Browsing by Author "Upadhyay, Shishir"

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    Design, synthesis and biological evaluation of novel indole-xanthendione hybrids as selective estrogen receptor modulators
    (Elsevier Ltd, 2018) Singla, Ramit; Gupt,a Kunj Bihari; Upadhyay, Shishir; Dhiman Monisha; Jaitak Vikas
    Ground breaking clinical therapeutic advances in the treatment of breast cancer (BC) is the introduction of selective estrogen receptor modulators (SERMs). We have expeditiously designed and synthesized indole-xanthendione hybrids by coalescing the indole nucleus with xanthendione. All the compounds were first screened for anti-proliferative activity, cytotoxicity and ER-? binding affinity by utilizing ER-? dominant T47D BC cell lines, PBMCs and ER-? competitor assay kit. From this study, two representative compounds 6e and 6f showing most promising activity were advanced for gene expression studies for targeting ER-?. Cell imaging experiment undoubtedly indicate that both the compounds were able to cross cellular bio membrane and accumulate thus instigating cytotoxicity. RT-PCR and Western blotting experiments further strengthened that both compounds altered the expression of mRNA and receptor protein of ER-?, thereby forestalling downstream transactivation and signalling pathway in T47D cells line. Structural investigation from induced fit simulation study suggest that indole moiety of the compounds 6e and 6f helps in the anchoring of the xanthendione moiety in the hydrophobic region of the cavity thus enabling the compound to bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these finding collectively imply that compound 6e and 6f represents a novel potent ER-? antagonist and in the development of SERMs for the management of BC.
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    Identification of novel indole based heterocycles as selective estrogen receptor modulator
    (Academic Press Inc., 2018) Singla, Ramit; Prakash, Kunal; Bihari Gupta, Kunj; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas
    In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-? competitor assay kit by utilizing estrogen receptor-? (ER-?) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-? thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-? antagonists and may be used in the development of chemotherapy for the management of BC. ? 2018 Elsevier Inc.
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    Identification of novel indole based heterocycles as selective estrogen receptor modulator.
    (Elsevier, 2018) Singla, Ramit; Prakash, Kunal; Gupta Kunj Bihari; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas
    In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5cand 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC.
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    Methods to Detect Nitric Oxide and Reactive Nitrogen Species in Biological Sample
    (Humana Press Inc., 2022-01-19T00:00:00) Kaur, Sharanjot; Gupta, Kunj Bihari; Kumar, Sandeep; Upadhyay, Shishir; Mantha, Anil Kumar; Dhiman, Monisha
    Oxidative stress has been implicated in various human diseases, including cancer, mainly through the generation of reactive nitrogen species (RNS), such as nitric oxide (NO), nitrite, nitroxyl, s-nitrosothiols, and reactive oxygen species (ROS) such as peroxides, superoxide, and hydroxyl radicals. NO being the main player among RNS induced altered cellular molecules and metabolisms, thus making it important to understand and detect the generation of NO in biological samples. There are many methods for direct and indirect detection of NO; out of these most commonly used are spectrophotometric-based Griess assay and fluorescence probe-based assays. In this chapter, we summarize these routinely used methods to detect NO and various challenges associated with these methods. � 2022, Springer Science+Business Media, LLC, part of Springer Nature.
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    Oxidative stress and inflammation in cardiovascular diseases: Two sides of the same coin
    (Springer India, 2015) Dhiman, Monisha; Thakur, Shweta; Upadhyay, Shishir; Kaur, Amandeep; Mantha, Anil K.
    Globally, the major cause of long- term disability and death is an ?epidemiologic transition? from infectious diseases and malnutrition complications to non-communicable chronic diseases like cardiovascular disease (CVD), cancer and diabetes. CVD accounts for major global mortality. Imbalance due to the generation of reactive oxygen species (ROS) levels above normal baseline levels and decreased antioxidant defence reserve makes the cardiovascular system (cardiac and vascular cells) susceptible to oxidative stress and damage. Growing evidences support the notion that oxidative stress plays a crucial role in the development and progression of CVD by altering normal functions such as inactivation of nitric oxide (NO) leading to endothelial dysfunction, intracellular Ca2+overload and others. Oxidative stress also mediates inflammation through various signalling cascades such as the activation of inflammatory transcription factors (TFs) namely NF-?B, AP-1 and Nrf-1. A vicious cycle of oxidative stress-mediated inflammation and inflammation- induced oxidative stress makes the CVD-related complications worse. Therefore, it is also very important to clearly understand the role of enzymatic sources of RO mechanisms underlying pathological conditions and link between oxidative stress and inflammation during each stage of CVD. The present chapter will elucidate the role of oxidative stress and inflammation in CVD development and progression. It is important to find the remedial measures, to develop the efficient biomarkers and to design the therapeutic strategies for CVD in the near future. ? Springer India 2015.
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    Oxidative stress and innate immune response in A549 lung carcinoma cells
    (Central University of Punjab, 2014) Upadhyay, Shishir; Dhiman, Manisha
    Cancer immunology is the study of cross-talk between the immune response and cancer cells. The immune response, including the recognition of cancer-specific antigens is of particular interest as knowledge gained drives the development of new vaccines and antibody therapies. The molecular mechanisms which are disturbed in the susceptible patients who proceed to develop cancer are very complicated and still largely unknown. It proposed that apart from the reported genetic modifications on tumor cells there are modifications due to oxidative stress (resulting in the formation of chemical adducts, e.g. 3-hydroxynonenal, 3- nitrotyrosine, carbonyl etc.) at the vicinity of tumor where the immune cells infiltrate. The central hypothesis of the present work is that respiratory burst which is host?s mechanism to kill the foreign particles (tumor cells) is used as defence mechanism by the tumor cells by forming neoantigen which in turn make them undetectable and can further help them to escape the host immune surveillance. The lung carcinoma A549 cells were treated with100μM H2O2 and using 1-D gel electrophoresis the oxidized tumor proteins in normal and treated cells were visualized. To confirm the oxidized modifications at membrane levels and at proteins levels the lipid peroxidation and protein carbonyls were detected respectively. It was observed that the oxidative stress induces the lipid peroxidation and protein carbonyls in tumor cells. To determine if neo (oxidized) tumor antigens elicit any alteration in immune responses where they show compromised phagocytosis, thus resulting in a failure to elicit effector immune functions were analyzed via phagocytosis and respiratory burst using spectrophotometry and microscopic techniques. The present study has identified a novel mechanism(s) of carcinogenesis initiation and which can further provide directions for the development of adjunct therapies to control cancer in its initial stages and at the same time it advocates for new ventures to increase the efficacy of the chemotherapeutic drugs.
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    A short review: Doxorubicin and its effect on cardiac proteins
    (Wiley-Liss Inc., 2020-12-26T00:00:00) Upadhyay, Shishir; Gupta, Kunj Bihari; Mantha, Anil Kumar; Dhiman, Monisha
    Doxorubicin (DOX) is a boon for cancer-suffering patients. However, the undesirable effect�on health on vital organs, especially the heart, is a�limiting factor, resulting in an increased number of patients with cardiac dysfunction. The present review focuses on the contractile machinery and associated factors, which get affected due to DOX toxicity in chemo-patients for which they are kept under life-long investigation for cardiac function. DOX-induced oxidative stress disrupts the integrity of cardiac contractile muscle proteins that alter�the rhythmic mechanism and oxygen consumption rate of the heart. DOX is an oxidant and it is further discussed that oxidative stress prompts the damage of contractile components and associated factors, which include Ca2+ load through Ca2+ ATPase, SERCA, ryanodine receptor-2, phospholamban, and calsequestrin, which ultimately results in left ventricular ejection and dilation. Based on data and evidence, the associated proteins can be considered as clinical markers to develop medications for patients. Even with the advancement of various diagnosing tools and modified drugs to mitigate DOX-induced cardiotoxicity, the risk could not be surmounted�with survivors of cancer. � 2020 Wiley Periodicals LLC