School Of Basic And Applied Sciences
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Item Recent advances in understanding brain cancer metabolomics: a review(Springer, 2023-07-10T00:00:00) Mukherjee, Anirban Goutam; Gopalakrishnan, Abilash Valsala; Jayaraj, Rama; Ganesan, Raja; Renu, Kaviyarasi; Vellingiri, Balachandar; Dey, Abhijit; Parveen, MohamudhaRegardless of the significant progress made in surgical techniques and adjuvant therapies, brain tumors are a major contributor to cancer-related morbidity and mortality in both pediatric and adult populations. Gliomas represent a significant proportion of cerebral neoplasms, exhibiting diverse levels of malignancy. The etiology and mechanisms of resistance of this malignancy are inadequately comprehended, and the optimization of patient diagnosis and prognosis is a challenge due to the diversity of the disease and the restricted availability of therapeutic options. Metabolomics refers to the comprehensive analysis of endogenous and exogenous small molecules, both in a targeted and untargeted manner, that enables the characterization of an individual�s phenotype and offers valuable insights into cellular activity, particularly in the context of cancer biology, including brain tumor biology. Metabolomics has garnered attention in current years due to its potential to facilitate comprehension of the dynamic spatiotemporal regulatory network of enzymes and metabolites that enables cancer cells to adapt to their environment and foster the development of tumors. Metabolic changes are widely acknowledged as a significant characteristic for tracking the advancement of diseases, treatment efficacy, and identifying novel molecular targets for successful medical management. Metabolomics has emerged as an exciting area for personalized medicine and drug discovery, utilizing advanced analytical techniques such as nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) to achieve high-throughput analysis. This review examines and highlights the latest developments in MRS, MS, and other technologies in studying human brain tumor metabolomics. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: A signature step hinting towards clinical perfection(Neoplasia Press, Inc., 2022-12-05T00:00:00) Tuli, Hardeep Singh; Garg, Vivek Kumar; Bhushan, Sakshi; Uttam, Vivek; Sharma, Uttam; Jain, Aklank; Sak, Katrin; Yadav, Vikas; Lorenzo, Jose M.; Dhama, Kuldeep; Behl, Tapan; Sethi, GautamCancer prevalence and its rate of incidence are constantly rising since the past few decades. Owing to the toxicity of present-day antineoplastic drugs, it is imperative to explore safer and more effective molecules to combat and/or prevent this dreaded disease. Flavonoids, a class of polyphenols, have exhibited multifaceted implications against several diseases including cancer, without showing significant toxicity towards the normal cells. Shredded pieces of evidence suggest that flavonoids can enhance drug sensitivity and suppress proliferation, metastasis, and angiogenesis of cancer cells by modulating several oncogenic or oncosuppressor microRNAs (miRNAs, miRs). They play pivotal roles in regulation of various biological and pathological processes, including various cancers. In the present review, the structure, chemistry and miR targeting efficacy of quercetin, luteolin, silibinin, genistein, epigallocatechin gallate, and cyanidin against several cancer types are comprehensively discussed. miRs are considered as next-generation medicine of recent times, and their targeting by naturally occurring flavonoids in cancer cells could be deemed as a signature step. We anticipate that our compilations related to miRNA-mediated regulation of cancer cells by flavonoids might catapult the clinical investigations and affirmation in the future. � 2022Item Herbal Remedies for Improving Cancer Treatment Through Modulation of Redox Balance(Springer Singapore, 2022-09-28T00:00:00) Kaur, Sukhchain; Verma, Harkomal; Kaur, Sharanjot; Singh, Subham; Mantha, Anil K.; Dhiman, MonishaThe redox modulation induced by oxidative stress is one of the major cause of the metabolic and inflammatory disorders including cancer. The reactive oxygen species (ROS) produced by various sources in the cell shift the redox homeostasis of cells towards more oxidizing or acidic environment. This shift results in the alterations of normal physiologic functioning of biomolecules as well as causes damage to these biomolecules (proteins, lipids, and DNA/RNA). The excessive ROS and redox modulation are the key factors that support growth, progression, and survival of cancer cells. ROS-induced redox modulation further activates pro-tumorigenic cellular pathways for e.g., PI3K/AKT, HIF-1, and MAPK signaling pathways as well as hinders epigenetic signaling. Increasing evidences demonstrate that long-term side effects of anti-cancer chemotherapy are major concern of medical sciences although modern treatments are quite effective. The combination of various herbal formulations with anti-cancer therapy shows improvement in treatment effectiveness in cancer patients. Bioactive compounds present in herbal formulations possess antioxidant and anti-cancer properties that help in the regulation of redox status of cancer cells. The synergetic effects of herbal remedies along with conventional treatment are proven as novel therapeutics in cancer progression management. Clinical studies have shown that broad range of herbs and bioactive compounds from various plants having antioxidant, anti-inflammatory properties can suppress the carcinogenesis. In this chapter we will discuss the role of various plants such as Glycyrrhiza glabra, Picrorhiza kurroa, Tinospora cordifolia, Curcuma longa, Ocimum sanctum, Viola odorata, and bioactive compound ferulic acid found in various cereals. The chapter will also focus on various mechanisms involved in the modulation of chemo-toxicity and improvement of efficacy of conventional anti-cancer therapies by these plants. � Springer Nature Singapore Pte Ltd. 2022.Item NOTCH signaling: Journey of an evolutionarily conserved pathway in driving tumor progression and its modulation as a therapeutic target(Elsevier Ireland Ltd, 2021-06-29T00:00:00) Aggarwal, Vaishali; Tuli, Hardeep Singh; Varol, Mehmet; Tuorkey, Muobarak; Sak, Katrin; Parashar, Nidarshana Chaturvedi; Barwal, Tushar Singh; Sharma, Uttam; Iqubal, Ashif; Parashar, Gaurav; Jain, AklankNotch signaling, an evolutionarily conserved signaling cascade, is critical for normal biological processes of cell differentiation, development, and homeostasis. Deregulation of the Notch signaling pathway has been associated with tumor progression. Thus, Notch presents as an interesting target for a variety of cancer subtypes and its signaling mechanisms have been actively explored from the therapeutic viewpoint. However, besides acting as an oncogene, Notch pathway can possess also tumor suppressive functions, being implicated in inhibition of cancer development. Given such interesting dual and dynamic role of Notch, in this review, we discuss how the evolutionarily conserved Notch signaling pathway drives hallmarks of tumor progression and how it could be targeted for a promising treatment and management of cancer. In addition, the up-to-date information on the inhibitors currently under clinical trials for Notch targets is presented along with how NOTCH inhibitors can be used in conjunction with established chemotherapy/radiotherapy regimes. � 2021 Elsevier B.V.Item Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement(Academic Press, 2020-05-24T00:00:00) Aggarwal, Vaishali; Tuli, Hardeep Singh; Tania, Mousumi; Srivastava, Saumya; Ritzer, Erin E.; Pandey, Anjana; Aggarwal, Diwakar; Barwal, Tushar Singh; Jain, Aklank; Kaur, Ginpreet; Sak, Katrin; Varol, Mehmet; Bishayee, AnupamEpigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed. � 2020 Elsevier LtdItem Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach(Taylor and Francis Ltd., 2023-09-11T00:00:00) Das, Agnidipta; Sarangi, Manaswini; Jangid, Kailash; Kumar, Vijay; Kumar, Amit; Singh, Praval Pratap; Kaur, Kamalpreet; Kumar, Vinod; Chakraborty, Sudip; Jaitak, VikasCancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between ?7.530 and ?9.719 kcal/mol while the reference compound Colchicine exerted docking score of ?7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Impact of cannabinoid receptors in the design of therapeutic agents against human ailments(Bentham Science Publishers, 2023-05-03T00:00:00) Kumar, Ankush; Gupta, Ojasvi; Bhatia, Rohit; Monga, VikramdeepThe Cannabinoid (CB) signalling cascade is widely located in the human body and is associated with several pathophysiological processes. The endocannabinoid system comprises cannabinoid receptors CB1 and CB2, which belong to G-protein Coupled Receptors (GPCRs). CB1 receptors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system contributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer�s disease, Huntington�s disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success story of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heterocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors. � 2023 Bentham Science Publishers.Item Synthetic Methodologies and SAR of Quinazoline Derivatives as PI3K Inhibitors(Bentham Science Publishers, 2023-01-19T00:00:00) Raj, Aditya; Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Kumar, PradeepPI3K is an important anticancer target as it controls cellular functions such as growth, transformation, pro-liferation, motility and differentiation. Plasma cell cancer (multiple myeloma) occurs more than 10% among all haema-tological malignancies and accounts for 2% of all cancer-related deaths each year, it is mainly regulated by PI3K/AKT signaling cascade. Quinazoline derivatives have been reported as promising PI3K inhibitors. Lapatinib, afatinib, ge-fitinib, erlotinib, idelalisib and copanlisib are quinazoline-based, FDA-approved PI3K inhibitors, while compounds like NVPBYL719, GDC-0032, AZD8186, AZD-6482, etc. are under different stages of clinical trials. In light of the above-mentioned facts, in the present study, we have reported different synthetic approaches, mechanisms of anticancer action, and structure-activity relationship analysis of reported quinazoline derivatives as PI3K inhibitors to help researchers working in the field in designing better and isoform-selective PI3K inhibitors. � 2023 Bentham Science Publishers.Item Flavonoids as P-glycoprotein inhibitors for multidrug resistance in cancer: an in-silico approach(Taylor and Francis Ltd., 2022-09-19T00:00:00) Kumar, Amit; Kalra, Sourav; Jangid, Kailash; Jaitak, VikasCancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of ?11.202 to ?9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was ?4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Item Pore-forming proteins and their role in cancer and inflammation: Mechanistic insights and plausible druggable targets(Elsevier Ireland Ltd, 2022-08-30T00:00:00) Sankar, Jishnu; Arora, Sahil; Joshi, Gaurav; Kumar, RajPerforin is a granular effector pore-forming protein formed in NK cells and Cytotoxic T lymphocytes. These cytotoxic proteins are part of the first-line immune defense in the human body. They ensure apoptosis of pathogen-infected cells or tumor cells in the human body. Activation of receptors on NK cell or T cell triggers secondary proteins in these cells. Further, it leads to Ca2+ dependent perforin egress towards the target cell, ensued by PI3K signaling pathway. Perforin undergoes oligomerization over the target cell membrane and forms transmembrane pores with the membrane-spanning domain-MACPF domain. Granzymes, proapoptotic serine proteases are released through these pores and initiate the target cell apoptotic pathway leading to the cell death. Although perforin is a savior for humans from tumor and viral infections, uncontrolled expression of the perforins leads to the autoimmune conditions, including Familial Hemophagocytic lymphohistiocytosis, insulin-dependent diabetes, and cerebral myocarditis. The present review is the concerted effort to highlight the mechanistic pathways concerning perforin secretion, NK cell and T cell-mediated cytotoxicity towards virus-infected and transformed cells. This is followed by the discussion on synthetic derivatives tested so far to inhibit the perforin in pre and clinical arena for certain unusual conditions. � 2022 Elsevier B.V.