Browsing by Author "Prashar, Vikash"

Now showing 1 - 8 of 8
  • No Thumbnail Available
    Item
    Comparative genomic and network analysis of nNOS by using different bioinformatics approaches
    (Bentham Science Publishers, 2021-06-17T00:00:00) Arora, Nymphaea; Prashar, Vikash; Arora, Tania; Singh, Randeep; Mishra, Anshul; Godara, Priya; Banerjee, Arpita; Sharma, Arti; Parkash, Jyoti
    Introduction: Nitric Oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis (growth of new blood vessels) and development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms, including nNOS (neuronal NOS), eNOS (endothelial NOS) and iNOS (inducible NOS). NOS1 is localized on chromosome 12 consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles and penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases. Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as physiological inter/intra-cellular messenger in central as well as peripheral nervous systems. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in brain, it is involved in differentiation, development, synaptic plasticity and neurosecretion. Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as therapeutic target in various neurodegenerative disorders that can surely provide ways to regulate its activity in different aspects. Materials and Methods: In this study, we employed various bioinformatics tools and databases initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence (GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post translational modifications, enhancing the research by network analysis (STRING), leading to its functional enrichment (Panther). Results: The results positively support the hypothesis of its role in various pathways related to neurodegeneration and its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered evolutionary trend of physical, chemical and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research. � 2021 Bentham Science Publishers.
  • No Thumbnail Available
    Item
    The Comparative Genomics and Network Analysis of eNOS by Using Different Bioinformatics Approaches
    (Bentham Science Publishers, 2023-01-27T00:00:00) Banerjee, Arpita; Singh, Randeep; Arora, Nymphaea; Arora, Tania; Prashar, Vikash; Godara, Priya; Sharma, Arti; Changotra, Harish; Parkash, Jyoti
    Background: Nitric oxide synthase (NOS) is an enzyme that catalyzes the synthesis of nitric oxide (NO) from L-arginine. It has three isoforms-(i) neuronal NOS (nNOS or NOS1), which participates in neural transmission; (ii) inducible NOS (iNOS or NOS2), which produces NO in macrophages; and (iii) endothelial NOS (eNOS or NOS3) that regulates blood pressure. The eNOS is mainly expressed in blood vessels and is a crucial regulator of endothelial homeostasis. Objective: The present study aimed to unravel the role of eNOS in different signaling pathways and its involvement as a therapeutic target in various neurodegenerative disorders. Methods: This study used various in silico methods for comprehensive genomic analysis of eNOS in 16 organisms from 7 different phyla. Prediction of conserved domains and evolutionary relationship for eNOS among 16 organisms was made. Various physical and chemical parameters, signal peptides, and transmembrane regions that helped understand its functional relevance were also studied. Results: Three transcription factor binding sites (TFBS), i.e., CP2, AR, and LDSPOLYA, were identified in human eNOS, while ATF1, T3R, and STAT1 were predicted in mouse eNOS. Transcription factors were identified for each regulatory region in human as well as mouse eNOS. eNOS protein was predicted to harbor 14 different post-translational modification (PTM) sites, most of which have phosphorylation (serine followed by threonine and tyrosine phosphorylation) followed by sumoylation and palmitoylation among all the organisms used in the current study. However, human eNOS has a relatively lower number of PTM sites for tyrosine phosphorylation. Conclusion: Structures of eNOS isoform, consistent with available biochemical and structural data, provide substantial insight into the NOS conformational changes, which give in-depth knowledge of the mechanism of eNOS, and will be helpful for better understanding the role of eNOS in pathophysiology. � 2023 Bentham Science Publishers.
  • No Thumbnail Available
    Item
    Design, Synthesis, and Pharmacological Evaluation of N-Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease
    (American Chemical Society, 2022-07-07T00:00:00) Kumar, Bhupinder; Dwivedi, Ashish Ranjan; Arora, Tania; Raj, Khadga; Prashar, Vikash; Kumar, Vijay; Singh, Shamsher; Prakash, Jyoti; Kumar, Vinod
    Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50value of 0.04 � 0.002 ?M. VP15 with an IC50value of 0.04 � 0.003 ?M and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15�HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD. � 2022 American Chemical Society. All rights reserved.
  • No Thumbnail Available
    Item
    Dysregulated miRNAs in Progression and Pathogenesis of Alzheimer�s Disease
    (Springer, 2022-07-22T00:00:00) Arora, Tania; Prashar, Vikash; Singh, Randeep; Barwal, Tushar Singh; Changotra, Harish; Sharma, Arti; Parkash, Jyoti
    Alzheimer�s disease (AD) is a progressive degeneration of neurons due to the accumulation of amyloid-? peptide (A?) and hyper-phosphorylation of tau protein in the neuronal milieu leading to increased oxidative stress and apoptosis. Numerous factors contribute towards the progression of AD, including miRNA, which are 22�24 nucleotides long sequence which acts as critical regulators of cellular processes by binding to 3? UTR of mRNA, regulating its expression post-transcriptionally. This review aims to determine the miRNA with the most significant dysregulation in the brain and cerebrospinal fluid (CSF) of human patients. A systemized inclusion/exclusion criterion has been utilized based on selected keywords followed by screening of those articles to conclude a list of 8 highly dysregulated miRNAs based on the fold change of AD vs control patients, which could be used in clinical testing as these miRNAs play central role in the pathophysiology of AD. Furthermore, a network study of highly dysregulated miRNA estimated the association of these miRNA in the mediation of A? generation and aggregation, inhibition of autophagy, reduction of A? clearance, microglial and astrocytic activation, neuro-inflammation, tau hyper-phosphorylation, and synaptic loss. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
  • No Thumbnail Available
    Item
    Hypothalamic Kisspeptin Neurons: Integral Elements of the GnRH System
    (Institute for Ionics, 2022-07-07T00:00:00) Prashar, Vikash; Arora, Tania; Singh, Randeep; Sharma, Arti; Parkash, Jyoti
    Highly sophisticated and synchronized interactions of various cells and hormonal signals are required to make organisms competent for reproduction. GnRH neurons act as a common pathway for multiple cues for the onset of puberty and attaining reproductive function. GnRH is not directly receptive to most of the signals required for the GnRH secretion during the various phases of the ovarian cycle. Kisspeptin neurons of the hypothalamus convey these signals required for the synchronized release of the GnRH. The steroid-sensitive anteroventral periventricular nucleus (AVPV) kisspeptin and arcuate nucleus (ARC) KNDy neurons convey steroid feedback during the reproductive cycle necessary for GnRH surge and pulse, respectively. AVPV region kisspeptin neurons also communicate with nNOS synthesizing neurons and suprachiasmatic nucleus (SCN) neurons to coordinate the process of the ovarian cycle. Neurokinin B (NKB) and dynorphin play roles in the GnRH pulse stimulation and inhibition, respectively. The loss of NKB and kisspeptin function results in the development of neuroendocrine disorders such as hypogonadotropic hypogonadism (HH) and infertility. Ca2+ signaling is essential for GnRH pulse generation, which is propagated through gap junctions between astrocytes-KNDy and KNDy-KNDy neurons. Impaired functioning of KNDy neurons could develop the characteristics associated with polycystic ovarian syndrome (PCOS) in rodents. Kisspeptin-increased synthesis led to excessive secretion of the LH associated with PCOS. This review provides the latest insights and understanding into the role of the KNDy and AVPV/POA kisspeptin neurons in GnRH secretion and PCOS. � 2022, Society for Reproductive Investigation.
  • No Thumbnail Available
    Item
    Interplay of KNDy and nNOS neurons: A new possible mechanism of GnRH secretion in the adult brain
    (Elsevier Sp. z o.o., 2021-09-09T00:00:00) Prashar, Vikash; Arora, Tania; Singh, Randeep; Sharma, Arti; Parkash, Jyoti
    Reproduction in mammals is favoured when there is sufficient energy available to permit the survival of offspring. Neuronal nitric oxide synthase expressing neurons produce nitric oxide in the proximity of the gonadotropin-releasing hormone neurons in the preoptic region. nNOS neurons are an integral part of the neuronal network controlling ovarian cyclicity and ovulation. Nitric oxide can directly regulate the activity of the GnRH neurons and play a vital role neuroendocrine axis. Kisspeptin neurons are essential for the GnRH pulse and surge generation. The anteroventral periventricular nucleus (AVPV), kisspeptin neurons are essential for GnRH surge generation. KNDy neurons are present in the hypothalamus's arcuate nucleus (ARC), co-express NKB and dynorphin, essential for GnRH pulse generation. Kisspeptin-neurokinin B-dynorphin (KNDy) neuroendocrine molecules of the hypothalamus are key components in the central control of GnRH secretion. The hypothalamic neurons kisspeptin, KNDy, nitric oxide synthase (NOS), and other mediators such as leptin, adiponectin, and ghrelin, play an active role in attaining puberty. Kisspeptin signalling is mediated by NOS, which further results in the secretion of GnRH. Neuronal nitric oxide is critical for attaining puberty, but its direct role in adult GnRH secretion is poorly understood. This review mainly focuses on the role of nNOS and its interplay with KNDy neurons in the hormonal regulation of reproduction. � 2021
  • No Thumbnail Available
    Item
    Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies
    (Royal Society of Chemistry, 2022-04-05T00:00:00) Dwivedi, Ashish Ranjan; Kumar, Vijay; Prashar, Vikash; Verma, Akash; Kumar, Naveen; Parkash, Jyoti; Kumar, Vinod
    A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 ?M and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 � 0.27 ?M, 6.44 � 0.29 ?M and 9.54 � 0.15 ?M against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 � 0.67 ?M, 3.15 � 0.23 ?M and 3.36 � 0.29 ?M against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules. � 2022 RSC
  • No Thumbnail Available
    Item
    Tinospora cordifolia: a potential neuroprotective agent against various neurodegenerative diseases
    (Elsevier GmbH, 2023-09-19T00:00:00) Singh, Randeep; Bhattacharyya, Chinmoyee; Prashar, Vikash; Arora, Tania; Sharma, Arti; Changotra, Harish; Parkash, Jyoti
    Introduction: Neurodegenerative diseases negatively affect the various neuronal populations of the central nervous system (CNS). Moreover, conventional treatment strategies are inefficient and have considerable side effects. Since Ayurveda has always been considered an effective alternative to synthetic drugs, Tinospora cordifolia, an age-old renowned herb in Ayurveda with great medicinal importance, is drawing the attention of researchers. The effect of the crude extract of T. cordifolia and its constituents in alleviating neurodegenerative diseases has been reported previously and recently. Methods: This study followed thorough research on scientific databases like PubMed, Google Scholar, and ScienceDirect regarding the practical implications of T. cordifolia extracts and compounds in alleviating neurodegeneration. Various search terms like �neurodegenerative diseases�, �T. cordifolia and neurodegeneration�, �signalling mechanisms of neurodegeneration�, and �neuroprotective effect of T. cordifolia� have been used. Results: Several in vitro studies have suggested that T. cordifolia extracts and compounds can improve memory, cognition, and learning deteriorated by various neurodegenerative diseases. They also enhance the potential of the antioxidant system by restoring Glutathione (GSH) and Superoxide dismutase (SOD) levels and scavenging the free radicals that cause neuronal oxidative stress and neurodegeneration. Conclusion: This review article summarises the various aspects of T. cordifolia against different neurodegenerative diseases and its future potential therapeutic values. It also emphasises the need to investigate other compounds present in T. cordifolia. Limitations and future prospects: Exploring anti-oxidative, anti-inflammatory, and neuroprotective properties proved T. cordifolia to be a life saviour. Despite this, extensive clinical and pharmacological studies are required to evaluate the precise dosage and formulation of its constituents. � 2023 Elsevier GmbH