Browsing by Author "Sharma, Nisha"

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    Design and synthesis of non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of EGFR and their anti-cancer assessment
    (MDPI AG, 2021-03-09T00:00:00) Kumar, Manvendra; Joshi, Gaurav; Arora, Sahil; Singh, Tashvinder; Biswas, Sajal; Sharma, Nisha; Bhat, Zahid Rafiq; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, Raj
    A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 �M) as compared to gefitinib (IC50 > 20 �M). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported. Copyright: � 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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    In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice
    (MDPI, 2022-08-30T00:00:00) Bhat, Zahid Rafiq; Kumar, Manvendra; Sharma, Nisha; Yadav, Umesh Prasad; Singh, Tashvinder; Joshi, Gaurav; Pujala, Brahmam; Raja, Mohd; Chatterjee, Joydeep; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, Raj
    Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes. � 2022 by the authors.
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    L-Methionine supplementation attenuates high-fat fructose diet-induced non-alcoholic steatohepatitis by modulating lipid metabolism, fibrosis, and inflammation in rats
    (Royal Society of Chemistry, 2022-03-31T00:00:00) Navik, Umashanker; Sheth, Vaibhav G.; Sharma, Nisha; Tikoo, Kulbhushan
    Recently, the protective effects of a methionine-rich diet on hepatic oxidative stress and fibrosis have been suggested but not adequately studied. We, therefore, hypothesized that l-methionine supplementation would ameliorate the progression of hepatic injury in a diet-induced non-alcoholic steatohepatitis (NASH) model and aimed to investigate the underlying mechanism. NASH was developed in male Sprague Dawley rats by feeding them with a high-fat-fructose diet (HFFrD) for 10 weeks. The results demonstrated that l-methionine supplementation to NASH rats for 16 weeks improved the glycemic, lipid, and liver function profiles in NASH rats. Histological analysis of liver tissue revealed a remarkable improvement in the three classical lesions of NASH: steatosis, inflammation, and ballooning. Besides, l-methionine supplementation ameliorated the HFFrD-induced enhanced lipogenesis and lipid peroxidation. An anti-inflammatory effect of l-methionine was also observed through the inhibition of the release of proinflammatory cytokines. Furthermore, the hepatic SIRT1/AMPK signaling pathway was associated with the beneficial effects of l-methionine. This study demonstrates that l-methionine supplementation in HFFrD-fed rats improves their liver pathology via regulation of lipogenesis, inflammation, and the SIRT1/AMPK pathway, thus encouraging its clinical evaluation for the treatment of NASH. � 2022 The Royal Society of Chemistry.
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    Mechanosensory stimulation via nanchung expressing neurons can induce daytime sleep in drosophila
    (Society for Neuroscience, 2021-10-11T00:00:00) Lone, Shahnaz Rahman; Potdar, Sheetal; Venkataraman, Archana; Sharma, Nisha; Kulkarni, Rutvij; Rao, Sushma; Mishra, Sukriti; Sheeba, Vasu; Sharma, Vijay Kumar
    The neuronal and genetic bases of sleep, a phenomenon considered crucial for well-being of organisms, has been under investigation using the model organism Drosophila melanogaster. Although sleep is a state where sensory threshold for arousal is greater, it is known that certain kinds of repetitive sensory stimuli, such as rocking, can indeed promote sleep in humans. Here we report that orbital motion-aided mechanosensory stimulation promotes sleep of male and female Drosophila, independent of the circadian clock, but controlled by the homeostatic system. Mechanosensory receptor nanchung (Nan)-expressing neurons in the chordotonal organs mediate this sleep induction: flies in which these neurons are either silenced or ablated display significantly reduced sleep induction on mechanosensory stimulation. Transient activation of the Nan-expressing neurons also enhances sleep levels, confirming the role of these neurons in sleep induction. We also reveal that certain regions of the antennal mechanosensory and motor center in the brain are involved in conveying information from the mechanosensory structures to the sleep centers. Thus, we show, for the first time, that a circadian clock-independent pathway originating from peripherally distributed mechanosensors can promote daytime sleep of flies Drosophila melanogaster. Copyright � 2021 the authors
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    Peculiar sleep features in sympatric species may contribute to the temporal segregation
    (Springer Science and Business Media Deutschland GmbH, 2022-10-22T00:00:00) Mishra, Sukriti; Sharma, Nisha; Singh, Sunil Kumar; Lone, Shahnaz Rahman
    Sleep is conserved in the animal kingdom and plays a pivotal role in the adaptation of species. Sleep in Drosophila melanogaster is defined as any continuous 5 min of quiescence, shows a�prominent siesta, and consolidated nighttime sleep. Here, we analyzed the sleep of�two other species D. malerkotliana�(DMK) and�D. ananassae�(DA), and compared it with�D. melanogaster�(DM). The DMK males and females have siesta like DM. However, unlike DM, flies continue to sleep beyond siesta till the evening. DA has a less prominent siesta compared to DM and DMK. In the morning, DA took a longer time to respond to the lights ON and continued to sleep for at least half an hour. The nighttime sleep of the DA flies is higher than the other two species. Average length of sleep episode is three times more than that of DM and DMK with few wake episodes. Thus, the nighttime sleep of DA�males and females is deep and needs exposure to more potent stimuli to wake up relative to the other two species. DA�males and females show higher sleep rebound than the other two species, suggesting the robustness of sleep homeostasis. Although total sleep of DMK and DA is similar, DA is a day-active species with highly consolidated night sleep. DMK, like DM, is a crepuscular species with a midday siesta.�Thus, our results suggest that temporal partitioning of sleep, in sympatric species may contribute to temporal segregation. � 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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    Understanding the impact of sociosexual interactions on sleep using Drosophila melanogaster as a model organism
    (Frontiers Media SA, 2023-08-21T00:00:00) Mishra, Sukriti; Sharma, Nisha; Lone, Shahnaz Rahman
    Sleep is conserved across species, and it is believed that a fixed amount of sleep is needed for normal neurobiological functions. Sleep rebound follows sleep deprivation; however, continuous sleep deprivation for longer durations is believed to be detrimental to the animal�s wellbeing. Under some physiologically demanding situations, such as migration in birds, the birth of new offspring in cetaceans, and sexual interactions in pectoral sandpipers, animals are known to forgo sleep. The mechanisms by which animals forgo sleep without having any obvious negative impact on the proper functioning of their neurobiological processes are yet unknown. Therefore, a simple assay is needed to study how animals forgo sleep. The assay should be ecologically relevant so it can offer insights into the physiology of the organisms. Equally important is that the organism should be genetically amenable, which helps in understanding the cellular and molecular processes that govern such behaviors. This paper presents a simple method of sociosexual interaction to understand the process by which animals forgo sleep. In the case of Drosophila melanogaster, when males and females are in proximity, they are highly active and lose a significant amount of sleep. In addition, there is no sleep rebound afterward, and instead, males engaged in sexual interactions continue to show normal sleep. Thus, sexual drive in the fruit flies is a robust assay to understand the underlying mechanism by which animals forgo sleep. Copyright � 2023 Mishra, Sharma and Lone.