Browsing by Author "Singh, S."

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Combinatorial Effect of DCA and Let-7a on Triple-Negative MDA-MB-231 Cells: A Metabolic Approach of Treatment
(SAGE Publications Inc., 2020) Sharma, P; Singh, S.
Dichloroacetate (DCA) is a metabolic modulator that inhibits pyruvate dehydrogenase activity and promotes the influx of pyruvate into the tricarboxylic acid cycle for complete oxidation of glucose. DCA stimulates oxidative phosphorylation (OXPHOS) more than glycolysis by altering the morphology of the mitochondria and supports mitochondrial apoptosis. As a consequence, DCA induces apoptosis in cancer cells and inhibits the proliferation of cancer cells. Recently, the role of miRNAs has been reported in regulating gene expression at the transcriptional level and also in reprogramming energy metabolism. In this article, we indicate that DCA treatment leads to the upregulation of let-7a expression, but DCA-induced cancer cell death is independent of let-7a. We observed that the combined effect of DCA and let-7a induces apoptosis, reduces reactive oxygen species generation and autophagy, and stimulates mitochondrial biogenesis. This was later accompanied by stimulation of OXPHOS in combined treatment and was thus involved in metabolic reprogramming of MDA-MB-231 cells. � 2020 Sage Publications.
Interaction between topoisomerases and histone deacetylases: Role in cancer progression and therapeutic interventions
(Nova Science Publishers, Inc., 2017) Joshi, G.; Thakur, A.; Kaur, G.; Kalra, S.; Singh, S.; Kumar, R.
DNA topoisomerases are termed as the magicians of the DNA world, as they are involved in overcoming all the topological DNA problems. Histone Deacetylases are the collection of enzymes that assist in the regulation of DNA control. The overexpression of topoisomerases and histone deacetylases are found in various diseases including cancer. Till date, many therapies have been discovered to target topoisomerases and histone deacetylases individually. However, most of these treatments are associated with the toxicities and drug resistance. The drug resistance apart from known mechanism(s) could occur due to crosstalk(s) of topoisomerases with various proteins associated directly or indirectly with the cancer prognosis. Histone deacetylases that render topoisomerase inhibitors resistant also insensitize them toward binding to the receptor. The chapter overlays the discussion on the underlying mechanism(s) involved in topoisomerase and histone deacetylases interactions. The chapter also congregates the information suggested for the essential pharmacophore development for such hybrid drug discovery. The attempt has also been made to give a preliminary virtual background on the fundamental interaction of these two proteins along with the primary amino acids involved in such interaction. ? 2017 Nova Science Publishers, Inc.
Marine macroalga Caulerpa: role of its metabolites in modulating cancer signaling
(Springer, 2019) Mehra, R; Bhushan, S; Bast, Felix; Singh, S.
Cancer, the leading causes of death worldwide, causes multiple metabolic and physiological alterations, leading to an unregulated proliferation of cells. The existing anticancer therapies are usually nonspecific with side effects and or are extremely expensive, thus hunt for better therapeutics is still on, specially efforts are made to look for naturally occurring molecules. Sea harbors several organisms which are unexplored for their biological potentials. Green macroalga genus, Caulerpa, is one such invaluable repository of bioactive metabolites like alkaloids, terpenoids, flavonoids, steroids and tannins with reported bioactivities against many diseases including cancer. Anti-cancerous metabolites of Caulerpa like caulerpenyne (Cyn), caulerpin, caulersin, and racemosin C, possess unique structural moieties and are known to exhibit distinct effects on cancer cells. Theses metabolites are reported to affect microtubule dynamics, unfolded protein response, mitochondrial health, cell cycle progression, metabolic and stress pathways by their cross-talk with signalling proteins like AMPK, GRP78, GADD153, Bid, Bax, AIF, Bcl2, P21, cyclin D, cyclin E, caspase 9, and PTP1B. Targeting of multiple cancer hallmarks by Caulerpa metabolites, with concomitant modulations of multiple signalling cascades, displays its multifactorial approach against cancer. Evaluation of anti-cancer properties of this genus is particularly important as Caulerpa species are widely edible and utilized in several delicacies in the coastal countries. This is the first review article providing a consolidated information about the role of Caulerpa in cancer with major contributing metabolites and plausible modulations in cancer signaling and prospects. © 2019, Springer Nature B.V.
The mitochondrial unfolded protein response: Role in cellular homeostasis and disease
(Bentham Science Publishers B.V., 2017) De, I.; Dogra, N.; Singh, S.
Mitochondria are the sole semiautonomous organelles of the human cell and play a very important role in not only energy production but also in apoptosis, metabolism and cell signaling. They are also known to be major producers of ROS and RNS free radicals during ATP production. These free radicals in excessive amount may damage the mitochondrial DNA as well as proteome resulting in accumulation of misfolded proteins which may prove deleterious to their functioning and are known to be involved in disease pathology. To maintain healthy proteome, mitochondria have developed as quality control machinery in semiautonomous manner, where cellular proteins such as proteases and heat shock proteins are used for quality control. The present review discusses various aspects of mitochondrial protein quality control operating at outer or inner membrane as well as intermembranal space. The various pathways involved in mitochondrial unfolded protein response have been discussed along with their implications in cancer and various neurodegenerative diseases. ? 2017 Bentham Science Publishers.
Topoisomerase inhibitors: Classification, mechanisms of action and adverse effects
(Nova Science Publishers, Inc., 2017) Kumar, R.; Singh, S.
This book aims to assist the scientists working with the medicinal, biochemical, biophysical, genetic and pharmacological aspects of topoisomerases and their inhibitors. The book has covered various aspects of topoisomerases like classification, structural aspects, basic genetics and mutations, disease implications and cell signaling networks, which may be helpful for researchers of the field for better therapeutics. Chapter One deals with structure, functions and role and of human topoisomerase-I in cancer progression. It describes a detailed classification, mechanism of action and recent updates on the development of camptothecin and non-camptothecin derivatives, along with their Structure-Activity Relationships (SAR) as topoisomerase-I inhibitors. Chapters Two and Three cover X-ray co-crystal structures, biological functions and the significant role of topoisomerase-II isoforms in cancer. A thorough discussion on classification and various pharmacoinformatics techniques employed in delineating the binding mode of topoisomerase-II inhibitors and their mechanism of action is well presented. Chapter Four deals not only with adverse effects associated with the use of topoisomerase-I and II inhibitors, but also includes approaches to overcome them. Chapter Five discusses various disorders associated with SNPs in topoisomerases and risks associated with their pharmacogenetics. Chapter Six sheds light on interactions and cross-talks between topoisomerases and histone deacetylases, leading to their significant role in drug resistance. The work is expected to assist the scientists to selectively design dual/multi-inhibitors of topoisomerases and histone deacetylases. The authors are thankful to the reviewers, who were so kind in reviewing and making suggestions for improving this book. This book could not have been completed without their commendable efforts. (Imprint: Nova Biomedical). ? 2017 by Nova Science Publishers, Inc. All rights reserved.