Sharma A

References (66)

Title : Design, synthesis, and pharmacological evaluation of indole-piperidine amides as Blood-brain barrier permeable dual cholinesterase and beta-secretase inhibitors - Banoo_2024_Eur.J.Med.Chem_266_116131
Author(s) : Banoo R , Nuthakki VK , Wadje BN , Sharma A , Bharate SB
Ref : Eur Journal of Medicinal Chemistry , 266 :116131 , 2024
Abstract : Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC(50) values of 0.32 and 0.39 microM, respectively. The MTDL 23a is a mixed-type inhibitor of both hAChE and hBACE-1 with K(i) values of 0.26 microM and 0.46 microM, respectively. The MD simulation studies revealed that both AChE and BACE-1 experience minor conformational changes on binding with 23a. In the PAMPA-BBB assay, analog 23a demonstrated CNS permeability, indicating the possibility for future investigation in preclinical models of AD.
ESTHER : Banoo_2024_Eur.J.Med.Chem_266_116131
PubMedSearch : Banoo_2024_Eur.J.Med.Chem_266_116131
PubMedID: 38215587

Title : Nano polystyrene induced changes in anxiety and learning behaviour are mediated through oxidative stress and gene disturbance in mouse brain regions - Sharma_2023_Neurotoxicol_99_139
Author(s) : Sharma A , Kaur M , Sharma K , Bunkar SK , John P , Bhatnagar P
Ref : Neurotoxicology , 99 :139 , 2023
Abstract : It is widely reported now that nanoplastic particles have potential neurotoxic effects and may disturb central nervous system (CNS) function. However, the mechanism behind these toxic effects still needs to be elucidated. In the current study, we investigated the effects of polystyrene nanoplastics (PS-NPs) on changes in learning, memory, and anxiety-related behavior in mice based on some selected biochemical, molecular, and histopathological changes in three important brain regions (Cortex, Hypothalamus, and Hippocampus). Male mice were orally administered daily with two doses of 50 nm PS-NPs (0.2 mg/ml and 1 mg/ml) for 8 weeks. We observed decreased expression of neurotransmitter-related genes (VAChT, GAD, and SYP) in the cortex, hypothalamus, and hippocampus areas of the mouse brain. Other biochemical variables including, antioxidant enzymes, biomarkers for oxidative stress, and acetylcholinesterase activity showed significant alterations in all three brain regions. Molecular and neurochemical data thus suggest significant neurobehavioral changes following sub-chronic exposure to PS-NPs which may lead to enhanced anxiety-related and spatial learning and memory-related impairments by affecting limbic areas of the brain.
ESTHER : Sharma_2023_Neurotoxicol_99_139
PubMedSearch : Sharma_2023_Neurotoxicol_99_139
PubMedID: 37865141

Title : Design, Synthesis, and Pharmacological Evaluation of Embelin-Aryl\/alkyl Amine Hybrids as Orally Bioavailable Blood-Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer's Disease: Discovery of SB-1448 - Nuthakki_2023_ACS.Chem.Neurosci_14_1193
Author(s) : Nuthakki VK , Choudhary S , Reddy CN , Bhatt S , Jamwal A , Jotshi A , Raghuvanshi R , Sharma A , Thakur S , Jadhav HR , Bharate SS , Nandi U , Kumar A , Bharate SB
Ref : ACS Chem Neurosci , 14 :1193 , 2023
Abstract : The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC(50) values of 0.15, 1.6, and 0.6 microM, respectively. It inhibits both ChEs noncompetitively with k(i) values of 0.21 and 1.3 microM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Abeta self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.
ESTHER : Nuthakki_2023_ACS.Chem.Neurosci_14_1193
PubMedSearch : Nuthakki_2023_ACS.Chem.Neurosci_14_1193
PubMedID: 36812360

Title : Synthesis and Biological Evaluation of Coumarin Triazoles as Dual Inhibitors of Cholinesterases and beta-Secretase - Sharma_2023_ACS.Omega_8_11161
Author(s) : Sharma A , Bharate SB
Ref : ACS Omega , 8 :11161 , 2023
Abstract : Coumarin is a naturally occurring bioactive pharmacophore with wide occurrence among central nervous system (CNS)-active small molecules. 8-Acetylcoumarin, one of the natural coumarins, is a mild inhibitor of cholinesterases and beta-secretase, which are vital targets of Alzheimer's disease. Herein, we synthesized a series of coumarin-triazole hybrids as potential multitargeted drug ligands (MTDLs) with better activity profiles. The coumarin-triazole hybrids occupy the cholinesterase active site gorge from the peripheral to the catalytic anionic site. The most active analogue, 10b, belonging to the 8-acetylcoumarin core, inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-secretase-1 (BACE-1) with IC(50) values of 2.57, 3.26, and 10.65 microM, respectively. The hybrid, 10b, crosses the blood-brain barrier via passive diffusion and inhibits the self-aggregation of amyloid-beta monomers. The molecular dynamic simulation study reveals the strong interaction of 10b with three enzymes and forming stable complexes. Overall, the results warrant a detailed preclinical investigation of the coumarin-triazole hybrids.
ESTHER : Sharma_2023_ACS.Omega_8_11161
PubMedSearch : Sharma_2023_ACS.Omega_8_11161
PubMedID: 37008108

Title : A supercritical fluid co-extract of turmeric powder and dried coconut shreds shows neuroprotection against AlCl(3)-induced Alzheimer's disease in rats through nose to brain delivery - Sharma_2023_Bioorg.Chem_143_107046
Author(s) : Sharma A , Ray A , Sathaye S , Singhal RS
Ref : Bioorg Chem , 143 :107046 , 2023
Abstract : This study was aimed at investigating the neuroprotective potential of a co-extract obtained by supercritical fluid extraction (SFE) of turmeric powder and dried coconut shreds against aluminium chloride (AlCl(3))-induced Alzheimer's disease (AD) in male Wistar rats. Fifty animals were allocated to five groups, which received saline (vehicle control, group 1), a combination of saline and aluminium chloride (AlCl(3)) (disease control, group 2), coconut oil (COO) (SFE extracted, treatment group 3), turmeric oleoresin (Cur) (SFE extracted, treatment group 4) and SFE co-extract of turmeric powder and coconut shreds (CurCOO) (treatment group 5). Animals were subjected to behavioural evaluation. In addition, the hippocampal section of the brain from all groups was subjected to biochemical, molecular and histopathological evaluations. The results showed CurCOO administered intranasally improved cognitive abilities, reversed histological alterations in the brain, reduced hippocampus inflammation studied through proinflammatory cytokine markers like TNF-alpha and IL-6 as compared to the disease control group. The impact of CurCOO on preventive neurodegeneration was also observed through a reduction in protein transcription factor NF-kB in the treated group 5 as compared to a disease control group. The effect of intranasal delivery of CurCOO on the neurons responsible for memory consolidation was evident from low acetylcholinesterase (AChE) enzyme activity in the treated groups with respect to AlCl(3) induced group. Summarily, the results demonstrated intranasal delivery of CurCOO to show better efficacy than Cur and COO in preventing neurodegeneration associated with AlCl(3) induced Alzheimer's disease.
ESTHER : Sharma_2023_Bioorg.Chem_143_107046
PubMedSearch : Sharma_2023_Bioorg.Chem_143_107046
PubMedID: 38141332

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 : Developing an adult stem cell derived microphysiological intestinal system for predicting oral prodrug bioconversion and permeability in humans - Sharma_2023_Lab.Chip__
Author(s) : Sharma A , Jin L , Wang X , Wang YT , Stresser DM
Ref : Lab Chip , : , 2023
Abstract : Microphysiological systems (MPS) incorporating human intestinal organoids have shown the potential to faithfully model intestinal biology with the promise to accelerate development of oral prodrugs. We hypothesized that an MPS model incorporating flow, shear stress, and vasculature could provide more reliable measures of prodrug bioconversion and permeability. Following construction of jejunal and duodenal organoid MPS derived from 3 donors, we determined the area under the concentration-time (AUC) curve for the active drug in the vascular channel and characterized the enzymology of prodrug bioconversion. Fosamprenavir underwent phosphatase mediated hydrolysis to amprenavir while dabigatran etexilate (DABE) exhibited proper CES2- and, as anticipated, not CES1-mediated de-esterification, followed by permeation of amprenavir to the vascular channel. When experiments were conducted in the presence of bio-converting enzyme inhibitors (orthovanadate for alkaline phosphatase; bis(p-nitrophenyl)phosphate for carboxylesterase), the AUC of the active drug decreased accordingly in the vascular channel. In addition to functional analysis, the MPS was characterized through imaging and proteomic analysis. Imaging revealed proper expression and localization of epithelial, endothelial, tight junction and catalytic enzyme markers. Global proteomic analysis was used to analyze the MPS model and 3 comparator sources: an organoid-based transwell model (which was also evaluated for function), Matrigel embedded organoids and finally jejunal and duodenal cadaver tissues collected from 3 donors. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) of global proteomic data demonstrated that all organoid-based models exhibited strong similarity and were distinct from tissues. Intestinal organoids in the MPS model exhibited strong similarity to human tissue for key epithelial markers via HCA. Quantitative proteomic analysis showed higher expression of key prodrug converting and drug metabolizing enzymes in MPS-derived organoids compared to tissues, organoids in Matrigel, and organoids on transwells. When comparing organoids from MPS and transwells, expression of intestinal alkaline phosphatase (ALPI), carboxylesterase (CES)2, cytochrome P450 3A4 (CYP3A4) and sucrase isomaltase (SI) was 2.97-, 1.2-, 11.3-, and 27.7-fold higher for duodenum and 7.7-, 4.6-, 18.1-, and 112.2-fold higher for jejunum organoids in MPS, respectively. The MPS approach can provide a more physiological system than enzymes, organoids, and organoids on transwells for pharmacokinetic analysis of prodrugs that account for 10% of all commercial medicines.
ESTHER : Sharma_2023_Lab.Chip__
PubMedSearch : Sharma_2023_Lab.Chip__
PubMedID: 38099395

Title : Acridine: A Scaffold for the development of drugs for Alzheimer's disease - Sharma_2023_Curr.Top.Med.Chem__
Author(s) : Sharma A , Piplani P
Ref : Curr Top Med Chem , : , 2023
Abstract : Alzheimer's disease (AD) is drawing scientists' consideration, being one of the gravest diseases mankind will have to battle against in the near future. The number of people with AD is expected to triple in the next 40 years. It is a most common age-related multifactorial neurodegenerative disease and characterized by two histopathological hallmarks; the formation of senile plaques composed of the amyloid-beta (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Discovery and development of rationally designed multi-targeted ligands for the management of AD could be more beneficial than classical single targeted molecules. Acridine, a heterocyclic nucleus is a sole moiety in various existing drug molecules such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer) and tacrine (anti-Alzheimer). It is proposed that acridine may combat the AD by acting on several targets like acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), dual specificity tyrosine kinase 1A (Dyrk 1A), amyloid and prion protein (PrPC) etc. involved in its pathogenesis. The main aim of this compilation is to review the most promising therapeutic developments within the vast research area dealing with acridine derivatives. Further research is required to evaluate the effectiveness of the acridine derivatives with various substitutions in the treatment of AD. In conclusion, our review will suggest the potentiality of the versatile acridine framework for drug designing and developing novel multi-target inhibitors for the Alzheimer's disease.
ESTHER : Sharma_2023_Curr.Top.Med.Chem__
PubMedSearch : Sharma_2023_Curr.Top.Med.Chem__
PubMedID: 36740790

Title : Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease Pathogenesis - Duarte_2023_Mol.Pharmacol_104_1
Author(s) : Duarte ML , Wang M , Gomes I , Liu C , Sharma A , Fakira AK , Gupta A , Mack SM , Zhang B , Devi LA
Ref : Molecular Pharmacology , 104 :1 , 2023
Abstract : Current treatments for Alzheimer's disease (AD) help reduce symptoms for a limited time but do not treat the underlying pathology. To identify potential therapeutic targets for AD, an integrative network analysis was previously carried out using 364 human postmortem control, mild cognitive impairment, and AD brains. This analysis identified proline endopeptidase-like protein (PREPL), an understudied protein, as a downregulated protein in late-onset AD patients. In this study we investigate the role of PREPL. Analyses of data from human postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression modulates pathways associated with protein trafficking, synaptic activities, and lipid metabolism. Furthermore, PREPL KD impairs cell proliferation and modulates the structure of vesicles, levels of neuropeptide-processing enzymes, and secretion of neuropeptides. In addition, decrease in PREPL levels leads to changes in the levels of a number of synaptic proteins as well as changes in the levels of secreted amyloid beta (Abeta) 42 peptide and Tau phosphorylation. Finally, we report that local decrease in PREPL levels in mouse hippocampus attenuates long-term potentiation, suggesting a role in synaptic plasticity. Together, our results indicate that PREPL affects neuronal function by modulating protein trafficking and synaptic function, an important mechanism of AD pathogenesis. SIGNIFICANCE STATEMENT: Integrative network analysis reveals proline endopeptidase-like protein (PREPL) to be downregulated in human sporadic late-onset Alzheimer's disease brains. Down regulation of PREPL leads to increases in amyloid beta secretion, Tau phosphorylation, and decreases in protein trafficking and long-term potentiation.
ESTHER : Duarte_2023_Mol.Pharmacol_104_1
PubMedSearch : Duarte_2023_Mol.Pharmacol_104_1
PubMedID: 37147110
Gene_locus related to this paper: human-PREPL

Title : Pathogenesis of Alzheimer's Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential - Singh_2023_ACS.Chem.Neurosci__
Author(s) : Singh A , Singh K , Kaur J , Kaur R , Sharma A , Kaur U , Chadha R , Bedi PMS
Ref : ACS Chem Neurosci , : , 2023
Abstract : Alzheimer's disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer's disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer's agents. The review will provide (A) precise insight of various established targets of Alzheimer's disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure-activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer's agents. This review will provide a baseline for various research groups working on Alzheimer's drug development in designing potent, safer, and effective multifunctional anti-Alzheimer's candidates of the future.
ESTHER : Singh_2023_ACS.Chem.Neurosci__
PubMedSearch : Singh_2023_ACS.Chem.Neurosci__
PubMedID: 37683129

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

Title : Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer's Agents - Singh_2022_ACS.Chem.Neurosci__
Author(s) : Singh JV , Thakur S , Kumar N , Singh H , Mithu VS , Bhagat K , Gulati HK , Sharma A , Sharma S , Bedi PMS
Ref : ACS Chem Neurosci , : , 2022
Abstract : In continuous efforts to develop anti-Alzheimer's agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound 4b showed multitargeting properties to act as an anti-Alzheimer's agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC(50)) value of 0.78 microM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against Abeta(1-42) aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b with the enzyme AChE, which showed that the enzyme-ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD(50) cutoff value (50 mg/kg) in comparison to donepezil (LD(50): 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound 4b and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer's disease (AD).
ESTHER : Singh_2022_ACS.Chem.Neurosci__
PubMedSearch : Singh_2022_ACS.Chem.Neurosci__
PubMedID: 35195392

Title : Synthesis and evaluation of small organic molecule as reactivator of organophosphorus inhibited acetylcholinesterase - Thakur_2022_Drug.Chem.Toxicol__1
Author(s) : Thakur A , Patwa J , Pant S , Jeet Singh Flora S , Sharma A
Ref : Drug & Chemical Toxicology , :1 , 2022
Abstract : A series of uncharged salicylaldehyde oximes were synthesized and evaluated for the reactivation of organophosphorus (OP) nerve agents simulants Diethylchlorophosphonate (DCP) & Diethylcyanophosphonate (DCNP) and pesticides (paraoxon & malaoxon) inhibited electric eel Acetylcholinesterase (AChE). The computational software Swiss ADME and molinspiration were used to unfold the probability of drug-likeness properties of the oximes derivatives. Substituted aromatic oximes with diethylamino or bromo group with free hydroxyl group ortho to oxime moiety were found efficient to regenerate the enzymatic activity in in-vitro AChE assay. The alkylation of the ortho hydroxyl group of derivatives led to the loss of reactivation potential. The derivatives with a hydroxyl group and without oxime group and vice versa did not show significant reactivation potency against tested OP toxicants. Further, we also evaluated the reactivation potential of these selected molecules on the rat brain homogenate against different OPs inhibited ChE and found maximum reactivation potency of oxime 2e. The in-vitro results were further validated by molecular docking and dynamic studies which showed that the hydroxyl group interacted with serine amino acids in the catalytic anionic site of AChE enzyme and was stable up to 200 ns consequently providing proper orientation to oxime moiety for reactivating the OP inhibited enzyme. It has thus been proved by the structure-activity relationship of oximes derivatives that hydroxyl group ortho to oxime is essential for reactivating OP inhibited electric eel AChE. Amongst the twenty-one oximes derivatives, 2e was found to be most active in regenerating the paraoxon, malaoxon, DCP and DCNP inhibited AChE enzyme.
ESTHER : Thakur_2022_Drug.Chem.Toxicol__1
PubMedSearch : Thakur_2022_Drug.Chem.Toxicol__1
PubMedID: 36514993

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 : A Coumarin-donepezil Hybrid as a Blood-brain Barrier Permeable Dual Cholinesterase Inhibitor: Isolation, Synthetic Modifications and Biological Evaluation of Natural Coumarins - Sharma_2022_ChemMedChem__
Author(s) : Sharma A , Nuthakki VK , Gairola S , Singh B , Bharate SB
Ref : ChemMedChem , : , 2022
Abstract : Plants have immensely contributed to the drug discovery for neurodegenerative diseases. Herein, we undertook the phytochemical investigation of Nardostachys jatamansi (D.Don) DC. rhizomes followed by semisynthetic modifications to discover cholinesterase (ChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. The 8-acetyl-7-hydroxycoumarin isolated from the bioactive extract moderately inhibits acetylcholinesterase (AChE) and BACE-1 with IC50 values of 22.1 and 17.7 microM, respectively. The semisynthetic trifluoromethyl substituted coumarin chalcone display a 5-fold improvement in BACE-1 inhibition (IC50 3.3 microM). Another semisynthetic derivative, a coumarin-donepezil hybrid, exhibits dual inhibition of both ChEs with IC50 values of 1.22 and 3.09 microM, respectively. Molecular modeling and enzyme kinetics revealed that the coumarin-donepezil hybrid is a non-competitive inhibitor of AChE. It crosses the blood-brain barrier and also inhibits Abeta self-aggregation. The results presented herein warrant a detailed investigation of the coumarin-donepezil hybrid in preclinical models of Alzheimer's disease.
ESTHER : Sharma_2022_ChemMedChem__
PubMedSearch : Sharma_2022_ChemMedChem__
PubMedID: 35892288

Title : Therapeutic effects of biochanin A, phloretin, and epigallocatechin-3-gallate in reducing oxidative stress in arsenic-intoxicated mice - Singh_2021_Environ.Sci.Pollut.Res.Int__
Author(s) : Singh G , Thaker R , Sharma A , Parmar D
Ref : Environ Sci Pollut Res Int , : , 2021
Abstract : One of the most common toxicant prevailing in our environment is the arsenic. The present study is an attempt to investigate the effects of some of the common flavonoids, such as biochanin A (BCA), phloretin, and epigallocatechin-3-gallate (EGCG), on arsenic toxicity in the Swiss albino mice. For this purpose, mice were orally treated with sodium meta-arsenite (20 mg/kg bw/day), along with co-administration of BCA (50 mg/kg bw/day), phloretin (50 mg/kg bw/day), and EGCG (40 mg/kg bw/day) for the 2-week duration. All the mice were euthanized at the end of the treatment period, and the observations were made in the following parameters. Arsenic reduced the sperm motility as compared with the control (p < 0.05) and was restored back to the normal status with the flavonoids treatment significantly (p < 0.05). The arsenic concentrations in the kidney and liver tissues were found significantly reduced with all the flavonoids co-treatment (p < 0.001). There was a reduction in the levels of superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione S-transferase (GST) antioxidant markers, with the increased lipid peroxidation (LPO), protein carbonyl content (PCC), and catalase (CAT) levels in the arsenic-intoxicated mice performed in the different tissues. The biochemical homeostasis alterations were well correlated with the estimations of cholinesterase enzyme levels in the brain tissues (p < 0.05) along with DNA damage analysis (Comet) carried out in the blood cells (p < 0.05). These above results are well corroborated with the histopathological findings performed in the brain tissue, along with the increased upregulation seen in the Nrf2 signalling, with all the flavonoid co-treatment carried in the kidney tissue. The administration of BCA, phloretin, and EGCG, in a major way, reversed the alterations in the abovementioned parameters in the arsenic-intoxicated mice. Our findings revealed the beneficial effects of the flavonoids against the arsenic-induced toxicity, due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2 signaling pathway.
ESTHER : Singh_2021_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Singh_2021_Environ.Sci.Pollut.Res.Int__
PubMedID: 33410021

Title : Oxidative damage in the liver and brain of the rats exposed to frequency-dependent radiofrequency electromagnetic exposure: Biochemical and histopathological evidence - Sharma_2021_Free.Radic.Res__1
Author(s) : Sharma A , Shrivastava S , Shukla S
Ref : Free Radical Research , :1 , 2021
Abstract : The study aimed to discover a link between the liver and brain's functional status due to frequency dependent-radiofrequency electromagnetic radiation (RF-EMR). 40 Wistar rats were randomly classified as control (sham-exposed) and EMR exposed groups. Animals were exposed to 900, 1800, and 2100 MHz with thespecific absorption rate (SAR) 0.434 (W/Kg), 0.433 (W/Kg), and 0.453 (W/Kg) respectively. Animal exposure was limited at 1 hour/day, 5 days/week for 1 month with a restricted power density (900 MHz- 11.638microW/m(2), 1800- 11.438 microW/m(2) and 2100 MHz frequency- 8.237 microW/m(2)). Exposure at various frequencies showed a frequency-dependent change in the body weight and hematologic parameters (RBCs, WBCs, platelets, hemoglobin, and hematocrit) as compared with the control group (P >= 0.01)(P >= 0.001). A significant elevation in serum transaminases and bilirubin, urea, uric acid, and creatinine was noted, whereas albumin significantly decreased after EMR exposure (P >= 0.01)(P >= 0.001). The blood glucose, lipid peroxidation, triglycerides, and cholesterol were elevated while adenosine triphosphatases, acetylcholinesterase, and tissue antioxidants such as glutathione, superoxide dismutase, catalase, glutathione reductase, glutathione Peroxidase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenases were decreased significantly (P >= 0.001). Histopathological observations of the liver showed centrilobular mononuclear cell infiltration and swelling in sinusoidal spaces, while in the brain degenerated pyramidal and Purkinje neurons were seen. Furthermore, Substantial evidence was found that the brain is more susceptible to oxidative mutilation compare to the liver of exposed animals. In conclusion, RF-EMR exposure showed oxidative damage to the liver, increasing the incidence of brain damage in a frequency-dependent manner.HighlightsEMR exposure showed frequency-dependent toxicity.Alterations in blood profile and modifications in the serological markers.Increasing lipid peroxidation indicating membrane damage.Inhibition of acetylcholinesterase activity affecting cholinergic neurotransmission.EMR exposure resulted in the loss of cellular energy and production of excess amounts of ROS thereby altering several antioxidant enzymes.Histopathological evidence of severe degenerative changes in the liver and brain.
ESTHER : Sharma_2021_Free.Radic.Res__1
PubMedSearch : Sharma_2021_Free.Radic.Res__1
PubMedID: 34404322

Title : Synthesis, Molecular Docking, BSA, and in-vitro reactivation study of imidazopyridine oxime against paraoxon inhibited acetylcholinesterase - Thakur_2021_Med.Chem__
Author(s) : Thakur A , Patwa J , Sharma A , Flora SJ
Ref : Med Chem , : , 2021
Abstract : AIM: To synthesize and evaluate the fused heterocyclic imidazopyridine oxime as a reactivator against paraoxon inhibited acetylcholinesterase. BACKGROUND: Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos, monocrotophos, and diazinon which are commonly used in agriculture for enhancing agricultural productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides unintentionally/intentionally via ingestion, inhalation or dermal. The current treatment regimen includes reactivator such as mono or bis-pyridinium oximes along with anticholinergic and an anticonvulsant drugs are recommended for the treatment of OP poisoning. Unfortunately, the drawback of the existing reactivator is that owing to the permanent charge present on the pyridinium makes them inefficient to cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase. Therefore, there is a need of reactivator that could cross the BBB and reactivate the OP inhibited acetylcholinesterase. OBJECTIVE: The objectives of the study were synthesis, molecular docking, BSA binding and in-vitro estimation of oximes of various substituted imidazo [1,2-a]pyridine against paraoxon inhibited acetylcholinesterase. METHOD: The reactivators were synthesized in three steps and characterized using various spectroscopic techniques. Molecular docking study was performed on 2WHP and 3ZLV PDB using Autodock tool. The acid dissociation constant (pKa) of oximes was calculated experimentally and drug-likeness properties of the oximes were calculated In silico using mole inspiration and Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated by UV-Vis spectrophotometer. The reactivation potential of the oximes was determined by in vitro enzymatic assay. RESULT: in-silico study inferred that synthesized molecules fulfilled the parameters that required for a successful CNS drug candidate. Further, in-vitro enzymatic assay indicated reasonable reactivation potential of the oximes against paraoxon-inhibited AChE. The binding of oximes with bovine serum albumin (BSA) revealed static quenching of intrinsic fluorescence of BSA by oxime. The binding constant value and number of binding sites were found 0.24 mol-1 and 1 respectively. CONCLUSION: The results of study concluded that this scaffold could be used for further designing of more efficient uncharged reactivators.
ESTHER : Thakur_2021_Med.Chem__
PubMedSearch : Thakur_2021_Med.Chem__
PubMedID: 33563155

Title : Organic-Molecule-Based Fluorescent Chemosensor for Nerve Agents and Organophosphorus Pesticides - Gori_2021_Top.Curr.Chem.(Cham)_379_33
Author(s) : Gori M , Thakur A , Sharma A , Flora SJS
Ref : Top Curr Chem (Cham) , 379 :33 , 2021
Abstract : Organophosphorus (OP) compounds are typically a broad class of compounds that possess various uses such as insecticides, pesticides, etc. One of the most evil utilizations of these compounds is as chemical warfare agents, which pose a greater threat than biological weapons because of their ease of access. OP compounds are highly toxic compounds that cause irreversible inhibition of enzyme acetylcholinesterase, which is essential for hydrolysis of neurotransmitter acetylcholine, leading to series of neurological disorders and even death. Due to the extensive use of these organophosphorus compounds in agriculture, there is an increase in the environmental burden of these toxic chemicals, with severe environmental consequences. Hence, the rapid and sensitive, selective, real-time detection of OP compounds is very much required in terms of environmental protection, health, and survival. Several techniques have been developed over a few decades to easily detect them, but still, numerous challenges and problems remain to be solved. Major advancement has been observed in the development of sensors using the spectroscopic technique over recent years because of the advantages offered over other techniques, which we focus on in the presented review.
ESTHER : Gori_2021_Top.Curr.Chem.(Cham)_379_33
PubMedSearch : Gori_2021_Top.Curr.Chem.(Cham)_379_33
PubMedID: 34346011

Title : Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity - Sharma_2021_ACS.Appl.Bio.Mater_4_2026
Author(s) : Sharma A , Chun J , Ji MS , Lee S , Kang C , Kim JS
Ref : ACS Appl Bio Mater , 4 :2026 , 2021
Abstract : The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.
ESTHER : Sharma_2021_ACS.Appl.Bio.Mater_4_2026
PubMedSearch : Sharma_2021_ACS.Appl.Bio.Mater_4_2026
PubMedID: 35014328

Title : Clinical Evidence of Evogliptin plus Metformin in Management of Type 2 Diabetes mellitus - Bajaj_2021_J.Assoc.Physicians.India_69_25
Author(s) : Bajaj S , Aiwale A , Trailokya A , Sharma A
Ref : J Assoc Physicians India , 69 :25 , 2021
Abstract : Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.
ESTHER : Bajaj_2021_J.Assoc.Physicians.India_69_25
PubMedSearch : Bajaj_2021_J.Assoc.Physicians.India_69_25
PubMedID: 33527807

Title : Purification of high molecular weight thermotolerant esterase from Serratia sp. and its characterization - Bhardwaj_2021_3.Biotech_11_308
Author(s) : Bhardwaj KK , Kishen S , Mehta A , Sharma A , Gupta R
Ref : 3 Biotech , 11 :308 , 2021
Abstract : In the present study, an extracellular esterase from Serratia sp. was purified 24.46 fold using an initial ammonium sulphate precipitation step (optimized concentration of 30-40%), followed by Diethylaminoethyl cellulose (DEAE-cellulose) chromatography and size exclusion Sephadex G-200 column chromatography steps. The molecular weight of the esterase using native polyacrylamide gel electrophoresis (PAGE) was determined to be 236 kDa and by using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) was found to be 60 kDa suggesting that the enzyme was a tetramer of 4 subunits. The purified esterase was able to catalyze the hydrolysis of p-nitrophenyl esters, especially p-nitrophenyl acetate. Maximum esterase activity was achieved in 0.15 M Tris-HCl buffer of pH 8.5 at 50 degreesC after 10 min. The enzyme was stable for at least 8 h at 4 and 35 degreesC but the half-life was determined to be 4.5 h at 50 degreesC and 3 h at 60 degreesC. The esterase activity was inhibited by detergents (1 mM) (Triton X-100, Tween 60, Tween 80, ethylenediamine tetraacetic acid and SDS) except Tween 20. The esterase activity was inhibited by organic solvents (1 mM) such as ethanol, methanol, acetone, acetonitrile and was stable in the presence of glycerol, isopropanol but the organic solvent dimethyl sulfoxide (DMSO) significantly (p < 0.05) enhanced esterase activity. The matrix-assisted laser desorption ionization-time of flight mass spectrometry showed that the enzyme exhibited similarity with the pimeloyl-[acyl carrier protein] methyl ester esterase of Serratia marcescens.
ESTHER : Bhardwaj_2021_3.Biotech_11_308
PubMedSearch : Bhardwaj_2021_3.Biotech_11_308
PubMedID: 34194900
Gene_locus related to this paper: serma-bioH

Title : Biomarkers for the toxicity of sublethal concentrations of triclosan to the early life stages of carps - Dar_2020_Sci.Rep_10_17322
Author(s) : Dar OI , Sharma S , Singh K , Sharma A , Bhardwaj R , Kaur A
Ref : Sci Rep , 10 :17322 , 2020
Abstract : Accumulation, contents of protein, non-enzymatic antioxidant glutathione (GSH and GSSG), lipid peroxidation product (melondialdehyde-MDA) and organic acids (fumarate, succinate, malate and citrate), and activities of neurological (acetylcholinesterase-AChE), detoxification (glutathione S-transferase-GST) and metabolic (lactate dehydrogenase-LDH, aspartate transaminase-AST and alanine transaminase-ALT) enzymes were recorded in the hatchlings of Cyprinus carpio, Ctenopharyngodon idella, Labeo rohita and Cirrhinus mrigala after 7 and 14 days exposure and 10 days post exposure (recovery period) to sublethal concentrations (0.005, 0.01, 0.02 and 0.05 mg/L) of triclosan, a highly toxic and persistent biocide used in personal care products. Accumulation was maximum between 7-14 days at 0.01 mg/L for C. carpio and L. rohita but at 0.005 mg/L for C. idella and C. mrigala. No triclosan was observed at 0.005 mg/L in C. carpio and C. mrigala after recovery. Significant decline in protein, glutathione and acetylcholinesterase but increase in glutathione S-transferase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, melondialdehyde and organic acids over control during exposure continued till the end of recovery period. Integrated biomarker response (IBR) analysis depicted higher star plot area for glutathione and glutathione S-transferase during initial 7 days of exposure, thereafter, during 7-14 days of exposure and the recovery period, higher star plot area was observed for acetylcholinesterase, aspartate transaminase, alanine transaminase and organic acids. Higher star plot area was observed for protein in all the species throughout the study. The study shows that L. rohita is most sensitive and glutathione, acetylcholinesterase, aspartate transaminase and alanine transaminase are the biomarkers for the toxicity of sublethal concentrations of TCS.
ESTHER : Dar_2020_Sci.Rep_10_17322
PubMedSearch : Dar_2020_Sci.Rep_10_17322
PubMedID: 33057045

Title : Efficacy of Bacopa Monnieri (Brahmi) and Donepezil in Alzheimer's Disease and Mild Cognitive Impairment: A Randomized Double-Blind Parallel Phase 2b Study - Prabhakar_2020_Ann.Indian.Acad.Neurol_23_767
Author(s) : Prabhakar S , Vishnu VY , Modi M , Mohanty M , Sharma A , Medhi B , Mittal BR , Khandelwal N , Goyal MK , Lal V , Singla R , Kansal A , Avasthi A
Ref : Ann Indian Acad Neurol , 23 :767 , 2020
Abstract : OBJECTIVES: Alzheimer's disease (AD) is the most common cause of dementia worldwide in the older population. There is no disease-modifying therapy available for AD. The current standard of care drug therapy for AD is cholinesterase inhibitors, including donepezil. Bacopa monnieri or brahmi is used in traditional Indian medicine for memory loss. We conducted a phase 2b randomized controlled trial (RCT) to find out the efficacy of brahmi and donepezil in AD and mild cognitive impairment (MCI). PATIENTS AND METHODS: The study was planned as a 52 week, randomized, double-blind, parallel-group, phase-2 single-center clinical trial comparing the efficacy and safety of Bacopa monnieri (brahmi) 300 mg OD and donepezil 10 mg OD for 12 months in 48 patients with AD and MCI-AD including cognitive and quality of life outcomes. The primary outcome was differences in the change from baseline of the neuropsychological tests [Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) and postgraduate institute (PGI) memory scale] at 12 months between the intervention group (brahmi) and active comparison group (donepezil). RESULTS: The study was terminated after 3 years and 9 months, after recruiting 34 patients, because of slow recruitment and a high dropout rate. Intention to treat analysis after adjusting for baseline confounders showed no difference in the rate of change in ADAS-Cog score from baseline at any time point, including the last follow-up. There was no difference in the rate of change in PGI Memory scale (PGIMS) at 3, 6, and 9 months. In the last follow-up, there was a significant difference in the change in total PGIMS score between brahmi and donepezil, while there was no difference in individual scores of the PGI memory scale. CONCLUSION: This phase-2 RCT on the efficacy of brahmi vs. donepezil showed no significant difference between them after 1 year of treatment. Larger phase-3 trials, preferably multicentric, are required to find the superiority of brahmi over donepezil.
ESTHER : Prabhakar_2020_Ann.Indian.Acad.Neurol_23_767
PubMedSearch : Prabhakar_2020_Ann.Indian.Acad.Neurol_23_767
PubMedID: 33688125

Title : Monoisoamyl DMSA reduced copper-induced neurotoxicity by lowering 8-OHdG level, amyloid beta and Tau protein expressions in Sprague-Dawley rats - Patwa_2020_Metallomics_12_1428
Author(s) : Patwa J , Thakur A , Sharma A , Flora SJS
Ref : Metallomics , 12 :1428 , 2020
Abstract : INTRODUCTION: copper dyshomeostasis has long been linked with several neurodegenerative disorders. The binding of Cu with amyloid beta and other neuronal proteins in the brain leads to the generation of oxidative stress, which eventually causes neurotoxicity. METHOD: the present study was aimed at elucidating the efficacy of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA) and d-penicillamine (DPA) (0.3 mEq kg-1, oral administration for 2 weeks) against Cu(ii)-induced (20 mg kg-1, oral administration for 16 weeks) neurotoxicity in Sprague-Dawley (SD) rats. RESULTS: we observed that the MiADMSA treatment modulated the altered oxidative and nitrosative stress parameters, antioxidant enzymes, and acetylcholinesterase (AChE) activity. Significant improvements were noticed in the neurobehavioral parameters except for the memory parameter. We also observed moderate improvement of memory impairment in the rats treated with MiADMSA and DPA post Cu(ii) exposure, as assessed by a passive avoidance test. Disease progression involves multiple factors and results in the up-regulation of intra and extracellular proteins such as amyloid beta and tau proteins; the expressions of these proteins were significantly reduced by the treatment proposed in our study, and these results were confirmed by ELISA and qRT-PCR. The expression of caspase-3 was higher in Cu(ii)-exposed rats, whereas it was lower in the MiADMSA-treated group. The proposed treatment reduced the copper-induced histological changes in the cortex and hippocampus regions of the brain. CONCLUSION: it can be summarised from the present study that MiADMSA is effective in reducing Cu(ii)-induced oxido-nitrosative stress, antioxidant defense enzymes, neurobehavioral changes, neuronal markers, apoptotic markers, and their genetic expressions. We conclude that chelation therapy using MiADMSA might be a promising approach for the treatment of copper-induced neurotoxicity.
ESTHER : Patwa_2020_Metallomics_12_1428
PubMedSearch : Patwa_2020_Metallomics_12_1428
PubMedID: 32677644

Title : Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives - Behl_2020_Biomedicines_8_
Author(s) : Behl T , Sharma A , Sharma L , Sehgal A , Zengin G , Brata R , Fratila O , Bungau S
Ref : Biomedicines , 8 : , 2020
Abstract : Withaferin A (WA), a manifold studied, C28-steroidal lactone withanolide found in Withania somnifera. Given its unique beneficial effects, it has gathered attention in the era of modern science. Cancer, being considered a "hopeless case and the leading cause of death worldwide, and the available conventional therapies have many lacunae in the form of side effects. The poly pharmaceutical natural compound, WA treatment, displayed attenuation of various cancer hallmarks by altering oxidative stress, promoting apoptosis, and autophagy, inhibiting cell proliferation, reducing angiogenesis, and metastasis progression. The cellular proteins associated with antitumor pathways were also discussed. WA structural modifications attack multiple signal transduction pathways and enhance the therapeutic outcomes in various diseases. Moreover, it has shown validated pharmacological effects against multiple neurodegenerative diseases by inhibiting acetylcholesterinases and butyrylcholinesterases enzyme activity, antidiabetic activity by upregulating adiponectin and preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARgamma), cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis. The current review is an extensive survey of various WA associated disease targets, its pharmacokinetics, synergistic combination, modifications, and biological activities.
ESTHER : Behl_2020_Biomedicines_8_
PubMedSearch : Behl_2020_Biomedicines_8_
PubMedID: 33291236

Title : Identification of embelin, a 3-undecyl-1,4-benzoquinone from Embelia ribes as a multitargeted anti-Alzheimer agent - Nuthakki_2019_Drug.Dev.Res_80_655
Author(s) : Nuthakki VK , Sharma A , Kumar A , Bharate SB
Ref : Drug Dev Res , 80 :655 , 2019
Abstract : Beta-secreatse (BACE-1) and cholinesterases are clinically validated targets of Alzheimer's disease (AD), for which natural products have provided immense contribution. The multifaceted nature of AD signifies the need of multitargeted agents to tackle this disease. In the search of new natural products as dual BACE-1/cholinesterase inhibitors, a library of pure natural products was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE-1. The screening efforts have identified 1,4-benzoquinone "embelin," a natural product derived from Embelia ribes displaying inhibition of all three enzymes, with IC50 values of 2.5, 5.4, and 2.1 muM, respectively. This screen has also identified isoquinoline alkaloids papaverine and L-tetrahydropalmatine as AChE inhibitors. Kinetic study has shown that embelin inhibits EeAChE and EqBChE with ki values of 4.59 and 0.57 muM, in an uncompetitive and noncompetitive manner, respectively. The interactions of embelin with allosteric peripheral anionic site of cholinesterases, has further supported the results of kinetic study. Embelin has also enhanced the activity of P-gp in LS-180 cells, the efflux pump which is involved in the clearance of amyloid-beta from AD brain. Further, the cell viability study in neuronal cell line has indicated the excellent therapeutic window of embelin. These results are indicative of the fact that embelin is a multitargeted agent playing role in stopping the formation of amyloid-beta oligomers (via inhibition of BACE-1), improves cholinergic-transmission (via inhibition of AChE/BChE) and increases amyloid-beta clearance (via P-gp induction).
ESTHER : Nuthakki_2019_Drug.Dev.Res_80_655
PubMedSearch : Nuthakki_2019_Drug.Dev.Res_80_655
PubMedID: 31050027

Title : Comprehensive genomic and transcriptomic analysis of polycyclic aromatic hydrocarbon degradation by a mycoremediation fungus, Dentipellis sp. KUC8613 - Park_2019_Appl.Microbiol.Biotechnol_103_8145
Author(s) : Park H , Min B , Jang Y , Kim J , Lipzen A , Sharma A , Andreopoulos B , Johnson J , Riley R , Spatafora JW , Henrissat B , Kim KH , Grigoriev IV , Kim JJ , Choi IG
Ref : Applied Microbiology & Biotechnology , 103 :8145 , 2019
Abstract : The environmental accumulation of polycyclic aromatic hydrocarbons (PAHs) is of great concern due to potential carcinogenic and mutagenic risks, as well as their resistance to remediation. While many fungi have been reported to break down PAHs in environments, the details of gene-based metabolic pathways are not yet comprehensively understood. Specifically, the genome-scale transcriptional responses of fungal PAH degradation have rarely been reported. In this study, we report the genomic and transcriptomic basis of PAH bioremediation by a potent fungal degrader, Dentipellis sp. KUC8613. The genome size of this fungus was 36.71 Mbp long encoding 14,320 putative protein-coding genes. The strain efficiently removed more than 90% of 100 mg/l concentration of PAHs within 10 days. The genomic and transcriptomic analysis of this white rot fungus highlights that the strain primarily utilized non-ligninolytic enzymes to remove various PAHs, rather than typical ligninolytic enzymes known for playing important roles in PAH degradation. PAH removal by non-ligninolytic enzymes was initiated by both different PAH-specific and common upregulation of P450s, followed by downstream PAH-transforming enzymes such as epoxide hydrolases, dehydrogenases, FAD-dependent monooxygenases, dioxygenases, and glycosyl- or glutathione transferases. Among the various PAHs, phenanthrene induced a more dynamic transcriptomic response possibly due to its greater cytotoxicity, leading to highly upregulated genes involved in the translocation of PAHs, a defense system against reactive oxygen species, and ATP synthesis. Our genomic and transcriptomic data provide a foundation of understanding regarding the mycoremediation of PAHs and the application of this strain for polluted environments.
ESTHER : Park_2019_Appl.Microbiol.Biotechnol_103_8145
PubMedSearch : Park_2019_Appl.Microbiol.Biotechnol_103_8145
PubMedID: 31482283
Gene_locus related to this paper: 9agam-a0a5b1qnb8 , 9agam-a0a5b1qwq3 , 9agam-a0a5b1qh04 , 9agam-a0a5b1qyk1 , 9agam-a0a5b1qmi3 , 9agam-a0a5b1qi91 , 9agam-a0a5b1qhi2

Title : Synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine and its bromo-derivative as dual cholinesterase inhibitors - Nuthakki_2019_Bioorg.Chem_90_103062
Author(s) : Nuthakki VK , Mudududdla R , Sharma A , Kumar A , Bharate SB
Ref : Bioorg Chem , 90 :103062 , 2019
Abstract : Alkaloids have always been a great source of cholinesterase inhibitors. Numerous studies have shown that inhibiting acetylcholinesterase as well as butyrylcholinetserase is advantageous, and have better chances of success in preclinical/ clinical settings. With the objective to discover dual cholinesterase inhibitors, herein we report synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine (1) and its bromo-derivative 2. Our study has shown that cryptolepine (1) and its 2-bromo-derivative 2 are dual inhibitors of acetylcholinesterase and butyrylcholinesterase, the enzymes which are involved in blocking the process of neurotransmission. Cryptolepine inhibits Electrophorus electricus acetylcholinesterase, recombinant human acetylcholinesterase and equine serum butyrylcholinesterase with IC50 values of 267, 485 and 699nM, respectively. The 2-bromo-derivative of cryptolepine also showed inhibition of these enzymes, with IC50 values of 415, 868 and 770nM, respectively. The kinetic studies revealed that cryptolepine inhibits human acetylcholinesterase in a non-competitive manner, with ki value of 0.88microM. Additionally, these alkaloids were also tested against two other important pathological events of Alzheimer's disease viz. stopping the formation of toxic amyloid-beta oligomers (via inhibition of BACE-1), and increasing the amyloid-beta clearance (via P-gp induction). Cryptolepine displayed potent P-gp induction activity at 100nM, in P-gp overexpressing adenocarcinoma LS-180 cells and excellent toxicity window in LS-180 as well as in human neuroblastoma SH-SY5Y cell line. The molecular modeling studies with AChE and BChE have shown that both alkaloids were tightly packed inside the active site gorge (site 1) via multiple pi-pi and cation-pi interactions. Both inhibitors have shown interaction with the allosteric "peripheral anionic site" via hydrophobic interactions. The ADME properties including the BBB permeability were computed for these alkaloids, and were found within the acceptable range.
ESTHER : Nuthakki_2019_Bioorg.Chem_90_103062
PubMedSearch : Nuthakki_2019_Bioorg.Chem_90_103062
PubMedID: 31220673

Title : Necrosis and necroptosis in germ cell depletion from mammalian ovary - Chaudhary_2019_J.Cell.Physiol_234_8019
Author(s) : Chaudhary GR , Yadav PK , Yadav AK , Tiwari M , Gupta A , Sharma A , Sahu K , Pandey AN , Pandey AK , Chaube SK
Ref : Journal of Cellular Physiology , 234 :8019 , 2019
Abstract : The maximum number of germ cells is present during the fetal life in mammals. Follicular atresia results in rapid depletion of germ cells from the cohort of the ovary. At the time of puberty, only a few hundred (<1%) germ cells are either culminated into oocytes or further get eliminated during the reproductive life. Although apoptosis plays a major role, necrosis as well as necroptosis, might also be involved in germ cell elimination from the mammalian ovary. Both necrosis and necroptosis show similar morphological features and are characterized by an increase in cell volume, cell membrane permeabilization, and rupture that lead to cellular demise. Necroptosis is initiated by tumor necrosis factor and operated through receptor interacting protein kinase as well as mixed lineage kinase domain-like protein. The acetylcholinesterase, cytokines, starvation, and oxidative stress play important roles in necroptosis-mediated granulosa cell death. The granulosa cell necroptosis directly or indirectly induces susceptibility toward necroptotic or apoptotic cell death in oocytes. Indeed, prevention of necrosis and necroptosis pathways using their specific inhibitors could enhance growth/differentiation factor-9 expression, improve survivability as well as the meiotic competency of oocytes, and prevent decline of reproductive potential in several mammalian species and early onset of menopause in women. This study updates the information and focuses on the possible involvement of necrosis and necroptosis in germ cell depletion from the mammalian ovary.
ESTHER : Chaudhary_2019_J.Cell.Physiol_234_8019
PubMedSearch : Chaudhary_2019_J.Cell.Physiol_234_8019
PubMedID: 30341907

Title : Mobile phone induced cognitive and neurochemical consequences - Sharma_2019_J.Chem.Neuroanat__101684
Author(s) : Sharma A , Sharma S , Shrivastava S , Singhal PK , Shukla S
Ref : Journal of Chemical Neuroanatomy , :101684 , 2019
Abstract : With the rapid advances in technology, extensive use of mobile phones has increased the risk of health problems. This study was performed to find out the effect of mobile phone frequency on male Wistar rats. Animals were divided into two groups (n = 6 in each group). Group one was considered as control and group two (experimental group) was exposed to microwave radiation (2100 MHz) for 4 hours/day (5 days/week) for 3 months. Exposure of microwave radiation frequency showed significant alterations in cholinesterase activity, muscular strength, learning ability and anxiety. MWR exposure was also associated with significant alteration in the oxidative defense system and hippocampus degeneration. Histopathological observations clearly depicted the neural degeneration. Thus, it can be concluded that MWR significantly affects the central nervous system and may lead to many severe illnesses. This study may reveal a platform to understand its toxic effect and can further be used for amendment in current guidelines of mobile radiation.
ESTHER : Sharma_2019_J.Chem.Neuroanat__101684
PubMedSearch : Sharma_2019_J.Chem.Neuroanat__101684
PubMedID: 31553920

Title : Molecular characterization and bioinformatics studies of a lipase from Bacillus thermoamylovorans BHK67 - Sharma_2018_Int.J.Biol.Macromol_107_2131
Author(s) : Sharma A , Meena KR , Kanwar SS
Ref : Int J Biol Macromol , 107 :2131 , 2018
Abstract : A bacterium isolated from a hot-water spring identified as Bacillus thermoamylovorans BHK67 successfully produced a thermotolerant extracellular alkaliphilic lipase. The lipase was purified to homogeneity by anion exchange chromatography with 15-fold purification and 12.1% yield. The lipase appeared to be a hexameric protein as it possessed a single band of Mr 25kDa in SDS PAGE and 150kDa in Native PAGE. DLS analysis of purified Bacillus thermoamylovorans BHK67 lipase (BTL) also showed the molecular integrity, homogeneity and stability of the enzyme. The purified lipase showed maximum activity at pH 7.5 with a half-life of 10.5h at 55 degrees C. Kinetic study of purified lipase by Lineweaver-Burk plot provided Km (7.7mM),Vmax (90.9U/mL/min),Kcat (227.3s(-1)) and Kspec (29.4mMs(-1)) for substrate p-nitrophenylpalmitate.The purified lipase also showed astonishing stability following exposure to ethanol, n-propanol, iso-propanol, n-butanol and DMSO. Amino acid characterization of BTL by MALDI-TOF-MS showed considerable resemblance with lysophospholipase L1 related esterase of Lactobacillus ozensis DSM 23829. Experimental coupled molecular modeling postulated a structure-activity correlation of BTL as a probable contender in degradation of xenobiotic compounds, biocatalysis, biotransformation of compounds, synthesis of optically active compounds, foodstuff industry, anticancer therapeutics etc.
ESTHER : Sharma_2018_Int.J.Biol.Macromol_107_2131
PubMedSearch : Sharma_2018_Int.J.Biol.Macromol_107_2131
PubMedID: 29051101

Title : Characterization of ML0314c of Mycobacterium leprae and deciphering its role in the immune response in leprosy patients - Kaur_2018_Gene_643_26
Author(s) : Kaur G , Sharma A , Narang T , Dogra S , Kaur J
Ref : Gene , 643 :26 , 2018
Abstract : Mycobacterium leprae has a reduced genome size due to the reductive evolution over a long period of time. Lipid metabolism plays an important role in the life cycle and pathogenesis of this bacterium. In comparison to 26 lip genes (Lip A-Z) of M. tuberculosis, M. leprae retained only three orthologs indicating their importance in its life cycle. ML0314c (LipU) is one of them. It is conserved throughout the mycobacterium species. Bioinformatics analysis showed the presence of an alpha/beta hydrolase fold and 'GXSXG' characteristic of the esterases/lipases. The gene was expressed in E. coli and purified to homogeneity. It showed preference towards short chain esters with pNP-acetate as the preferred substrate. The enzyme showed optimal activity at 45 degrees C and pH8.0. ML0314c protein was stable between temperatures ranging from 20 to 60 degrees C and pH5.0-8.0, i.e., relatively acidic and neutral conditions. The active site residues predicted bioinformatically were confirmed to be Ser168, Glu267, and His297 by site directed mutagenesis. E-serine, DEPC and Tetrahydrolipstatin (THL) completely inhibited the activity of ML0314c. The protein was localized in cell wall and extracellular medium. Several antigenic epitopes were predicted in ML0314c. Protein elicited strong humoral immune response in leprosy patients, whereas, a reduced immune response was observed in the relapsed cases. No humoral response was observed in treatment completed patients. Overexpression of ml0314c in the surrogate host M. smegmatis showed marked difference in the colony morphology and growth rate. In conclusion, ML0314c is a secretary carboxyl esterase that could modulate the immune response in leprosy patients.
ESTHER : Kaur_2018_Gene_643_26
PubMedSearch : Kaur_2018_Gene_643_26
PubMedID: 29208413
Gene_locus related to this paper: mycle-ML0314

Title : Jasmonic Acid Seed Treatment Stimulates Insecticide Detoxification in Brassica juncea L - Sharma_2018_Front.Plant.Sci_9_1609
Author(s) : Sharma A , Kumar V , Yuan H , Kanwar MK , Bhardwaj R , Thukral AK , Zheng B
Ref : Front Plant Sci , 9 :1609 , 2018
Abstract : The present study focused on assessing the effects of jasmonic acid (JA) seed treatment on the physiology of Brassica juncea seedlings grown under imidacloprid (IMI) toxicity. It has been observed that IMI application declined the chlorophyll content and growth of seedlings. However, JA seed treatment resulted in the significant recovery of chlorophyll content and seedling growth. Contents of oxidative stress markers like superoxide anion, hydrogen peroxide, and malondialdehyde were enhanced with IMI application, but JA seed treatment significantly reduced their contents. Antioxidative defense system was activated with IMI application which was further triggered after JA seed treatment. Activities of antioxidative enzymes and contents of non-enzymatic antioxidants were enhanced with the application of IMI as well as JA seed treatment. JA seed treatment also regulated the gene expression of various enzymes under IMI stress. These enzymes included respiratory burst oxidase (RBO), Ribulose-1,5-bisphosphate carboxylase/oxygenase (RUBISCO), NADH-ubiquinone oxidoreductase (NADH), carboxylesterase (CXE), chlorophyllase (CHLASE), cytochrome P450 monooxygenase (P450). JA seed treatment up-regulated the expressions of RUBISCO, NADH, CXE, and P450 under IMI toxicity. However, expressions of RBO and CHLASE were down-regulated in seedlings germinated from JA seed treatment and grown in presence of IMI. Seed soaking with JA also resulted in a significant reduction of IMI residues in B. juncea seedlings. The present study concluded that seed soaking with JA could efficiently reduce the IMI toxicity by triggering the IMI detoxification system in intact plants.
ESTHER : Sharma_2018_Front.Plant.Sci_9_1609
PubMedSearch : Sharma_2018_Front.Plant.Sci_9_1609
PubMedID: 30450109

Title : Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease - Sharma_2018_Front.Pharmacol_9_1247
Author(s) : Sharma A , Pachauri V , Flora SJS
Ref : Front Pharmacol , 9 :1247 , 2018
Abstract : Alzheimer's disease (AD) is the age linked neurodegenerative disorder with no disease modifying therapy currently available. The available therapy only offers short term symptomatic relief. Several hypotheses have been suggested for the pathogenesis of the disease while the molecules developed as possible therapeutic agent in the last decade, largely failed in the clinical trials. Several factors like tau protein hyperphosphorylation, amyloid-beta (Abeta) peptide aggregation, decline in acetyl cholinesterase and oxidative stress might be contributing toward the pathogenesis of AD. Additionally, biometals dyshomeostasis (Iron, Copper, and Zinc) in the brain are also reported to be involved in the pathogenesis of AD. Thus, targeting these metal ions may be an effective strategy for the development of a drug to treat AD. Chelation therapy is currently employed for the metal intoxication but we lack a safe and effective chelating agents with additional biological properties for their possible use as multi target directed ligands for a complex disease like AD. Chelating agents possess the ability to disaggregate Abeta aggregation, dissolve amyloid plaques, and delay the cognitive impairment. Thus there is an urgent need to develop disease modifying therapeutic molecules with multiple beneficial features like targeting more than one factor responsible of the disease. These molecules, as disease modifying therapeutic agents for AD, should possess the potential to inhibit Abeta-metal interactions, the formation of toxic Abeta aggregates; and the capacity to reinstate metal homeostasis.
ESTHER : Sharma_2018_Front.Pharmacol_9_1247
PubMedSearch : Sharma_2018_Front.Pharmacol_9_1247
PubMedID: 30498443

Title : Design, synthesis and pharmacological evaluation of some novel indanone derivatives as acetylcholinesterase inhibitors for the management of cognitive dysfunction - Piplani_2018_Bioorg.Med.Chem_26_215
Author(s) : Piplani P , Jain A , Devi D , Anjali , Sharma A , Silakari P
Ref : Bioorganic & Medicinal Chemistry , 26 :215 , 2018
Abstract : The present study reports the effect of indanone derivatives on scopolamine induced deficit cholinergic neurotransmission serving as promising leads for the therapeutics of cognitive dysfunction. Eleven compounds 54-64 have been designed, synthesised and evaluated against behavioural alterations using step down passive avoidance protocol at a dose of 0.5mg/kg with Donepezil (1) as the reference standard. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Compounds 54, 56, 59 and 64 displayed appreciable activity with an IC50 value of 14.06microM, 12.30microM, 14.06microM and 12.01microM, respectively towards acetylcholinesterase inhibition. The molecular docking study performed to predict the binding mode of the compounds suggested that these compounds could bind appreciably to the amino acids present at the active site of recombinant human acetylcholinesterase (rhAChE). The behavioural, biochemical and in silico pharmacokinetic studies were in concordance with each other.
ESTHER : Piplani_2018_Bioorg.Med.Chem_26_215
PubMedSearch : Piplani_2018_Bioorg.Med.Chem_26_215
PubMedID: 29195794

Title : Arsenic-induced oxidative stress, cholinesterase activity in the brain of Swiss albino mice, and its amelioration by antioxidants Vitamin E and Coenzyme Q10 - Sharma_2018_Environ.Sci.Pollut.Res.Int_25_23946
Author(s) : Sharma A , Kshetrimayum C , Sadhu HG , Kumar S
Ref : Environ Sci Pollut Res Int , 25 :23946 , 2018
Abstract : Arsenic toxicity becomes one of the major public health issues in several countries. Chronic and acute exposure to arsenic has been reported to be toxic to various systems of the human body and also observed in controlled experimental studies. The study was conducted to evaluate the neurotoxic effect of arsenic in Swiss albino mice and its amelioration by Vitamin E, Coenzyme Q10 and their combination. Swiss albino mice were treated with arsenic of 136 ppm for 15 days. The daily dose is 1/3 of LD 50 (acute) reported dose of arsenic. Thereafter, the animals were maintained either on drinking water or treated with Vitamin E (50 mg/kg bwt), Coenzyme Q10 (10 mg/kg bwt), and their combination by i.p.daily for 15 days. After the treatment, animals were sacrificed. The weight of the brain was marginally lower (ns), in arsenic-treated group as compared to control and antioxidant-protected groups. The LPO (lipid peroxidation) level was higher in arsenic-treated group, and this elevation was checked to some extent by the selected antioxidants which were statistically significant in combination of antioxidant-protected group. A significant reduction was found in GSH (reduced glutathione) level in the brain of arsenic-treated mice whereas GSH level was considerably higher in antioxidant-protected groups. Further, total thiol and total protein level were lower in arsenic-treated group. However, total thiol was significantly higher in antioxidant-protected groups. CAT (catalase) activity was significantly lower while SOD (superoxide dismutase) activity was marginally lowered in arsenic-treated group, and it was slightly higher in antioxidant-protected groups. Further, reduction in AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) and motor coordination activity were also observed in arsenic-treated groups. Whereas, a higher AChE, BChE, and motor coordination activity was observed in antioxidant-protected group. These data indicate a positive role of selected antioxidant against the toxicity of arsenic in the brain of mice.
ESTHER : Sharma_2018_Environ.Sci.Pollut.Res.Int_25_23946
PubMedSearch : Sharma_2018_Environ.Sci.Pollut.Res.Int_25_23946
PubMedID: 29948670

Title : 24-epibrassinolide stimulates imidacloprid detoxification by modulating the gene expression of Brassica juncea L - Sharma_2017_BMC.Plant.Biol_17_56
Author(s) : Sharma A , Thakur S , Kumar V , Kesavan AK , Thukral AK , Bhardwaj R
Ref : BMC Plant Biol , 17 :56 , 2017
Abstract : BACKGROUND: Pesticides cause oxidative stress to plants and their residues persist in plant parts, which are a major concern for the environment as well as human health. Brassinosteroids (BRs) are known to protect plants from abiotic stress conditions including pesticide toxicity. The present study demonstrated the effects of seed-soaking with 24-epibrassinolide (EBR) on physiological responses of 10-day old Brassica juncea seedlings grown under imidacloprid (IMI) toxicity.
RESULTS: In the seedlings raised from EBR-treated seeds and grown under IMI toxicity, the contents of hydrogen peroxide (H2O2) and superoxide anion (O.2-) were decreased, accompanied by enhanced activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST), guaiacol peroxidase (POD) and the content of glutathione (GSH). As compared to controls, the gene expressions of SOD, CAT, GR, POD, NADH (NADH-ubiquinone oxidoreductase), CXE (carboxylesterase), GSH-S (glutathione synthase), GSH-T (glutathione transporter-1), P450 (cytochrome P450 monooxygenase) and GST1-3,5-6 were enhanced in the seedlings raised from EBR-treated seeds and grown in IMI supplemented substratum. However, expression of RBO (respiratory burst oxidase, the gene responsible for H2O2 production) was decreased in seedlings raised from EBR treated seeds and grown under IMI toxicity. Further, the EBR seed treatment decreased IMI residues by more than 38% in B. juncea seedlings.
CONCLUSIONS: The present study revealed that EBR seed soaking can efficiently reduce oxidative stress and IMI residues by modulating the gene expression of B. juncea under IMI stress. In conclusion, exogenous EBR application can protect plants from pesticide phytotoxicity.
ESTHER : Sharma_2017_BMC.Plant.Biol_17_56
PubMedSearch : Sharma_2017_BMC.Plant.Biol_17_56
PubMedID: 28245791

Title : Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis - Kumari_2017_Parasitol__1
Author(s) : Kumari P , Nigam R , Singh A , Nakade UP , Sharma A , Garg SK , Singh SK
Ref : Parasitology , :1 , 2017
Abstract : Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis.
ESTHER : Kumari_2017_Parasitol__1
PubMedSearch : Kumari_2017_Parasitol__1
PubMedID: 28583218

Title : The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion - Sharma_2017_Mol.Oncol_11_655
Author(s) : Sharma A , Mendonca J , Ying J , Kim HS , Verdone JE , Zarif JC , Carducci M , Hammers H , Pienta KJ , Kachhap S
Ref : Mol Oncol , 11 :655 , 2017
Abstract : Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1-deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1-deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1-deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three-dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1-deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin-mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.
ESTHER : Sharma_2017_Mol.Oncol_11_655
PubMedSearch : Sharma_2017_Mol.Oncol_11_655
PubMedID: 28371345

Title : Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction - Sharma_2017_Chem.Biol.Drug.Des_90_926
Author(s) : Sharma A , Piplani P
Ref : Chemical Biology Drug Des , 90 :926 , 2017
Abstract : A novel series of hybrid molecules (5a-5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold, and the structures of the target compounds were confirmed by IR, (1) H NMR, (13) C NMR, and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step-down passive avoidance and elevated plus maze at a dose 0.5 mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC50 0.33 mum). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase, and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine-induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site, and mid-gorge of AChE simultaneously. The calculated absorption, distribution, metabolism and excretion properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also.
ESTHER : Sharma_2017_Chem.Biol.Drug.Des_90_926
PubMedSearch : Sharma_2017_Chem.Biol.Drug.Des_90_926
PubMedID: 28544619

Title : mesT, a unique epoxide hydrolase, is essential for optimal growth of Mycobacterium tuberculosis in the presence of styrene oxide - Chownk_2017_Future.Microbiol_12_527
Author(s) : Chownk M , Sharma A , Singh K , Kaur J
Ref : Future Microbiol , 12 :527 , 2017
Abstract : AIM: mesT of Mycobacterium tuberculosis, a hypothetical/putative epoxide hydrolase, is predicted to convert toxic epoxides to the more water-soluble and less toxic diols. Detailed characterization of the protein was carried out.
RESULTS: mesT demonstrated esterase as well as epoxide hydrolase activity. It was membrane bound and was upregulated under hypoxic conditions. The enzyme was able to degrade styrene oxide. The presence of antisense against this gene resulted in the inhibition of in vitro bacterial growth/survival in the presence of styrene oxide. Conclusion & future perspective: We demonstrated that mesT possessed epoxide hydrolase activity and styrene oxide might be its physiological substrate. Inhibition of mesT reduced the growth of the bacteria in presence of styrene oxide and its expression under hypoxic condition suggested its role in intracellular survival of bacteria.
ESTHER : Chownk_2017_Future.Microbiol_12_527
PubMedSearch : Chownk_2017_Future.Microbiol_12_527
PubMedID: 28492351
Gene_locus related to this paper: myctu-LIPS

Title : Potential association of reduced cholinesterase activity with Trypanosoma evansi pathogenesis in buffaloes - Singh_2016_Vet.Parasitol_225_29
Author(s) : Singh SK , Singh VK , Yadav BK , Nakade UP , Kumari P , Srivastava MK , Sharma A , Choudhary S , Swain D , Garg SK
Ref : Vet Parasitol , 225 :29 , 2016
Abstract : The present study aimed to investigate the association of cholinesterase activity with trypanosomosis in buffaloes. Thirty-three clinical cases of trypanosomosis in water buffaloes, found positive for trypomastigotes of T. evansi on blood smear examination, were divided into two groups based on clinical manifestations. Twenty diseased buffaloes revealing only common clinical signs were allocated to Group I, while the remaining 13 buffaloes showing common clinical manifestations along with neurological disturbances were allocated to Group II. Twelve clinically healthy buffaloes, free from any haemoprotozoa infection, were kept as healthy control (Group III). Blood samples were collected from buffaloes of all three groups to determine serum cholinesterase activity. Compared to buffaloes of healthy control group, cholinesterase activity in T. evansi-infected buffaloes of Group I and II was significantly (P<0.001) lower. However, no significant difference was observed in cholinesterase activity between the T. evansi-infected buffaloes exhibiting neurological disorders and no neurological disorders. Summing up, reduced cholinesterase activity seems to be associated with the pathogenesis of natural T. evansi infection and its clinical manifestations in buffaloes possibly by evading immune response. Further studies are warranted on association of cholinesterase activity in T. evansi-infected buffaloes with neurological disorders.
ESTHER : Singh_2016_Vet.Parasitol_225_29
PubMedSearch : Singh_2016_Vet.Parasitol_225_29
PubMedID: 27369572

Title : Functional characterization of hypothetical proteins of Mycobacterium tuberculosis with possible esterase\/lipase signature: A Cumulative in silico and in vitro approach - Kumar_2016_J.Biomol.Struct.Dyn_35_1226
Author(s) : Kumar A , Sharma A , Kaur G , Makkar P , Kaur J
Ref : J Biomol Struct Dyn , 35 :1226 , 2016
Abstract : The functional aspect of several mycobacterium proteins annotated as hypothetical are yet to be discovered. In the present investigation, in silico approaches were used to predict the biological function of some of the unknown Mtb proteins, which were further validated by wet lab experiments. After screening thousands of Mtb proteins, functionally unknown hypothetical proteins Rv0421c, Rv0519c, Rv0774c, Rv1191, Rv1592c and Rv3591c were chosen on the basis of their importance in Mtb life cycle. All these proteins posses the alpha/beta-hydrolase topological fold, characteristic of lipases/esterases, with serine, aspartate, and histidine as the putative members of the catalytic triad. The catalytic serine is located in pentapeptide motif "GXSXG" and oxyanion residue is in dipeptide motif HG. To further support our observation, molecular docking was performed with conventional synthetic lipolytic substrates (pNP-esterss) and specific lipase/esterase inhibitors (tetrahydrolipstatin, PMSF). Significant docking score and strong interaction of substrates/inhibitors with these proteins revealed that these could be possible lipases/esterases. To validate the in silico studies, these genes were cloned from Mtb genome and the proteins were over-expressed in pQE-30/Escherichia coli M15 system. The expressed proteins were purified to homogeneity and enzymatic activity was determined by using pNP esters as substrate. The enzyme activity of recombinant proteins was inhibited by tetrahydrolipstatin and PMSF pre-treatment. Outcome of the present investigation provided a basic platform to analyse and characterize unknown hypothetical proteins.
ESTHER : Kumar_2016_J.Biomol.Struct.Dyn_35_1226
PubMedSearch : Kumar_2016_J.Biomol.Struct.Dyn_35_1226
PubMedID: 27050490
Gene_locus related to this paper: myctu-MT1628 , myctu-RV0421C , myctu-RV0519C , myctu-RV0774C , myctu-Rv1191 , myctu-Rv3591c

Title : NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability - Croessmann_2015_Proc.Natl.Acad.Sci.U.S.A_112_11583
Author(s) : Croessmann S , Wong HY , Zabransky DJ , Chu D , Mendonca J , Sharma A , Mohseni M , Rosen DM , Scharpf RB , Cidado J , Cochran RL , Parsons HA , Dalton WB , Erlanger B , Button B , Cravero K , Kyker-Snowman K , Beaver JA , Kachhap S , Hurley PJ , Lauring J , Park BH
Ref : Proc Natl Acad Sci U S A , 112 :11583 , 2015
Abstract : The tumor protein 53 (TP53) tumor suppressor gene is the most frequently somatically altered gene in human cancers. Here we show expression of N-Myc down-regulated gene 1 (NDRG1) is induced by p53 during physiologic low proliferative states, and mediates centrosome homeostasis, thus maintaining genome stability. When placed in physiologic low-proliferating conditions, human TP53 null cells fail to increase expression of NDRG1 compared with isogenic wild-type controls and TP53 R248W knockin cells. Overexpression and RNA interference studies demonstrate that NDRG1 regulates centrosome number and amplification. Mechanistically, NDRG1 physically associates with gamma-tubulin, a key component of the centrosome, with reduced association in p53 null cells. Strikingly, TP53 homozygous loss was mutually exclusive of NDRG1 overexpression in over 96% of human cancers, supporting the broad applicability of these results. Our study elucidates a mechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.
ESTHER : Croessmann_2015_Proc.Natl.Acad.Sci.U.S.A_112_11583
PubMedSearch : Croessmann_2015_Proc.Natl.Acad.Sci.U.S.A_112_11583
PubMedID: 26324937

Title : Evaluation of pesticide residues in human blood samples from Punjab (India) - Bedi_2015_Vet.World_8_66
Author(s) : Bedi JS , Gill JP , Kaur P , Sharma A , Aulakh RS
Ref : Vet World , 8 :66 , 2015
Abstract : AIM: The present study was undertaken to estimate the current status of residues of organochlorine pesticides (OCPs), organophosphates (OPs) and synthetic pyrethroids (SPs) pesticides in human blood. MATERIALS AND
METHODS: Human blood samples were analyzed by gas chromatography and confirmed by gas chromatography-mass spectrometry in selective ion monitoring mode.
RESULTS: The gas chromatographic analysis of human blood samples collected from Punjab revealed the presence of p,p'-dichlorodiphenyl dichloroethylene (DDE), p,p' dichlorodiphenyl dichloroethane (DDD), o,p' DDE and beta-endosulfan at mean levels of 15.26, 2.71, 5.62 and 4.02 ng/ml, respectively. p,p' DDE residue was observed in 18.0% blood samples, and it contributes 55% of the total pesticide burden in human blood. The difference of total dichlorordiphenyl trichloroethane (DDT) between different age groups of humans was found to be statistically significant (p<0.05). The difference of DDT and endosulfan between dietary habits, gender and spraying of pesticides was found statistically non-significant, however endosulfan residues were observed only in pesticide sprayer's population. CONCLUSION: Occurrence of p,p' DDE, p,p' DDD, o,p' DDE in human blood indicated restricted use of DDT. However, presence of endosulfan residues in occupationally exposed population is a matter of public health concern.
ESTHER : Bedi_2015_Vet.World_8_66
PubMedSearch : Bedi_2015_Vet.World_8_66
PubMedID: 27046999

Title : Effect of ethanolic extract of Acacia auriculiformis leaves on learning and memory in rats - Sharma_2014_Pharmacognosy.Res_6_246
Author(s) : Sharma A , Shetty M , Parida A , Adiga S , Kamath S , Sowjanya
Ref : Pharmacognosy Res , 6 :246 , 2014
Abstract : BACKGROUND: The effects and benefits of Acacia auriculiformis on health are not well established. This study was planned to evaluate the effect of ethanolic extract of Acacia auriculiformis leaves on learning and memory in rats. MATERIALS AND
METHODS: Learning and memory were evaluated using passive avoidance paradigm and rewarded alternation test (T-maze) after the oral administration of two doses (200mg/kg and 400mg/kg) of ethanolic extract of Acacia auriculiformis with rivastigmine as positive control. Forty eight rats were divided into 4 groups in each study model. Estimation of brain cholinesterase activity was done to substantiate the results of the above mentioned tests. Data was analyzed using one way Analysis of Variance (ANOVA) followed by Tukey's post-hoc test using GraphPad InStat software, version 3.06.
RESULTS: The extract produced a dose-dependent improvement in the memory score namely the step through latency in passive avoidance model (P < 0.001) and the percentage of correct responses in rewarded alternation test (P < 0.05). Dose-dependent inhibition of brain cholinesterase activity (P < 0.001) was also noted. CONCLUSION: The acetylcholinesterase inhibiting property of Acacia auriculiformis contributes to its memory enhancing potential. Further large scale studies are required to elucidate its benefits on cognitive function. This may offer a promising new option for the treatment of dementia and other cognitive deficits.
ESTHER : Sharma_2014_Pharmacognosy.Res_6_246
PubMedSearch : Sharma_2014_Pharmacognosy.Res_6_246
PubMedID: 25002806

Title : Role of Medium Chain Triglycerides (Axona(R)) in the Treatment of Mild to Moderate Alzheimer's Disease - Sharma_2014_Am.J.Alzheimers.Dis.Other.Demen_29_409
Author(s) : Sharma A , Bemis M , Desilets AR
Ref : Am J Alzheimers Dis Other Demen , 29 :409 , 2014
Abstract : Treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists provides symptomatic relief but do not prevent its progression. Thus, additional approaches aimed at slowing the progression of the disease have been investigated. Reports detailing reduced brain glucose metabolism in the early stages of AD led to the hypothesis that alternate energy sources aimed at increasing neuronal metabolism may protect neurons and thus benefit patients with AD. Medium-chain triglycerides (MCTs) are metabolized to ketone bodies that serve as an alternative source of energy for neurons. Data from clinical trials suggest that MCTs improve cognition in patients with mild to moderate AD in apolipoprotein E4-negative patients. Adverse events observed were mild and included minor gastrointestinal problems such as diarrhea, dyspepsia, and flatulence. However, since genomic profiles are not routinely conducted in patients with AD in a clinical setting, the role of MCTs in clinical practice seems to be minimal.
ESTHER : Sharma_2014_Am.J.Alzheimers.Dis.Other.Demen_29_409
PubMedSearch : Sharma_2014_Am.J.Alzheimers.Dis.Other.Demen_29_409
PubMedID: 24413538

Title : Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi - Jiang_2014_Genome.Biol_15_459
Author(s) : Jiang X , Peery A , Hall AB , Sharma A , Chen XG , Waterhouse RM , Komissarov A , Riehle MM , Shouche Y , Sharakhova MV , Lawson D , Pakpour N , Arensburger P , Davidson VL , Eiglmeier K , Emrich S , George P , Kennedy RC , Mane SP , Maslen G , Oringanje C , Qi Y , Settlage R , Tojo M , Tubio JM , Unger MF , Wang B , Vernick KD , Ribeiro JM , James AA , Michel K , Riehle MA , Luckhart S , Sharakhov IV , Tu Z
Ref : Genome Biol , 15 :459 , 2014
Abstract : BACKGROUND: Anopheles stephensi is the key vector of malaria throughout the Indian subcontinent and Middle East and an emerging model for molecular and genetic studies of mosquito-parasite interactions. The type form of the species is responsible for the majority of urban malaria transmission across its range.
RESULTS: Here, we report the genome sequence and annotation of the Indian strain of the type form of An. stephensi. The 221 Mb genome assembly represents more than 92% of the entire genome and was produced using a combination of 454, Illumina, and PacBio sequencing. Physical mapping assigned 62% of the genome onto chromosomes, enabling chromosome-based analysis. Comparisons between An. stephensi and An. gambiae reveal that the rate of gene order reshuffling on the X chromosome was three times higher than that on the autosomes. An. stephensi has more heterochromatin in pericentric regions but less repetitive DNA in chromosome arms than An. gambiae. We also identify a number of Y-chromosome contigs and BACs. Interspersed repeats constitute 7.1% of the assembled genome while LTR retrotransposons alone comprise more than 49% of the Y contigs. RNA-seq analyses provide new insights into mosquito innate immunity, development, and sexual dimorphism.
CONCLUSIONS: The genome analysis described in this manuscript provides a resource and platform for fundamental and translational research into a major urban malaria vector. Chromosome-based investigations provide unique perspectives on Anopheles chromosome evolution. RNA-seq analysis and studies of immunity genes offer new insights into mosquito biology and mosquito-parasite interactions.
ESTHER : Jiang_2014_Genome.Biol_15_459
PubMedSearch : Jiang_2014_Genome.Biol_15_459
PubMedID: 25244985
Gene_locus related to this paper: anoga-Q7PVF9 , anoga-q7q837 , anost-a0a1a9thh9 , anost-a0a182xxz0 , anost-a0a182xzf1 , anost-a0a182xxy9 , anoga-q7q887

Title : Genome sequencing of four Aureobasidium pullulans varieties: biotechnological potential, stress tolerance, and description of new species - Gostincar_2014_BMC.Genomics_15_549
Author(s) : Gostincar C , Ohm RA , Kogej T , Sonjak S , Turk M , Zajc J , Zalar P , Grube M , Sun H , Han J , Sharma A , Chiniquy J , Ngan CY , Lipzen A , Barry K , Grigoriev IV , Gunde-Cimerman N
Ref : BMC Genomics , 15 :549 , 2014
Abstract : BACKGROUND: Aureobasidium pullulans is a black-yeast-like fungus used for production of the polysaccharide pullulan and the antimycotic aureobasidin A, and as a biocontrol agent in agriculture. It can cause opportunistic human infections, and it inhabits various extreme environments. To promote the understanding of these traits, we performed de-novo genome sequencing of the four varieties of A. pullulans.
RESULTS: The 25.43-29.62 Mb genomes of these four varieties of A. pullulans encode between 10266 and 11866 predicted proteins. Their genomes encode most of the enzyme families involved in degradation of plant material and many sugar transporters, and they have genes possibly associated with degradation of plastic and aromatic compounds. Proteins believed to be involved in the synthesis of pullulan and siderophores, but not of aureobasidin A, are predicted. Putative stress-tolerance genes include several aquaporins and aquaglyceroporins, large numbers of alkali-metal cation transporters, genes for the synthesis of compatible solutes and melanin, all of the components of the high-osmolarity glycerol pathway, and bacteriorhodopsin-like proteins. All of these genomes contain a homothallic mating-type locus.
CONCLUSIONS: The differences between these four varieties of A. pullulans are large enough to justify their redefinition as separate species: A. pullulans, A. melanogenum, A. subglaciale and A. namibiae. The redundancy observed in several gene families can be linked to the nutritional versatility of these species and their particular stress tolerance. The availability of the genome sequences of the four Aureobasidium species should improve their biotechnological exploitation and promote our understanding of their stress-tolerance mechanisms, diverse lifestyles, and pathogenic potential.
ESTHER : Gostincar_2014_BMC.Genomics_15_549
PubMedSearch : Gostincar_2014_BMC.Genomics_15_549
PubMedID: 24984952
Gene_locus related to this paper: aurpu-a0a1a7mdx5 , 9pezi-a0a074w0m0 , 9pezi-a0a074wgq7 , aurpu-a0a074xfg8 , 9pezi-a0a074y586 , 9pezi-a0a074yqf6 , 9pezi-a0a074w5k8 , aurpu-a0a074x6a3 , 9pezi-a0a074z3s4 , 9pezi-a0a074x4q0 , 9pezi-a0a074w2e2 , 9pezi-a0a074x294 , aurpu-a0a074y1y2 , aurpu-a0a074x9w9 , 9pezi-a0a074ydw7 , 9pezi-a0a074w1z9 , 9pezi-a0a074wvx0 , 9pezi-a0a074vkc4 , 9pezi-a0a074y2z2 , 9pezi-a0a074vlb9 , aurpu-a0a074x490 , 9pezi-a0a074ydn0 , 9pezi-a0a074wng0 , 9pezi-a0a074yhi1 , 9pezi-a0a074yp94 , 9pezi-a0a074wbe1 , 9pezi-a0a074wm90 , 9pezi-a0a074ww95 , aurpu-a0a074xg41 , aurpu-a0a074xtu4 , 9pezi-a0a074y8g8 , aurpu-a0a074ysb8 , 9pezi-a0a074zem7 , 9pezi-a0a074yvw8 , 9pezi-a0a074w278 , aurpu-a0a074xxz9 , 9pezi-a0a074y9f0 , aurpu-a0a074xzv0 , 9pezi-a0a074wce5 , 9pezi-a0a074wmz5 , 9pezi-a0a074vr83 , 9pezi-a0a074w4l5 , 9pezi-a0a074wwv4 , 9pezi-a0a074w5f4 , aurpu-a0a074xir3 , aurpu-a0a074xnm6 , 9pezi-a0a074zhr2 , 9pezi-a0a074vzq8 , 9pezi-a0a074web5 , aurpu-a0a074xz32 , 9pezi-a0a074ybl0 , aurpu-a0a074xl81 , 9pezi-a0a074vaq7 , 9pezi-a0a074wuj9 , aurpu-a0a074xyu0 , 9pezi-a0a074vfi8 , 9pezi-a0a074wih8 , aurpu-a0a074xj03 , 9pezi-a0a074vze0 , 9pezi-a0a074w5u8 , 9pezi-a0a074wui5 , 9pezi-a0a074xhu0 , aurpu-a0a074xyg1 , 9pezi-a0a074yct6 , 9pezi-a0a074zd60 , 9pezi-a0a074w686 , aurpu-a0a074xr93 , 9pezi-a0a074y1r2 , 9pezi-a0a074z801 , 9pezi-a0a074y6a8 , 9pezi-a0a074vg30 , aurpu-a0a074wzm8 , 9pezi-a0a074y7g9 , 9pezi-a0a074vwd1 , 9pezi-a0a074whl7 , aurpu-a0a074x6c3 , 9pezi-a0a074yak1 , aurpu-a0a074x5y4 , 9pezi-a0a074yaq1 , aurpu-a0a074xm87 , 9pezi-a0a074wgg7 , 9pezi-a0a074vky7 , aurpu-a0a074xpr5 , 9pezi-a0a074zrg4 , 9pezi-a0a074w1f9 , aurpu-a0a074xft8 , 9pezi-a0a074y5i5 , aurpu-a0a074xla0 , 9pezi-a0a074w5n7 , 9pezi-a0a074wey0 , aurpu-a0a074y3b0 , 9pezi-a0a074vrn9 , 9pezi-a0a074zgu9 , aurpu-a0a074xlv7 , 9pezi-a0a074wgb6 , 9pezi-a0a074wgj7 , 9pezi-a0a074vrg4 , 9pezi-a0a074ya42 , 9pezi-a0a074xnr8 , aurpu-a0a074x443 , 9pezi-a0a074yex2 , 9pezi-a0a074xu89 , aurpu-a0a074xxq7 , 9pezi-a0a074vih4 , aurse-a0a074ydf4 , aurse-a0a074yt75 , aurpu-a0a074y000

Title : Structural basis of malaria parasite lysyl-tRNA synthetase inhibition by cladosporin - Khan_2014_J.Struct.Funct.Genomics_15_63
Author(s) : Khan S , Sharma A , Belrhali H , Yogavel M
Ref : J Struct Funct Genomics , 15 :63 , 2014
Abstract : Malaria parasites inevitably develop drug resistance to anti-malarials over time. Hence the immediacy for discovering new chemical scaffolds to include in combination malaria drug therapy. The desirable attributes of new chemotherapeutic agents currently include activity against both liver and blood stage malaria parasites. One such recently discovered compound called cladosporin abrogates parasite growth via inhibition of Plasmodium falciparum lysyl-tRNA synthetase (PfKRS), an enzyme central to protein translation. Here, we present crystal structure of ternary PfKRS-lysine-cladosporin (PfKRS-K-C) complex that reveals cladosporin's remarkable ability to mimic the natural substrate adenosine and thereby colonize PfKRS active site. The isocoumarin fragment of cladosporin sandwiches between critical adenine-recognizing residues while its pyran ring fits snugly in the ribose-recognizing cavity. PfKRS-K-C structure highlights ample space within PfKRS active site for further chemical derivatization of cladosporin. Such derivatives may be useful against additional human pathogens that retain high conservation in cladosporin chelating residues within their lysyl-tRNA synthetase.
ESTHER : Khan_2014_J.Struct.Funct.Genomics_15_63
PubMedSearch : Khan_2014_J.Struct.Funct.Genomics_15_63
PubMedID: 24935905
Gene_locus related to this paper: clacd-cla3

Title : Acetylcholinesterase Inhibitors from QSAR Point of View: How Close are We? - Sharma_2013_Cent.Nerv.Syst.Agents.Med.Chem_13_71
Author(s) : Sharma A , Piplani P
Ref : Cent Nerv Syst Agents Med Chem , 13 :71 , 2013
Abstract : In view of the large libraries of acetylcholinesterase inhibitors (AChEIs) that are now being handled in organic synthesis, the identification of drug biological activity is advisable prior to synthesis and this can be achieved by employing predictive biological property methods. In this sense, Quantitative Structure-Activity Relationships (QSAR) or docking approaches have emerged as promising tools. The intention of this review is to summarize the present knowledge concerning computational predictions of AChEIs and AChE.
ESTHER : Sharma_2013_Cent.Nerv.Syst.Agents.Med.Chem_13_71
PubMedSearch : Sharma_2013_Cent.Nerv.Syst.Agents.Med.Chem_13_71
PubMedID: 23013375

Title : Draft Genome Sequence of the Halophilic Bacterium Halobacillus sp. Strain BAB-2008 - Joshi_2013_Genome.Announc_1_e00222
Author(s) : Joshi MN , Pandit AS , Sharma A , Pandya RV , Saxena AK , Bagatharia SB
Ref : Genome Announc , 1 : , 2013
Abstract : The Halobacillus sp. strain BAB-2008 is a moderately halophilic, rod-shaped, Gram-positive, orange-pigmented, carotenoid-producing bacterium isolated from saline soil near Zazam-Solar Park Road, Gujarat, India. Here we present the 3.7-Mb genome sequence to provide insights into its functional genomics and potential applications for carotenoid and enzyme production.
ESTHER : Joshi_2013_Genome.Announc_1_e00222
PubMedSearch : Joshi_2013_Genome.Announc_1_e00222
PubMedID: 23469348
Gene_locus related to this paper: 9baci-l5nd62 , 9baci-l5ndy7 , 9baci-l5n7k4 , 9baci-l5n726

Title : Draft Genome Sequence of Sphingobium quisquiliarum Strain P25T, a Novel Hexachlorocyclohexane (HCH)-Degrading Bacterium Isolated from an HCH Dumpsite - Kumar_2013_Genome.Announc_1_e00717
Author(s) : Kumar Singh A , Sangwan N , Sharma A , Gupta V , Khurana JP , Lal R
Ref : Genome Announc , 1 : , 2013
Abstract : Here, we report the draft genome sequence (4.2 Mb) of Sphingobium quisquiliarum strain P25(T), a natural lin (genes involved in degradation of hexachlorocyclohexane [HCH] isomers) variant genotype, isolated from a heavily contaminated (450 mg HCH/g of soil) HCH dumpsite.
ESTHER : Kumar_2013_Genome.Announc_1_e00717
PubMedSearch : Kumar_2013_Genome.Announc_1_e00717
PubMedID: 24029763
Gene_locus related to this paper: 9sphn-t0gfp3 , 9sphn-t0gjp1 , 9sphn-t0iek2

Title : Draft Genome Sequence of Arthrobacter crystallopoietes Strain BAB-32, Revealing Genes for Bioremediation - Joshi_2013_Genome.Announc_1_e00452
Author(s) : Joshi MN , Pandit AS , Sharma A , Pandya RV , Desai SM , Saxena AK , Bagatharia SB
Ref : Genome Announc , 1 : , 2013
Abstract : Arthrobacter crystallopoietes strain BAB-32, a Gram-positive obligate aerobic actinobacterium having potential application in bioremediation and bioreduction of a few metals, was isolated from rhizosphere soil of Gandhinagar, Gujarat, India. The draft genome (4.3 Mb) of the strain revealed a few vital gene clusters involved in the metabolism of aromatic compounds, zinc, and sulfur.
ESTHER : Joshi_2013_Genome.Announc_1_e00452
PubMedSearch : Joshi_2013_Genome.Announc_1_e00452
PubMedID: 23833141
Gene_locus related to this paper: 9micc-n1uz94 , 9micc-n1uzr0 , 9micc-n1v107 , 9micc-n1v806

Title : Draft Genome Sequence of Brevibacillus sp. Strain BAB-2500, a Strain That Might Play an Important Role in Agriculture - Joshi_2013_Genome.Announc_1_e00021
Author(s) : Joshi MN , Sharma A , Pandit AS , Pandya RV , Saxena AK , Bagatharia SB
Ref : Genome Announc , 1 :e00021 , 2013
Abstract : A Gram-positive bacterium, Brevibacillus sp. strain BAB-2500, was isolated as a lab contaminant in Gandhinagar, Gujarat, India. The draft genome (5.3 Mb) of the strain possesses genes for the reduction of arsenate and aluminum. These findings might provide insights into the utilization of this strain for improving crop production.
ESTHER : Joshi_2013_Genome.Announc_1_e00021
PubMedSearch : Joshi_2013_Genome.Announc_1_e00021
PubMedID: 23472223
Gene_locus related to this paper: 9bacl-l5mp14

Title : Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors - Deb_2012_Mol.Divers_16_803
Author(s) : Deb PK , Sharma A , Piplani P , Akkinepally RR
Ref : Mol Divers , 16 :803 , 2012
Abstract : The reversible inhibition of acetylcholinesterase (AChE) has become a promising target for the treatment of Alzheimer's disease (AD) which is mainly associated with low in vivo levels of acetylcholine (ACh). The availability of AChE crystal structures with and without a ligand triggered the effort to find a structure-based design of acetylcholinesterase inhibitors (AChEIs) for AD. The major problem observed with the structure-based design was the feeble robustness of the scoring functions toward the correlation of docking scores with inhibitory potencies of known ligands. This prompted us to develop new prediction models using the stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LigandFit, and GLIDE). In the present investigation, a dataset of 91 molecules belonging to 9 different structural classes of heterocyclic compounds with an activity range of 0.008 to 281,000 nM was considered for docking studies and development of AChE-specific 3D-QSAR models. The model (M1) developed using consensus of docking scores of scoring functions viz. Glide score, Gold score, Chem score, ASP score, PMF score, and DOCK score was found to be the best (R (2) = 0.938, Q (2) = 0.925,R (2) (pred) = 0.919,R (2)m((overall)) = 0.936) compared to other consensus models. Docking studies revealed that the molecules with proper alignment in the active site gorge and the ability to interact with all the crucial amino acid residues, in particular by forming pi-pi stacking interactions with Trp84 at the catalytic anionic site (CAS) and Trp279 at peripheral anionic site (PAS), showed augmented potencies with consequent improvement in patient cognition and reduced the formation of senile plaques associated with AD. Further, the descriptors that signify the association of the ligands with the receptor as well as ADME properties of the ligands were also analyzed by means of the set of ligands that have been pre-positioned with respect to a receptor after docking analysis and considered as independent variables to generate a linear model (M3 and M4) using a stepwise multiple linear regression method to get additional insight into the physicochemical requirements for effective binding of ligands with AChE as well as for prediction of AChE inhibition. The developed AChE-specific prediction models (M1-M4) satisfactorily reflect the structure-activity relationship of the existing AChEIs and have all the potential to facilitate the process of design and development of new potent AChEIs.
ESTHER : Deb_2012_Mol.Divers_16_803
PubMedSearch : Deb_2012_Mol.Divers_16_803
PubMedID: 22996404

Title : Organochlorine pesticide, endosulfan induced cellular and organismal response in Drosophila melanogaster - Sharma_2012_J.Hazard.Mater_221-222_275
Author(s) : Sharma A , Mishra M , Shukla AK , Kumar R , Abdin MZ , Chowdhuri DK
Ref : J Hazard Mater , 221-222 :275 , 2012
Abstract : The effect of endosulfan (0.02-2.0mugmL(-1)) to Drosophila melanogaster (Oregon R(+)) at the cellular and organismal levels was examined. Third instar larvae of D. melanogaster and the strains transgenic for hsp70, hsp83 and hsp26 were exposed to endosulfan through food for 12-48h to examine the heat shock proteins (hsps), reactive oxygen species (ROS) generation, anti-oxidant stress markers and xenobiotic metabolism enzymes. We observed a concentration- and time-dependent significant induction of only small hsps (hsp23>hsp22) in the exposed organism in concurrence with a significant induction of ROS generation, oxidative stress and xenobiotic metabolism markers. Sub-organismal response was to be propagated towards organismal response, i.e., delay in the emergence of flies and decreased locomotor behaviour. Organisms with diminished locomotion also exhibited significantly lowered acetylcholinesterase activity. A significant positive correlation observed among ROS generation and different cellular endpoints (small hsps, oxidative stress markers, cytochrome P450 activities) in the exposed organism indicate a modulatory role of ROS in endosulfan-mediated cellular toxicity. The study thus suggests that the adverse effects of endosulfan in exposed Drosophila are manifested both at cellular and organismal levels and recommends Drosophila as an alternative animal model for screening the risk caused by environmental chemicals.
ESTHER : Sharma_2012_J.Hazard.Mater_221-222_275
PubMedSearch : Sharma_2012_J.Hazard.Mater_221-222_275
PubMedID: 22579458

Title : The B73 maize genome: complexity, diversity, and dynamics - Schnable_2009_Science_326_1112
Author(s) : Schnable PS , Ware D , Fulton RS , Stein JC , Wei F , Pasternak S , Liang C , Zhang J , Fulton L , Graves TA , Minx P , Reily AD , Courtney L , Kruchowski SS , Tomlinson C , Strong C , Delehaunty K , Fronick C , Courtney B , Rock SM , Belter E , Du F , Kim K , Abbott RM , Cotton M , Levy A , Marchetto P , Ochoa K , Jackson SM , Gillam B , Chen W , Yan L , Higginbotham J , Cardenas M , Waligorski J , Applebaum E , Phelps L , Falcone J , Kanchi K , Thane T , Scimone A , Thane N , Henke J , Wang T , Ruppert J , Shah N , Rotter K , Hodges J , Ingenthron E , Cordes M , Kohlberg S , Sgro J , Delgado B , Mead K , Chinwalla A , Leonard S , Crouse K , Collura K , Kudrna D , Currie J , He R , Angelova A , Rajasekar S , Mueller T , Lomeli R , Scara G , Ko A , Delaney K , Wissotski M , Lopez G , Campos D , Braidotti M , Ashley E , Golser W , Kim H , Lee S , Lin J , Dujmic Z , Kim W , Talag J , Zuccolo A , Fan C , Sebastian A , Kramer M , Spiegel L , Nascimento L , Zutavern T , Miller B , Ambroise C , Muller S , Spooner W , Narechania A , Ren L , Wei S , Kumari S , Faga B , Levy MJ , McMahan L , Van Buren P , Vaughn MW , Ying K , Yeh CT , Emrich SJ , Jia Y , Kalyanaraman A , Hsia AP , Barbazuk WB , Baucom RS , Brutnell TP , Carpita NC , Chaparro C , Chia JM , Deragon JM , Estill JC , Fu Y , Jeddeloh JA , Han Y , Lee H , Li P , Lisch DR , Liu S , Liu Z , Nagel DH , McCann MC , SanMiguel P , Myers AM , Nettleton D , Nguyen J , Penning BW , Ponnala L , Schneider KL , Schwartz DC , Sharma A , Soderlund C , Springer NM , Sun Q , Wang H , Waterman M , Westerman R , Wolfgruber TK , Yang L , Yu Y , Zhang L , Zhou S , Zhu Q , Bennetzen JL , Dawe RK , Jiang J , Jiang N , Presting GG , Wessler SR , Aluru S , Martienssen RA , Clifton SW , McCombie WR , Wing RA , Wilson RK
Ref : Science , 326 :1112 , 2009
Abstract : We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.
ESTHER : Schnable_2009_Science_326_1112
PubMedSearch : Schnable_2009_Science_326_1112
PubMedID: 19965430
Gene_locus related to this paper: maize-b4ffc7 , maize-b6u7e1 , maize-c0pcy5 , maize-c0pgf7 , maize-c0pgw1 , maize-c0pfl3 , maize-b4fpr7 , maize-k7vy73 , maize-a0a096swr3 , maize-k7v3i9 , maize-b6u9v9 , maize-a0a3l6e780 , maize-b4fv80 , maize-a0a1d6nse2 , maize-c4j9a1 , maize-k7uba1

Title : Optimization of physical parameters for lipase production from Arthrobacter sp. BGCC#490 - Sharma_2009_Indian.J.Biochem.Biophys_46_178
Author(s) : Sharma A , Bardhan D , Patel R
Ref : Indian J Biochem Biophys , 46 :178 , 2009
Abstract : The physical parameters for the production of thermostable, alkaline lipase from Arthrobacter sp. BGCC# 490 were optimized using response surface methodology (RSM), employing face centered central composite design (FCCCD). The design was employed by selecting pH, temperature and incubation period as the model factors and to achieve maximum yield, interaction of these factors was studied by RSM. A second-order quadratic model and response surface method showed that the optimum conditions for lipase production (pH 10.0, temperature 40 degrees C and incubation period 48 h) resulted in 1.6-fold increase in lipase production (13.75 EUml(-1)), as compared to the initial level (8.6 EUml(-1)) after 48 h of incubation, whereas its value predicted by the quadratic model was 12.8 EUml(-1). Lipase showed stability in the pH range 8-10 and temperature range 40-60 degrees C, with maximum activity at pH 9.0 and temperature 50 degrees C. Lipase activity was enhanced in the presence of K+, Ca2+ and Mg2+ ions, but inhibited by Hg2+ ions. The enzyme exhibited high activity in the presence of acetone, isopropanol and ethanol, but was unaffected by methanol. These properties suggest that the lipase may find potential applications in the detergent industry. The present work also demonstrated the feasibility of using experimental design tools to optimize physical parameters for lipase production by an indigenous Arthrobacter sp.
ESTHER : Sharma_2009_Indian.J.Biochem.Biophys_46_178
PubMedSearch : Sharma_2009_Indian.J.Biochem.Biophys_46_178
PubMedID: 19517996

Title : A high performance lipase preparation: characterization and atomic force microscopy - Shah_2007_J.Nanosci.Nanotechnol_7_2157
Author(s) : Shah S , Sharma A , Varandani D , Mehta B , Gupta MN
Ref : J Nanosci Nanotechnol , 7 :2157 , 2007
Abstract : The goal of obtaining enzyme forms which show greater stability, higher catalytic efficiency, and reusability has been pursued since last several decades. Some novel biocatalyst designs have been evolved and protein coated micro-crystals (PCMCs) is one of them. Pseudomonas cepacia lipase coated micro-crystals were prepared by simultaneous precipitation of mixture of aqueous lipase solution and salts such as potassium sulphate by organic solvents. This resulted in lipase coated micro-crystals. The structures of micro-crystals were studied by atomic force microscopy (AFM). The AFM picture confirmed the enzyme coating over the potassium sulphate crystals. These PCMCs are in the size range of 500-1000 nm. These enzyme coated micro-crystals showed enhanced transesterification rates. Also, the PCMC were stable at 60 degrees C whereas the free enzyme lost all its activity. The enzyme coated micro-crystals prepared by 50 mg Pseudomonas cepacia lipase gave 96% conversion in 90 min whereas free enzyme gave 8% conversion. Even PCMCs prepared from 3.12 mg lipase gave 90% conversion in 10 h at 60 degrees C where as free lipase was inactive at 60 degrees C.
ESTHER : Shah_2007_J.Nanosci.Nanotechnol_7_2157
PubMedSearch : Shah_2007_J.Nanosci.Nanotechnol_7_2157
PubMedID: 17655009

Title : Preparation of cross-linked enzyme aggregates by using bovine serum albumin as a proteic feeder - Shah_2006_Anal.Biochem_351_207
Author(s) : Shah S , Sharma A , Gupta MN
Ref : Analytical Biochemistry , 351 :207 , 2006
Abstract : Addition of bovine serum albumin (BSA) as a proteic feeder facilitates obtaining cross-linked enzyme aggregates (CLEAs) in cases where the protein concentration in the enzyme preparation is low and/or the enzyme activity is vulnerable to the high concentration of glutaraldehyde required to obtain aggregates. CLEAs of Pseudomonas cepacia lipase and penicillin acylase were prepared. CLEA of lipase prepared in the presence of BSA retained 100% activity whereas CLEA prepared without BSA retained only 0.4% activity of the starting enzyme preparation. Lipase CLEA showed 12-fold increase in activity over free enzyme powder when the CLEA was used in transesterification of tributyrin. For the transesterification of Jatropha oil, while free enzyme powder required 8 h and 50 mg lipase to obtain 77% conversion, CLEA required only 6 h and 6.25 mg lipase to obtain 90% conversion. In the case of penicillin acylase, 86% activity could be retained in CLEA prepared with BSA whereas CLEA made without BSA retained only 50% activity. CLEA prepared without BSA lost 20% activity after 8 h at 45 degrees C whereas CLEA with BSA retained full activity. CLEA prepared with BSA showed Vmax/Km of 36.3 min-1 whereas CLEA prepared without BSA had Vmax/Km of 17.4 min-1 only. Scanning electron microscopy analysis showed that CLEAs prepared in the presence of BSA were less amorphous and closer in morphology to CLEAs of other enzymes described in the literature.
ESTHER : Shah_2006_Anal.Biochem_351_207
PubMedSearch : Shah_2006_Anal.Biochem_351_207
PubMedID: 16500610

Title : Novel biotinylated phenylarsonous acids as bifunctional reagents for spatially close thiols: studies on reduced antibodies and the agonist binding site of reduced Torpedo nicotinic receptors - Moaddel_1999_Bioconjug.Chem_10_629
Author(s) : Moaddel R , Sharma A , Huseni T , Jones GS, Jr. , Hanson RN , Loring RH
Ref : Bioconjug Chem , 10 :629 , 1999
Abstract : We synthesized three novel organoarsenicals as prototype bifunctional reagents for spatially close thiols, N-(4-arsenosophenyl) hexahydro-2-oxo-(3aS,4S,6aR)-1H-thieno[3, 4-d]imidazole-4-pentamide (1), 2-[4-[(4-arsenosophenyl)amino]-1, 4-dioxobutyl] hydrazide, (3aS,4S,6aR)-hexahydro-2-oxo- 1H-thieno[3, 4-d] imidazole-4-pentanoic acid (2), and [4-[[12-[[5-[(3aS,4S, 6aR)-hexahydro-2-oxo-1H-thieno[3, 4-d]imidazol-4-yl]-1-oxopentyl]amino]-1-oxododecyl]amino]phe nyl]-arso nous acid (3) containing both biotin and arsenic with intervening varying length spacers extending from 2 to 15 A beyond biotin bound to streptavidin. Conceptually, the arsenical group can form a stable, covalent ring structure with appropriately spaced thiols and thereby anchor the reagent to a macromolecule, while biotin allows for the detection of the reagent-macromolecule complex via avidin binding. Because the alpha-subunits of all characterized nicotinic receptors contain an easily reducible disulfide bond between adjacent cysteine residues, the reduced alpha-subunit is an attractive site for labeling. Compounds 1-3 all simultaneously bound streptavidin and dithiols, and all three decreased the number of [125I]alpha-bungarotoxin-binding sites in reduced Torpedo nicotinic receptors (IC50s 10-300 nM). Moreover, arsenylation of the receptors prevented their reoxidation with dithio-bis(nitrobenzoic acid), was reversible with 2,3-dimercaptopropanesulfonic acid, and protected the receptor from irreversible alkylation by bromoacetylcholine. However, in no case did 1-3 allow simultaneous binding to reduced nicotinic receptors and to [125I]streptavidin, although 3 alone allowed simultaneous labeling of a spatially close dithiol located in reduced antibodies.
ESTHER : Moaddel_1999_Bioconjug.Chem_10_629
PubMedSearch : Moaddel_1999_Bioconjug.Chem_10_629
PubMedID: 10411461

Title : Effects of BN-50730 (PAF receptor antagonist) and physostigmine (AChE inhibitor) on learning and memory in mice - Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
Author(s) : Singh N , Sharma A , Singh M
Ref : Methods Find Exp Clin Pharmacol , 19 :585 , 1998
Abstract : The present study was designed to investigate the effect of BN-50730, a PAF receptor antagonist, on learning and memory in mice using elevated plus-maze and to delineate the role of acetylcholine in modulating the effect of PAF receptor antagonist on learning and memory. BN-50730 administered immediately after plus-maze training on day 1 induced retrograde amnesia as indicated by a dose-dependent increase in transfer latency (TL) measured on day 2 whereas no such increase in TL was noted when BN-50730 (2.5 mg/kg, i.p.) was administered prior to plus-maze training. Physostigmine (0.5 mg/kg; 1.0 mg/kg, i.p.) administered 30 min prior to plus-maze training attenuated BN-50730-induced increase in TL measured on day 2. These results suggest that BN-50730, a PAF receptor antagonist, produced retrograde amnesia and physostigmine attenuated BN-50730-induced amnesia possibly through increased concentration of cerebral acetylcholine and a consequent increase in PAF release.
ESTHER : Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
PubMedSearch : Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
PubMedID: 9500121

Title : Pharmacological basis of drug therapy of Alzheimer's disease - Sharma_1997_Indian.J.Exp.Biol_35_1146
Author(s) : Sharma A , Parikh V , Singh M
Ref : Indian J Exp Biol , 35 :1146 , 1997
Abstract : Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease patients. A considerable deficiency of cholinergic neurons is a consistent finding in Alzheimer's disease. Therefore, many therapeutic strategies to augment cerebral concentration of acetylcholine such as cholinergic precursors, cholinergic receptor agonists, cholinesterase inhibitors and acetylcholine release modulators have been evaluated in Alzheimer's disease. Although cholinesterase inhibitors such as tacrine and galanthamine offer modest clinical benefits, other cholinergic agents have proved to be of limited therapeutic value. Efforts to enhance monoaminergic neurotransmission have also been largely disappointing. Therefore, emphasis is not being put on the use of combination of two class of drugs. Moreover, use of therapeutic agents based on the putative pathogenic etiology of the disease such as excitotoxicity, amyloidosis, aluminium accumulation, inflammatory mechanisms and free radical production is being evaluated. Desferrioxamine, non-steroidal anti-inflammatory drugs, prednisone, dapsone, vitamin E and idebenone are some such agents that are currently under investigation for the preventive or palliative effect in Alzheimer's disease. Neurotrophic factors such as nerve growth factor, brain derived neurotrophic factor and epidermal growth factor have shown promising results in animal studies. However, novel methods for delivering these molecules into the brain required to be developed before launching their clinical trials in man.
ESTHER : Sharma_1997_Indian.J.Exp.Biol_35_1146
PubMedSearch : Sharma_1997_Indian.J.Exp.Biol_35_1146
PubMedID: 9567741