will aid in efficacious and safe clinical use of the above-mentioned compounds.
ESTHER : Nazam_2015_Biotechnol.Appl.Biochem_62_407
PubMedSearch : Nazam_2015_Biotechnol.Appl.Biochem_62_407
PubMedID: 25082528

Title : Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response - Bayry_2014_Infect.Immun_82_3141
Author(s) : Bayry J , Beaussart A , Dufrene YF , Sharma M , Bansal K , Kniemeyer O , Aimanianda V , Brakhage AA , Kaveri SV , Kwon-Chung KJ , Latge JP , Beauvais A
Ref : Infect Immun , 82 :3141 , 2014
Abstract : In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface.
ESTHER : Bayry_2014_Infect.Immun_82_3141
PubMedSearch : Bayry_2014_Infect.Immun_82_3141
PubMedID: 24818666
Gene_locus related to this paper: aspfu-AYG1

Title : Characterization and evolution of a metagenome-derived lipase towards enhanced enzyme activity and thermostability - Kumar_2013_Mol.Cell.Biochem_373_149
Author(s) : Kumar R , Sharma M , Singh R , Kaur J
Ref : Molecular & Cellular Biochemistry , 373 :149 , 2013
Abstract : In the present investigation, we used directed evolution approach to engineer a lipase from metagenomic origin. A variant S311C, was generated, characterized in detail and compared with wild type. Wild type and variant lipases were overexpressed and purified to homogeneity. The temperature optima of the purified lipases (Variant and wild type) were almost same, and found to be 45 and 50 degrees C, respectively. The variant protein was highly thermostable (54 times) as compared with the wild type at 60 degrees C. The variant displayed very high kinetic efficiency over the wild type protein. Analysis of the homology models of wild type and variant lipase showed that the substitution is on the surface of the protein. This substitution, along with hydrophobic residues in near vicinity may be involved in formation of strong hydrophobic channel leading to active site. This study identifies the role of hydrophobic interactions in protein stability along with enhancement of enzyme activity.
ESTHER : Kumar_2013_Mol.Cell.Biochem_373_149
PubMedSearch : Kumar_2013_Mol.Cell.Biochem_373_149
PubMedID: 23104399

Title : Reference genome sequence of the model plant Setaria - Bennetzen_2012_Nat.Biotechnol_30_555
Author(s) : Bennetzen JL , Schmutz J , Wang H , Percifield R , Hawkins J , Pontaroli AC , Estep M , Feng L , Vaughn JN , Grimwood J , Jenkins J , Barry K , Lindquist E , Hellsten U , Deshpande S , Wang X , Wu X , Mitros T , Triplett J , Yang X , Ye CY , Mauro-Herrera M , Wang L , Li P , Sharma M , Sharma R , Ronald PC , Panaud O , Kellogg EA , Brutnell TP , Doust AN , Tuskan GA , Rokhsar D , Devos KM
Ref : Nat Biotechnol , 30 :555 , 2012
Abstract : We generated a high-quality reference genome sequence for foxtail millet (Setaria italica). The approximately 400-Mb assembly covers approximately 80% of the genome and >95% of the gene space. The assembly was anchored to a 992-locus genetic map and was annotated by comparison with >1.3 million expressed sequence tag reads. We produced more than 580 million RNA-Seq reads to facilitate expression analyses. We also sequenced Setaria viridis, the ancestral wild relative of S. italica, and identified regions of differential single-nucleotide polymorphism density, distribution of transposable elements, small RNA content, chromosomal rearrangement and segregation distortion. The genus Setaria includes natural and cultivated species that demonstrate a wide capacity for adaptation. The genetic basis of this adaptation was investigated by comparing five sequenced grass genomes. We also used the diploid Setaria genome to evaluate the ongoing genome assembly of a related polyploid, switchgrass (Panicum virgatum).
ESTHER : Bennetzen_2012_Nat.Biotechnol_30_555
PubMedSearch : Bennetzen_2012_Nat.Biotechnol_30_555
PubMedID: 22580951
Gene_locus related to this paper: setit-k3xwe0 , setit-k3xfs7 , setit-k3yh36 , setit-k3zes3 , setit-k3zlj8 , setvi-a0a4u6wd58 , setit-a0a368qif6 , setit-a0a368sru6 , setit-a0a368q9x4 , setit-k3zri0 , setit-k3ysv0 , setit-k3xj49 , setit-k4ac30

Title : An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus - Etherton_2011_EMBO.J_30_2908
Author(s) : Etherton MR , Tabuchi K , Sharma M , Ko J , Sudhof TC
Ref : EMBO Journal , 30 :2908 , 2011
Abstract : Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.
ESTHER : Etherton_2011_EMBO.J_30_2908
PubMedSearch : Etherton_2011_EMBO.J_30_2908
PubMedID: 21642956

Title : Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function - Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
Author(s) : Etherton M , Foldy C , Sharma M , Tabuchi K , Liu X , Shamloo M , Malenka RC , Sudhof TC
Ref : Proc Natl Acad Sci U S A , 108 :13764 , 2011
Abstract : Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an approximately 1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.
ESTHER : Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
PubMedSearch : Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
PubMedID: 21808020
Gene_locus related to this paper: human-NLGN3

Title : Evaluation of cholinesterase to differentiate pleural exudates and transudates - Sharma_2004_J.Assoc.Physicians.India_52_387
Author(s) : Sharma M , Gupta KB , Goyal KM , Nand N
Ref : J Assoc Physicians India , 52 :387 , 2004
Abstract : AIMS AND OBJECTIVES: The present study was undertaken to evaluate the usefulness of pleural fluid cholinesterase (PChE) level in pleural fluid and its ratio to serum cholinesterase (P/SChE) in order to differentiate transudates and exudates and to compare their diagnostic efficacy with the Light's criteria. MATERIAL AND
METHODS: A total of 110 patients of pleural effusion of diverse etiology were studied. Eighty patients were of exudative pleural effusion of tubercular, malignant or parapneumonic origin and 30 patients were of transudative effusion. Cholinesterase was estimated in the pleural fluid and serum in all the patients.
RESULTS: The mean PChE and P/S ChE were significantly higher in exudates as compared to transudates (p < 0.001). P/S ChE was 0.79 +/- 0.45 and 0.14 +/- 0.11 in exudates and transudates, respectively. When a cut-off value of 469 IU/L for PChE was taken for the diagnosis, it was found that 10% of exudates and 2.5% of transudates were misclassified. However percentage of misclassification decreased to 1.25% in exudates and 3.3% in transudates when the cut-off value of 0.24 for P/S ChE ratio was used. Using Light's criteria, a sensitivity of 91.25% and specificity of 90% with positive predictive value (PPV) of 96.05% and negative predictive value (NPV) of 79.42% was observed. However using P/S ChE, the PPV was 98.75% and NPV was 96.67%.
CONCLUSIONS: The estimation of PChE and P/SChE ratio had better discriminatory capacity than Light's criteria. It is cost effective and more specific, therefore its routine estimation is recommended.
ESTHER : Sharma_2004_J.Assoc.Physicians.India_52_387
PubMedSearch : Sharma_2004_J.Assoc.Physicians.India_52_387
PubMedID: 15656028

Title : Effects of carbon dioxide-induced anesthesia on cholinergic parameters in rat brain - Berger-Sweeney_1994_Lab.Animal.Sci_44_369
Author(s) : Berger-Sweeney J , Berger UV , Sharma M , Paul CA
Ref : Laboratory Animal Science , 44 :369 , 1994
Abstract : We report that acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities in rat brain were virtually identical whether the rat was anesthetized with carbon dioxide (CO2) before decapitation or decapitated without prior sedation. The AChE and ChAT activities were measured in three brain regions: the hippocampus, cerebral cortex, and cerebellum. Enzyme activities varied significantly by brain region, with the highest values in the hippocampus and the lowest values in the cerebellum. Enzyme activities, however, did not vary with the method of euthanasia, either CO2-induced anesthesia prior to decapitation or decapitation without anesthesia. These data suggest that CO2-induced anesthesia prior to decapitation does not alter activities of these cholinergic markers in rat hippocampus, cerebral cortex, and cerebellum. This method of euthanasia eliminates the need to capture a conscious animal, which reduces stress to the animal and the experimenter.
ESTHER : Berger-Sweeney_1994_Lab.Animal.Sci_44_369
PubMedSearch : Berger-Sweeney_1994_Lab.Animal.Sci_44_369
PubMedID: 7983851

Title : Poster: Bambuterol, a selective inhibitor of human plasma butyrylcholinesterase -
Author(s) : Sharma M , Svensson LA
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :345 , 1991

Title : The influence of bambuterol (carbamylated terbutaline) on the duration of action of succinylcholine-induced paralysis in humans -
Author(s) : Fisher DM , Caldwell JE , Sharma M , Wiren JE
Ref : Anesthesiology , 69 :757 , 1988
PubMedID: 3056118

Title : Metabolites of neostigmine and pyridostigmine do not contribute to antagonism of neuromuscular blockade in the dog - Hennis_1984_Anesthesiology_61_534
Author(s) : Hennis PJ , Cronnelly R , Sharma M , Fisher DM , Miller RD
Ref : Anesthesiology , 61 :534 , 1984
Abstract : The authors sought to determine whether the metabolites of neostigmine and pyridostigmine contribute to antagonism of neuromuscular blockade. Accordingly, the dose-response relationship, onset and duration of action (n = 60), and pharmacokinetics (n = 22) of neostigmine, pyridostigmine, their metabolites 3-hydroxyphenyltrimethylammonium (PTMA) and 3-hydroxy-N-methylpyridinium (MP), and edrophonium were determined in dogs anesthetized with sodium pentobarbital. The force of contraction of the anterior tibialis muscle was maintained at constant 90% depression by infusing pancuronium. Then, a single iv bolus dose of one of the drugs under study was injected while the pancuronium infusion was continued. Venous blood, urine, and bile were sampled for four hours. Concentrations were determined by liquid chromatographic techniques; a three-compartment pharmacokinetic model was fitted to the serum concentration data. The doses producing 50% antagonism were 6.5, 52, 69, and 40 micrograms/kg for neostigmine, pyridostigmine, edrophonium, and PTMA, respectively. MP was inactive as an antagonist. By comparing approximately equipotent doses, time to peak antagonism (onset) and until 30% of peak antagonism remained (duration) were shorter for both edrophonium and PTMA than for neostigmine and pyridostigmine. Slow distribution and elimination half-lives, volume of distribution at steady state (VDss), and total plasma clearance (Cl) were similar for the drugs except for a smaller Vdss and lower Cl for MP. More than 60% of the dose of each drug was recovered unchanged from urine; less than 1% was recovered from bile. Less than 10% of the dose of neostigmine was recovered as PTMA.(ABSTRACT TRUNCATED AT 250 WORDS)
ESTHER : Hennis_1984_Anesthesiology_61_534
PubMedSearch : Hennis_1984_Anesthesiology_61_534
PubMedID: 6149707