Browsing by Author "Parkash, Jyoti"

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4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease
(American Chemical Society, 2019) Kumar, B; Dwivedi, A.R; Sarkar, B; Gupta, S.K; Krishnamurthy, S; Mantha, Anil K; Parkash, Jyoti; Kumar, Vinod
Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC 50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC 50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC 50 value of 9.54 ± 0.07 nM and displayed an IC 50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H 2 O 2 -induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease. © 2018 American Chemical Society.
Association of IRGM gene promoter polymorphisms with hepatitis B virus infection
(John Wiley and Sons Inc, 2022-06-04T00:00:00) Sharma, Ambika; Duseja, Ajay; Parkash, Jyoti; Changotra, Harish
Background: In response to intracellular pathogens, the autophagy gene IRGM plays an essential role in the innate immune response. Various identified IRGM gene risk loci are associated with several diseases but, so far, no study is available that shows the association of IRGM with hepatitis B virus (HBV) infection. Methods: We genotyped promoter variants (rs4958842, rs4958843, and rs4958846) of IRGM in HBV infected patients (551) and healthy controls (247) for their role in HBV infection. The genotyping was performed by applying methods developed in our laboratory and various biochemical parameters were assessed applying commercially available kits. Results: Data analysis has shown that the mutant allele A of rs4958842 plays a role in the protection from HBV infection in various genetic models that includes allelic, co-dominant and dominant models with the respective statistical data: allelic (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.48�0.78; p = 0.0003), co-dominant (OR = 0.52; 95% CI = 0.38�0.71; p = 0.0008) and dominant (OR = 0.51; 95% CI = 0.38�0.70, p = 0.0004). In chronic hepatitis B (CHB), protective association was observed in the allelic (OR = 0.48; 95% CI = 0.35�0.65, p = 0.0004), co-dominant (OR = 0.38; 95% CI = 0.26�0.54, p = 0.0004) and dominant (OR = 0.38; 95% CI = 0.26�0.54, p = 0.0002) models. Mutant allele C of rs49598843 was associated with the risk of CHB in co-dominant (OR = 1.52; 95% CI = 1.07�2.16, p = 0.04) and dominant (OR = 1.41; 95% CI = 1.00�2.00, p = 0.04) models. The mutant allele C of rs4958846 decreased the risk of HBV infection in allelic (OR = 0.74; 95% CI = 0.59�0.92, p = 0.01), dominant (OR = 0.72; 95% CI = 0.53�0.98, p = 0.05), homozygous (OR = 0.42; 95% CI = 0.24�0.74, p = 0.01) and recessive (OR = 0.42; 95% CI = 0.24�0.74, p = 0.0004) models. However, in the asymptomatic group, it was associated with the increased chance of HBV infection. Haplotypes, ATT (OR = 0.47; 95% CI = 0.33�0.68, p = 0.001) and GTC (OR = 0.68; 95% CI = 0.51�0.92, p = 0.01) protect, whereas GTT (OR = 2.01; 95% CI = 1.55�2.60, p < 0.0001) predisposes the individuals to HBV infection. All of these p�values mentioned here were obtained after performing Bonferroni correction. Conclusions: In conclusion, our findings revealed that mutant allele A of rs4958842, mutant allele C of rs4958843 and rs4958846 were associated with hepatitis B virus infection in the North Indian population. � 2022 John Wiley & Sons Ltd.
ATG5: A central autophagy regulator implicated in various human diseases
(John Wiley and Sons Ltd, 2022-09-05T00:00:00) Changotra, Harish; Kaur, Sargeet; Yadav, Suresh Singh; Gupta, Girdhari Lal; Parkash, Jyoti; Duseja, Ajay
Autophagy, an intracellular conserved degradative process, plays a central role in the renewal/recycling of a cell to maintain the homeostasis of nutrients and energy within the cell. ATG5, a key component of autophagy, regulates the formation of the autophagosome, a hallmark of autophagy. ATG5 binds with ATG12 and ATG16L1 resulting in E3 like ligase complex, which is necessary for autophagosome expansion. Available data suggest that ATG5 is indispensable for autophagy and has an imperative role in several essential biological processes. Moreover, ATG5 has also been demonstrated to possess autophagy-independent functions that magnify its significance and therapeutic potential. ATG5 interacts with various molecules for the execution of different processes implicated during physiological and pathological conditions. Furthermore, ATG5 genetic variants are associated with various ailments. This review discusses various autophagy-dependent and autophagy-independent roles of ATG5, highlights its various deleterious genetic variants reported until now, and various studies supporting it as a potential drug target. � 2022 John Wiley & Sons Ltd.
A bioinformatics approach to solving the puzzle of autoimmune diseases
(Inderscience Publishers, 2022-12-13T00:00:00) Chatterjee, Durbadal; Parkash, Jyoti; Sharma, Arti
Autoimmune diseases are conditions in which the body attacks its own cells. In our study, we have taken eight autoimmune diseases, which are Addison�s disease, Graves� disease, Hashimoto�s thyroiditis, myasthenia gravis, psoriatic arthritis, pernicious anaemia, systematic lupus erythematosus and vasculitis. The pathways associated with these diseases are yet to be found. The underlying genes associated with each disease were predicted from the NCBI database. The mutual genes among these diseases have been identified. The digital gene expression of each gene has been anticipated. There are 668 genes associated with these eight diseases, and PTPN22 is identified as a mutual gene among seven out of the eight diseases. Most genes are involved in pathways related to the immune system, signal transduction and metabolism. All genes are expressed in the normal body condition, but in the case of disease, some genes are silenced, some show expression level changes in the diseased phenotypes and some genes have shown mutations but no expression change is reported, which leaves a question for further research. Copyright � 2022 Inderscience Enterprises Ltd.
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.
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.
Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase
(Elsevier, 2019) Kumar, Bhupinder; Kumar, V; Prashar, V; Saini, S; Dwivedi, A.R; Bajaj, B; Mehta, D; Parkash, Jyoti; Kumar, Vinod
Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ± 0.09 μM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ± 0.03 μM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug. © 2019
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.
Efficient synthesis and mechanistic insights for the formation of imidazo[1,2-a]pyridines via multicomponent decarboxylative coupling using chitosan-supported copper catalysts
(Elsevier B.V., 2023-10-03T00:00:00) Kaur, Pavneet; Gurjar, Kamlesh K.; Arora, Tania; Bharti, Divya; Kaur, Manpreet; Kumar, Vinod; Parkash, Jyoti; Kumar, Rakesh
An efficient multicomponent decarboxylative coupling of 2-aminopyridines, aldehydes and alkynoic acids for the synthesis of imidazo[1,2-a]pyridines was developed using recyclable chitosan-supported copper (chit@CuSO4) as a heterogeneous catalyst. Computational and experimental evidence revealed that in situ generated propargylamine undergoes cyclization to the desired imidazopyridine via prototropic isomerization involving allene type intermediates. Control experiments on isolated propargylamine demonstrated that cyclization could proceed without any metal catalyst. In literature, the cyclization step is assumed to be facilitated by metal catalyst and experimental proof for the involvement of actual intermediates is not available. The synthesized imidazopyridines were further evaluated for antiproliferative activity against human neuroblastoma cells (SHSY-5Y) using MTT assay. � 2023 Elsevier B.V.
Gametogenic and steroidogenic action of kisspeptin-10 in the Asian catfish, Clarias batrachus: Putative underlying mechanistic cascade
(Elsevier Inc., 2021-06-28T00:00:00) Singh, Ankur; Lal, Bechan; Parkash, Jyoti; Millar, Robert P.
Unlike mammals, two kisspeptins genes encoding, kiss1 and kiss2 are detected in fishes with highly varied and contradictory difference in their reproductive activities. The present study was undertaken to examine the direct action of kisspeptin-10 and its role in gonadal activities in the gonadally quiescent Asian catfish using native mammalian kisspeptin decapeptide (KP-10) involving in vivo and in vitro approaches. The in vivo KP-10 treatment caused precocious onset of gametogenesis and its rapid progression, as was evident from the appearance of advanced stages of ovarian follicles in ovary, and advanced germ cells (spermatocytes/ spermatids) in the testis of the treated Clarias batrachus in comparison to the control gonads. It also elevated the steroid levels in gonads of the catfish in vivo and in vitro conditions. Simultaneously, it increased the expressions of key steroidogenic enzymes like 3?-HSD, 17?-HSD, and StAR protein, responsible for transfer of cholesterol from outer to inner membrane of the mitochondria of steroidogenic cells. Concurrently, it augmented the activities of 3?-HSD and 17?-HSD in the ovarian explants. The expressions of MAPK component (pERK1/2 and ERK1/2) were also up-regulated by KP-10 in gonadal explants. Thus, the data suggest that kisspeptin-10 stimulates gametogenesis by enhancing gonadal steroid production. The study also describes the putative mechanistic cascade of steroidogenic actions of kisspeptin-10 in the catfish so much so in teleost fish. The study also suggests that, kisspeptin may act locally to regulate gonadal activities in an autocrine/paracine manner, independent of known extra-gonadal factors in the catfish. � 2021 Elsevier Inc.
Hormones of hypothalamus and ageing
(Springer, 2018) Kaur, Gurcharan; Parkash, Jyoti
Hypothalamus being the master regulator of the vertebrate endocrine system undergoes many adjustments/alterations which body makes during the course of aging. Moreover, the endocrinological basis of aging in male and female organisms is very complex, with multiple hormones along the hypothalamic-pituitary (HP) axis interacting with each other via different feedback loops to maintain homeodynamic state. Also the sensitivity of the hypothalamus to the external stimuli decreases with age mainly due to its lack of sensitivity towards the feedback system The endocrine system is although severely affected by aging but all the organ systems are not affected at the same time or in the same way. During aging cellular protein synthesis machinery as well as immune functions are diminished and gradually physiological functions decline. There is also an increase in fat mass, a loss of muscle mass and strength, and a decrease in bone mineral density profile that contribute to declining health status with increasing age. The hallmarks of aging such as Genomic instability, Telomere attrition, Epigenetic alterations, Loss of proteostasis, Dysregulated Nutrient Sensing, Mitochondrial dysfunction, Altered intracellular communication, Cellular senescence etc. are well reported in literature. In this chapter we have compiled information and discussed various hormonal changes that occur with age in hypothalamus and pituitary gland and how these two master regulators gradually lose their sensitivity with the increasing age.
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.
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
Investigating regulatory signatures of human autophagy related gene 5 (ATG5) through functional in silico analysis
(Elsevier B.V., 2016) Vij, Avni; Randhawa, Rohit; Parkash, Jyoti; Changotra, Harish; Vij, A.; Randhawa, R.; Parkash, J.; Changotra, H.
Autophagy is an essential, homeostatic process which removes damaged cellular proteins and organelles for cellular renewal. ATG5, a part of E3 ubiquitin ligase-like complex (Atg12-Atg5/Atg16L1), is a key regulator involved in autophagosome formation - a crucial phase of autophagy. In this study, we used different in silico methods for comprehensive analysis of ATG5 to investigate its less explored regulatory activity. We have predicted various physico-chemical parameters and two possible transmembrane models that helped in exposing its functional regions. Twenty four PTM sites and 44 TFBS were identified which could be targeted to modulate the autophagy pathway. Furthermore, LD analysis identified 3 blocks of genotyped SNPs and 2 deleterious nsSNPs that may have damaging impact on protein function and thus could be employed for carrying genome-wide association studies. In conclusion, the information obtained in this study could be helpful for better understanding of regulatory roles of ATG5 and provides a base for its implication in population-based studies. ? 2016 Elsevier B.V.
A microRNA switch regulates the rise in hypothalamic GnRH production before puberty
(Nature Publishing Group, 2016) Messina, Andrea; Langlet, Fanny; Chachlaki, Konstantina; Roa, Juan; Rasika, Sowmyalakshmi; Jouy, Nathalie; Gallet, Sarah; Gaytan, Francisco; Parkash, Jyoti; Tena-Sempere, Manuel; Giacobini, Paolo; Prevot, Vincent; Messina, A.; Langlet, F.; Chachlaki, K.; Roa, J.; Rasika, S.; Jouy, N.; Gallet, S.; Gaytan, F.; Parkash, J.; Tena-Sempere, M.; Giacobini, P.; Prevot, V.
A sparse population of a few hundred primarily hypothalamic neurons forms the hub of a complex neuroglial network that controls reproduction in mammals by secreting the 'master molecule' gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH expression are essential for puberty and adult fertility. Here we report that a multilayered microRNA-operated switch with built-in feedback governs increased GnRH expression during the infantile-to-juvenile transition and that impairing microRNA synthesis in GnRH neurons leads to hypogonadotropic hypogonadism and infertility in mice. Two essential components of this switch, miR-200 and miR-155, respectively regulate Zeb1, a repressor of Gnrh transcriptional activators and Gnrh itself, and Cebpb, a nitric oxide-mediated repressor of Gnrh that acts both directly and through Zeb1, in GnRH neurons. This alteration in the delicate balance between inductive and repressive signals induces the normal GnRH-fuelled run-up to correct puberty initiation, and interfering with this process disrupts the neuroendocrine control of reproduction. ? 2016 Nature Publishing Group. All rights reserved.
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
Nanotoxicology: Toxicity Evaluation, Risk Assessment and Management
(CRC Press Taylor and Francis group, 2018) Parkash, Jyoti; Sharma, Arti; Jairath, Ankur
Nanoparticles have an interesting surface chemistry and are used in a wide variety of applications ranging from consumer products like socks, medical dressings, and computer chips. They have also been shown antimicrobial, anti-bacterial activity and wound healing properties. The small size of the particles makes nanotechnology so useful for the drug delivery system, but this small size is also one of the main factors that make them a potential threat to human health. Nanomedicines have played a very important role in the field of diagnosis and therapy in the past decade and still continue to be an important element of success in the field of medicine. The effect of nanoparticles on the proliferation and differentiation of stem cells has been studied under regeneration medicine and material science. However, advances in nanotechnology innovation related to stem cell biology and cell reprogramming remain less progressive. It is very crucial to study the cell-nanoparticle interactions in depth to eradicate any negative effects of the nanoparticles. The cellular toxicity of nanoparticles has been extensively studied in Mesenchymal-epithelial stem cells (mESCs) and human mesenchymal stem cells (hMSCs). Investigations purporting to study the toxicity of metal particulates are still in their infancy at this time and have concentrated on revealing the toxicity, tissue distribution, and antibacterial properties of metallic nanoparticles, and in addition the tissue distribution and cellular uptake of gold nanoparticles. Therefore, more study is needed to understand the role of these nanoparticles on human health.
Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors
(Nature Publishing Group, 2017) Jongbloets, Bart C.; Lemstra, Suzanne; Schellino, Roberta; Broekhoven, Mark H.; Parkash, Jyoti; Hellemons, Anita J.C.G.M.; Mao, Tianyi; Giocobini, Paolo; Praag, Henriette Van; Marchis, Silvia De; Ramakers, Geert M.J.; Pasterkamp, R. Jeroen; Jongbloets, B.C.; Lemstra, S.; Schellino, R.; Broekhoven, M.H.; Parkash, J.; Hellemons, A.J.C.G.M.; Mao, T.; Giacobini, P.; Van Praag, H.; De Marchis, S.; Ramakers, G.M.J.; Pasterkamp, R.J.
The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through ?1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain.
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
To check the glioprotective effect of Withaferin A on C6 Glioma cell Culture challenged with Kainic Acid
(Central University of Punjab, 2018) Dash, Bindu Balaya; Parkash, Jyoti
Last many years perception of glial cell function in CNS has been changed. In fact abnormalities in glial cells also contribute to various disorders. Glutamate induced excitotoxicity attributed to various CNS related diseases. Kainic acid is a potent agonist of kainate receptors, a subclass of glutamate receptors, is 30 fold more neurotoxic than glutamate. Natural herbal extracts are attracting researchers for their pharmacologic properties against diseases associated with CNS. Root and leaf extracts of Withania somnifera, used since many years to treat several diseases in traditional medicine system. Present study was designed to see the glioprotective potential of Withaferin A, a natural extract from Withania somnifera or Ashwagandha, against Kainic acid induced excitotoxicity in C6 glioma cell line. Pretreatment of 0.5 µM Withaferin A showed defensive potential against 100 µM and 200 µM concentration of Kainic acid. To check expression of GFAP (well known marker of astrocytes) and NCAM, Immunocytochemistry was performed. Withaferin A treatment helps in normalizing of GFAP (Glial Fibrillary Acidic Protein) and NCAM (Neural Cell Adhesion Molecule) expression in kainic acid exposed cells. Our result suggested that Withaferin A have defensive potential against kainic acid induced excitotoxicity. As a potent glioprotective agent, Withaferin A could be used as therapeutic drug to treat glioblastomas and other neurological disorders.