Browsing by Author "Munendra Singh Tomar"

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Activation of p53-dependent/-independent pathways of apoptotic cell death by chelerythrine in a murine T cell lymphoma
(Informa Healthcare, 2015) Sanjay Kumar; Munendra Singh Tomar; Arbind Acharya
The p53 tumor suppressor protein has been implicated as an activator of apoptosis. In order to investigate the effect of chelerythrine and staurosporine on the activation of p53-dependent/-independent pathways of Dalton lymphoma (DL) cell death, cells were treated with chelerythrine and staurosporine for 1 h, 3 h and 6 h, respectively. It was found that treatment with chelerythrine and staurosporine increased the expression of total-p53/phospho-53 (ser-15) significantly at protein and mRNA levels, which resulted in activation of the p53-dependent apoptotic pathway in DL cells. In addition, increased activities of cyt-c, caspase-9 and caspase-3 and degradation of DNA into fragments confirmed activation of the p53-independent apoptotic pathway in p53 knockdown RNAi-DL cells. In brief, the present study demonstrated activation of p53-dependent/-independent apoptotic pathways in DL cells. Therefore, targeting of p53-dependent/-independent apoptotic pathways may lead to the possibility of designing and developing better therapeutic regimens to treat DL and other human cancers. © 2015 Informa UK, Ltd.
Carboxylic group-induced synthesis and characterization of selenium nanoparticles and its anti-tumor potential on Dalton's lymphoma cells
(Elsevier B.V., 2015) Sanjay Kumar; Munendra Singh Tomar; Arbind Acharya
Carboxylic group-induced synthesis of selenium nanoparticles (SeNPs) was achieved using sodium selenosulphate as a precursor. The particles were stabilized and capped with 0.01% polyvinyl alcohol under ambient conditions. This is a simple and easy method of producing SeNPs in a size range from 35 to 105. nm. The synthesized SeNPs were purified by centrifugation at 11,500. ×. g for 20. min and characterized by UV-visible spectroscopy, FTIR spectroscopy, XRD, DSC and TEM. It was observed that the synthesized SeNPs showed differences in their absorption spectra, phase composition and crystal structure, thermodynamic behaviour, size and shape. Further, to confirm anti-tumour potential of the synthesized SeNPs induced by the carboxylic group of acetic acid, pyruvic acid and benzoic acid, cell viability assay, nuclear morphology testing and DNA fragmentation assay were carried out using Dalton's lymphoma (DL) cells. DL cells treated with the SeNPs showed reduced cell viability, altered nuclear morphology, typical apoptotic DNA ladder and apoptosis. Therefore, these SeNPs may have therapeutic relevance to treat this type of cancer. © 2015 Elsevier B.V.
CD28-mediated T cell response is upregulated by exogenous application of autologous Hsp70–peptide complex in a tumor-bearing host
(Humana Press Inc., 2016) Sanjay Kumar; Pramod Kumar Gautam; Munendra Singh Tomar; Arbind Acharya
Hsp70, a highly conserved protein, has gained plenty of attention by virtue of its adjuvant capability to induce peptide-specific cytotoxic T lymphocyte responses. In this study, we have investigated the effect of autologous Hsp70–peptide complex (or simply autologous Hsp70) on the expression of CD28 on T cells and its effector functions through macrophage activation. Further, we investigated the effect of Hsp70 on the expression of CD80 and CD86 on macrophages isolated from normal and tumor-bearing host to provide costimulatory signal for T cell activation and secretion of IL-2 and IFN-γ during interaction. We found that treatment of autologous Hsp70 effectively activated TAMs to induce higher expression of CD28 on T cells through T cells–macrophage interaction. Treatment of autologous Hsp70 induces higher expression of CD80 and CD86 on TAMs, as a result, increases B7/CD28 interaction, which in turns activates T cells and induces higher production of IL-2 and IFN-γ, thereby increasing antigen-specific T cell proliferation. With our novel study, we have provided the strong insights into the role of extracellular Hsp70 on the expression of CD28 costimulatory molecule on T cells, which helps in the activation and generation of antigen-specific T cell effector functions in a tumor-bearing host to curb malignancy. © 2015, Springer Science+Business Media New York.
Chelerythrine delayed tumor growth and increased survival duration of Dalton's lymphoma bearing BALB/c H 2d mice by activation of NK cells in vivo
(Medknow Publications, 2015) Sanjay Kumar; Munendra Singh Tomar; Arbind Acharya
Aim: The aims of the present investigation were to evaluate the antitumor effect of chelerythrine (CHE) on in vivo growth and survival duration of BALB/c (H 2d ) mice bearing Dalton's lymphoma (DL) and enhanced function of tumor associated NK cells (TANK cells). Materials and Methods: BALB/c (H 2d ) mice at 8-10 weeks of age of either sex were used. Increasing concentration of CHE (1.25, 2.5, and 5.0 mg/kg), staurosporine (0.625, 1.0, 1.5, and 2.0 mg/kg) and cyclophosphamide (25, 50, 100, and 200 mg/kg) were administered intraperitoneally and tumor regression and survival duration of tumor bearing host were determined, and thereafter expression of NKG2D and NKG2A on TANK cells were detected. Results: Our results show that treatment with 2.5 mg/kg of CHE results in a significant reduction in mean tumor volume and increased survival duration of DL bearing BALB/c (H 2d ) mice when compared to control. Activating receptor NKG2D on TANK cells were observed upregulated in contrast to inhibitory receptor NKG2A. Conclusions: CHE reduced mean tumor volume and increased survival duration of DL bearing BALB/c (H 2d ) mice. Increased expression of activating receptor NKG2D on TANK cells results in recovery of immunosuppression during tumor progression. Therefore, CHE could be a potential anticancer therapeutic agent that may be used to replace chemo-radio-therapy in future. © 2015 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow.
Developing a nontoxic and biocompatible polymeric self-assembly by using RAFT methodology for biomedical application
(Elsevier Ltd, 2019) Deepak; Swati Sharma; Ashok Kumar; Rajesh Kumar; Koushik Nandy; Arti Srivastava; Munendra Singh Tomar; Arbind Acharya
The amphiphilic block copolymer poly(N-vinylpyrrolidone)-b-poly(N-vinylcarbazole) (PVP-b-PVK) was synthesized by reversible-deactivation radical polymerization (RDRP)using reversible addition-fragmentation chain transfer (RAFT) methodology by new chain transfer agent (CTA) i.e. benzyl piperidine dithiocarbamate (BPDC). The pseudo-first-order kinetics and linear evolution of the molar mass with N-vinylpyrrolidone (NVP) conversion were obtained with the molar mass dispersity (Ð) 1.30–1.41 in toluene. 1H NMR spectrum indicates the presence of chain-end functional groups on homopolymer and block copolymer. The above block copolymer get self-assembled and form micelles in the aqueous medium, the size of micelles is characterized by 1H NMR, transmission electron micrographs (TEM) and dynamic laser light scattering (DLS) analyses, and critical micelles concentration (CMC) was determined by UV–vis spectroscopy. Trypan blue exclusion and MTT assay were done to ensure the cytotoxic effect of PVP-b-PVK on different types of normal cells (thymocytes, splenocytes and macrophage), and no cytotoxic effect was shown by block copolymer on cells, while observed biocompatibility with cells was 200 mg/mL. Further, the beads of block copolymer releases (65%) highly water-soluble levofloxacin drug up to 8 h in a controlled manner at pH 7.4 (37 ± 0.2 °C), while loading of levofloxacin drug was 62% (w/w). © 2018 Elsevier Ltd
HSF1-mediated regulation of tumor cell apoptosis: A novel target for cancer therapeutics
(2013) Sanjay Kumar; Munendra Singh Tomar; Arbind Acharya
Programmed cell death/apoptosis is a genetically conserved phenomenon involved in many biological processes including reconstruction of multicellular organisms and elimination of old or damaged cells. It is regulated by the activation/deactivation of PKC in response to exogenous and endogenous stimuli. PKC is activated under stress by a series of downstream signaling cascades, which ultimately induce HSF1 activation, which results in overexpression of heat shock proteins. Overexpression of heat shock proteins interferes in the apoptotic pathway, while their blocking results in apoptosis. Therefore, HSF1 could be a novel therapeutic target against a variety of tumors. Several pharmacological inhibitors of PKC have been demonstrated to exert inhibitory effects on the activation of HSF1 and, therefore, induce apoptosis in tumor cells. However, studies regarding the role of pharmacological inhibitors in the regulation of apoptosis and possible anti-tumor therapeutic intervention are still unknown or in their infancy. Therefore, an attempt has been made to delineate the precise role of HSF1 in the regulation of apoptosis and its prospects in cancer therapeutics. © 2013 Future Medicine Ltd.
Long-term exposure of 2450 MHz electromagnetic radiation induces stress and anxiety like behavior in rats
(Elsevier Ltd, 2019) Sukesh Kumar Gupta; Shishir Kumar Patel; Munendra Singh Tomar; Shio Kumar Singh; Manoj Kumar Mesharam; Sairam Krishnamurthy
Long term exposure of electromagnetic radiations (EMR) from cell phones and Wi-Fi hold greater propensity to cause anxiety disorders. However, the studies investigating the effects of repeated exposure of EMR are limited. Therefore, we investigated the effects of repeated exposure of discrete frequencies of EMR in experimental animals. Male rats were exposed to EMR (900, 1800 and 2450 MHz) for 28 (1 h/day) days. Long term exposure of EMR (2450 MHz) induced anxiety like behavior. It deregulated the hypothalamic pituitary adrenal (HPA) axis in rats as observed by increase in plasma corticosterone levels apart from decreased corticotrophin releasing hormone-2 (CRH-2) and Glucocorticoid receptor (GR) expression in amygdala. Further, it impaired mitochondrial function and integrity. The expression of Bcl 2 showed significant decrease while Bax and ratio of Bax: Bcl 2 were increased in the mitochondria and vice versa in cytoplasm indicating altered regulation of apoptosis. EMR exposure caused release of cytochrome-c and expression of caspase-9 ensuing activation of apoptotic cell death. Additional set of experiments performed to estimate the pattern of cell death showed necrotic and apoptotic amygdalar cell death after EMR exposure. Histopathological studies also revealed a significant decrease in neuronal cells in amygdala. The above findings indicate that long-term exposure of EMR radiation (2450 MHz) acts as a stressor and induces anxiety-like behaviors with concomitant pathophysiological changes in EMR subjected rats. © 2019
NK Cell Effector Functions Regulation by Modulating nTreg Cell Population During Progressive Growth of Dalton’s Lymphoma in Mice
(Taylor and Francis Ltd, 2018) Munendra Singh Tomar; Sanjay Kumar; Pramod Kumar Gautam; Rishi Kant Singh; Praveen Kumar Verma; Surya Pratap Singh; Arbind Acharya
Natural killer (NK) cells are large granular lymphocytes of the innate immune system and play a pivotal role against virus-infected cells, microbial pathogens, and tumor cells. NK cells secrete several cytokine,s but IFN-γ secreted by NK cells play a vital role in the activation of the innate and adaptive immune systems. But during any infection or tumor burden, functional activity of NK cells is downregulated significantly by nTreg cells. It is also found that during tumor progression, the number of nTreg cells increases as a result; it effectively suppresses the antitumor activity of NK cells. Therefore, in the present investigation, we intend to examine the mechanism of downregulation of antitumor immune response mediated by NK cells. We observed increased NK cell population at an early stage of Dalton’s lymphoma (DL) growth, while at late stage, NK cell numbers were decreased. The NK cell functional activity was govern by high level of IFN-γ measurement during tumor progression. The FoxP3+ CD25+ CD4+ T regulatory cell population was found to be continuously increased with high-level expression of FoxP3 during DL growth. The rapid increase in the number of Treg cells during DL progression may be due to high level of the FoxP3 transcription factor. The tumor microenvironment of DL cell progression has highly deleterious effect on NK cells after massive growth of tumor burden in BALB/c mice. This result also indicates that NK cell proliferation, activation, and accumulation are under the control of regulatory T cells. © 2017 Taylor & Francis.
Protein kinase C-α and the regulation of diverse cell responses
(Walter de Gruyter GmbH, 2017) Rishi Kant Singh; Sanjay Kumar; Pramod Kumar Gautam; Munendra Singh Tomar; Praveen Kumar Verma; Surya Pratap Singh; Arbind Acharya
Protein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-α is a member of classical PKC with ubiquitous expression and different cellular localization. This unique PKC isoform is activated by various signals which evoke lipid hydrolysis, after activation it interacts with various adapter proteins and is localized to specific cellular compartments where it is devised to work. The universal expression and activation by various stimuli make it a perfect player in uncountable cellular functions including differentiation, proliferation, apoptosis, cellular transformation, motility, adhesion and so on. However, these functions are not intrinsic properties of PKC-α, but depend on cell types and conditions. The activities of PKC-α are managed by the various pharmacological activators/inhibitors and antisense oligonucleotides. The aim of this review is to elaborate the structural feature, and provide an insight into the mechanism of PKC-α activation and regulation of its key biological functions in different cellular compartments to develop an effective pharmacological approach to regulate the PKC-α signal array. © 2018 Walter de Gruyter GmbH. All rights reserved.
Putative role of natural products as Protein Kinase C modulator in different disease conditions
(Springer Science and Business Media Deutschland GmbH, 2021) Rishi Kant Singh; Sanjay Kumar; Munendra Singh Tomar; Praveen Kumar Verma; Amit Kumar; Sandeep Kumar; Naveen Kumar; Jai Prakash Singh; Arbind Acharya
Introduction: Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have been used by humans as medicine from prehistoric times. Recently, several compounds derived from plants have been found to modulate PKC activities through competitive binding with ATP binding site, and other allosteric regions of PKC. As a result fresh race has been started in academia and pharmaceutical companies to develop an effective naturally derived small-molecule inhibitor to target PKC activities. Herein, in this review, we have discussed several natural products and their derivatives, which are reported to have an impact on PKC signaling cascade. Methods: All information presented in this review article regarding the regulation of PKC by natural products has been acquired by a systematic search of various electronic databases, including ScienceDirect, Scopus, Google Scholar, Web of science, ResearchGate, and PubMed. The keywords PKC, natural products, curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, protocatechuic acid, tannic acid, PKC modulators from marine organism, bryostatin, staurosporine, midostaurin, sangivamycin, and other relevant key words were explored. Results: The natural products and their derivatives including curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, bryostatin, staurosporine, and midostaurin play a major role in the management of PKC activity during various disease progression. Conclusion: Based on the comprehensive literature survey, it could be concluded that various natural products can regulate PKC activity during disease progression. However, extensive research is needed to circumvent the challenge of isoform specific regulation of PKC by natural products. © 2021, Springer Nature Switzerland AG.
Refurbishment of NK cell effector functions through their receptors by depleting the activity of nTreg cells in Dalton’s Lymphoma-induced tumor microenvironment: an in vitro and in vivo study
(Springer Science and Business Media Deutschland GmbH, 2023) Munendra Singh Tomar; Rishi Kant Singh; Ilya V. Ulasov; Kaushalendra; Arbind Acharya
Natural killer (NK) cells play a crucial role in the anti-tumor transaction through cytolytic activity with the help of proportionate expression of their activating receptors (ARs) and inhibitory receptors (IRs). The proliferation, differentiation, and effector’s functions of NK cells were affected and regulated by CD4+CD25+ regulatory T (Treg) cells through the NKG2D receptor expressed on NK cells. It has not yet been established whether Treg cells also affects the expression and functions of other receptors of NK cell. Moreover, the effect of cyclophosphamide (CYP) treatment on the expression and functions of AR and IR receptors of NK cells regulated by Treg cells during cancer progression is not clearly understood. Therefore, we have used the metronomic dose of CYP and anti-CD25 and anti-TGF-β to inhibit the effects of Treg cells in DL-induced tumor microenvironment and analyze the expression of ARs and IRs on NK cells and the FoxP3 level on Treg cells. It was observed that treatment of CYP and blocking antibodies not only affects the functions of tumor-associated NK cells (TANK cells) by modulating the expression of ARs and IRs in DL-induced tumor microenvironment, but also downregulates the functions of Treg cells. The findings of our study supported and suggested that the use of CYP in combination with other therapeutic approaches will effectively reduce tumor growth directly and/or indirectly by modulating the NK cell-mediated immune response of the host. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Therapeutic application of Carica papaya leaf extract in the management of human diseases
(Springer Science and Business Media Deutschland GmbH, 2020) Surya P. Singh; Sanjay Kumar; Sivapar V. Mathan; Munendra Singh Tomar; Rishi Kant Singh; Praveen Kumar Verma; Amit Kumar; Sandeep Kumar; Rana P. Singh; Arbind Acharya
Introduction: Papaya (Carica papaya Linn.) belongs to the family Caricaceae and is well known for its therapeutic and nutritional properties all over the world. The different parts of the papaya plant have been used since ancient times for its therapeutic applications. Herein, we aimed to review the anticancer, anti-inflammatory, antidiabetic and antiviral activities of papaya leaf. Methods: All information presented in this review article regarding the therapeutic application of Carica papaya leaf extract has been acquired by approaching various electronic databases, including Scopus, Google scholar, Web of science, and PubMed. The keywords Carica papaya, anticancer, anti-inflammatory, immunomodulatory, and phytochemicals were explored until December 2019. Results: The papaya plant, including fruit, leaf, seed, bark, latex, and their ingredients play a major role in the management of disease progression. Carica papaya leaf contains active components such as alkaloids, glycosides, tannins, saponins, and flavonoids, which are responsible for its medicinal activity. Additionally, the leaf juice of papaya increases the platelet counts in people suffering from dengue fever. Conclusion: The major findings revealed that papaya leaf extract has strong medicinal properties such as antibacterial, antiviral, antitumor, hypoglycaemic and anti-inflammatory activity. Furthermore, clinical trials are needed to explore the medicative potential of papaya leaf. [Figure not available: see fulltext.]. © 2020, Springer Nature Switzerland AG.