School Of Basic And Applied Sciences
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Item Molecular mechanisms of action of genistein in cancer: Recent advances(Frontiers Media S.A., 2019) Tuli H.S.; Tuorkey M.J.; Thakral F.; Sak K.; Kumar M.; Sharma A.K.; Sharma U.; Jain A.; Aggarwal V.; Bishayee A.Background: Genistein is one among the several other known isoflavones that is found in different soybeans and soy products. The chemical name of genistein is 4?,5,7-trihydroxyisoflavone. Genistein has drawn attention of scientific community because of its potential beneficial effects on human grave diseases, such as cancer. Mechanistic insight of genistein reveals its potential for apoptotic induction, cell cycle arrest, as well as antiangiogenic, antimetastatic, and anti-inflammatory effects. Objective: The purpose of this review is to unravel and analyze various molecular mechanisms of genistein in diverse cancer models. Data sources: English language literature was searched using various databases, such as PubMed, ScienceDirect, EBOSCOhost, Scopus, Web of Science, and Cochrane Library. Key words used in various combinations included genistein, cancer, anticancer, molecular mechanisms prevention, treatment, in vivo, in vitro, and clinical studies. Study selection: Study selection was carried out strictly in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-analyses. Data extraction: Four authors independently carried out the extraction of articles. Data synthesis: One hundred one papers were found suitable for use in this review. Conclusion: This review covers various molecular interactions of genistein with various cellular targets in cancer models. It will help the scientific community understand genistein and cancer biology and will provoke them to design novel therapeutic strategies.Item Anti-inflammatory and immune-modulating effects of rice callus suspension culture (RCSC) and bioactive fractions in an in vitro inflammatory bowel disease model(Elsevier GmbH, 2019) Driscoll K.; Deshpande A.; Chapp A.; Li K.; Datta R.; Ramakrishna W.Background: Rice callus suspension culture (RCSC) has been shown to exhibit potent antiproliferative activity in multiple cancer cell lines. RCSC and its bioactive compounds can fill the need for drugs with no side effects. Hypothesis/Purpose: The anti-inflammatory potential of RCSC and its bioactive fractions on normal colon epithelial cell lines, was investigated. Study design: Three cell lines, InEpC, NCM356 and CCD841-CoN were treated with proinflammatory cytokines followed by RCSC. Cytoplasmic and nuclear ROS were assayed with fluorescent microscopy and flow cytometer. Expression analysis of immune-related genes was performed in RCSC-treated cell lines. RCSC was fractionated using column chromatography and HPLC. Pooled fractions 10–18 was used to test for antiproliferative activity using colon adenocarcinoma cell line, SW620 and anti-inflammatory activity using CCD841-CoN. Mass spectrometric analysis was performed to identify candidate compounds in four fractions. Results: RCSC treatment showed differential effects with higher cytoplasmic ROS levels in NCM356 and CCD841-CoN and lower ROS levels in InEpC. Nuclear generated ROS levels increased in all three treated cell lines. Flow cytometry analysis of propidium iodide stained cells indicated mitigation of cell death caused by inflammation in RCSC treated groups in both NCM356 and CCD841-CoN. Genes encoding transcription factors and cytokines were differentially regulated in NCM356 and CCD841-CoN cell lines treated with RCSC which provided insights into possible pathways. Analysis of pooled fractions 10–18 by HPLC identified 8 peaks. Cell viability assay with fractions 10–18 using SW620 showed that the number of viable cells were greatly reduced which was similar to 6X and 33X RCSC with very little effect on normal cells which similar to 1X RCSC. RCSC fractions increased nuclear and cytoplasmic ROS vs. both untreated and inflammatory control. Analysis of four fractions by mass spectrometry identified 4-deoxyphloridzin, 5?-methoxycurcumin, piceid and lupeol as candidate compounds which are likely to be responsible for the antiproliferative, anti-inflammatory and immune-regulating properties of RCSC. Conclusion: RCSC and its fractions showed anti-inflammatory activity on inflamed colon epithelial cells. Downstream target candidate genes which are likely to mediate RCSC effects were identified. Candidate compounds responsible for the antiproliferative and anti-inflammatory activity of RCSC and its fractions provide possible drug targets.Item Bulbine frutescens phytochemical inhibits notch signaling pathway and induces apoptosis in triple negative and luminal breast cancer cells(Elsevier Inc., 2019) Kushwaha P.P.; Vardhan P.S.; Kapewangolo P.; Shuaib M.; Prajapati S.K.; Singh A.K.; Kumar S.Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC–MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8–28.4 μg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.Item Molecular mechanisms of action of tocotrienols in cancer: Recent trends and advancements(MDPI AG, 2019) Aggarwal, V; Kashyap, D; Sak, K; Tuli, H.S; Jain, Aklank; Chaudhary, A; Garg, V.K; Sethi, G; Yerer, M.B.Tocotrienols, found in several natural sources such as rice bran, annatto seeds, and palm oil have been reported to exert various beneficial health promoting properties especially against chronic diseases, including cancer. The incidence of cancer is rapidly increasing around the world not only because of continual aging and growth in global population, but also due to the adaptation of Western lifestyle behaviours, including intake of high fat diets and low physical activity. Tocotrienols can suppress the growth of different malignancies, including those of breast, lung, ovary, prostate, liver, brain, colon, myeloma, and pancreas. These findings, together with the reported safety profile of tocotrienols in healthy human volunteers, encourage further studies on the potential application of these compounds in cancer prevention and treatment. In the current article, detailed information about the potential molecular mechanisms of actions of tocotrienols in different cancer models has been presented and the possible effects of these vitamin E analogues on various important cancer hallmarks, i.e., cellular proliferation, apoptosis, angiogenesis, metastasis, and inflammation have been briefly analyzed. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Item Vitex negundo and its medicinal value(Springer, 2018) Gill, Balraj Singh; Mehra, Richa; Navget; Kumar, SanjeevNatural products are rich in several potent bioactive compounds, targeting complex network of proteins involved in various diseases. Vitex negundo (VN), commonly known as “chaste tree”, is an ethnobotanically important plant with enormous medicinal properties. Different species of Vitex vary in chemical composition, thus producing different phytochemicals. Several bioactive compounds have been extracted from leaves, seeds, roots in form of volatile oils, flavonoids, lignans, iridoids, terpenes, and steroids. These bioactive compounds exhibit anti-inflammatory, antioxidant, antidiabetic, anticancer, antimicrobial. VN is typically known for its role in the modulation of cellular events like apoptosis, cell cycle, motility of sperms, polycystic ovary disease, and menstrual cycle. VN, reportedly, perturbs many cancer-signaling pathways involving p-p38, p-ERK1/2, and p-JNK in LPS-elicited cells, N-terminal kinase (JNK), COX-1 pathways, MAPK, NF-κB, tumor necrosis factor α (TNF-α), Akt, mTOR, vascular endothelial growth factor, hypoxia-inducible factor (HIF-1α). Several bioactive compounds obtained from VN have been commercialized and others are under investigation. This is the first review presenting up-to-date information about the VN, its bioactive constituents and their mode of action.Item Evaluation of chemical composition and groundwater and anticancer properties of citrullus colocynthis(Central University of Punjab, 2014) Kaur, Jatinder; Bhardwaj, PankajColocynth (Citrullus colocynthis (L.)) is medicinal plant of family Cucurbitaceae which is the native of Turkey. This plant has been used as anti-inflammatory agent, for the treatment of jaundice, skin infections, and urinary diseases from ancient times. It is anti-diabetic, anti-microbial, anti-parasitic, antifungal and anti-oxidant in nature and thought to possess anti-cancer properties also. There is no proper study available regarding its anticancer nature. The aim of the study was to estimate the chemical composition of C. colocynthis fruit and the effect of different extracts prepared from C. colocynthis pulp and seeds on various cancer cell lines. These extracts were found to contain number of secondary metabolites which may further have useful and healing properties. When cancer cells were treated with different prepared extracts, the cell viability of various cancer cells was reduced effectively. Effect of p53 gene was also analysed by using intact p53 as well as p53 mutant cell lines. Antioxidant activity of C. colocynthis was also determined by performing H2DCFDA. Assessment of various antioxidant enzymes such as Catalase, SOD, and Glutathione reductase was also done and found to be present in this fruit. We also analysed the protective effect of C. colocynthis by first treating the cells with pesticides and then with colocynthis extracts. Results indicate that C. colocynthis neutralized the harmful effect of pesticides. The results obtained are encouraging and confirm the value of the use of C. colocynthis as an anticancer agent for fighting against various cancers. It may be helpful to find the exact component responsible for the protective action of C. colocynthis.Item Metformin inhibits human breast cancer cell growth by promoting apoptosis via a ROS-independent pathway involving mitochondrial dysfunction: pivotal role of superoxide dismutase (SOD)(Springer, 2018) Sharma, Prateek; Kumar, SanjeevPurpose Despite a growing body of evidence indicating a potential efficacy of the anti-diabetic metformin as anti-cancer agent, the exact mechanism underlying this efficacy has remained largely unknown. Here, we aimed at assessing putative mechanisms associated with the ability of metformin to reduce the proliferation and migration of breast cancer cells. Methods A battery of in vitro assays including MTT, colony formation, NBT and scratch wound healing assays were performed to assess the viability, proliferation, anti-oxidative potential and migration of breast cancer-derived MCF-7, MDA-MB-231 and T47D cells, respectively. Reactive oxygen species (ROS) assays along with fluorescence microscopy were used to assess apoptotic parameters. Quantification of SOD, Bcl-2, Bax, MMPs, miR-21 and miR-155 expression was performed using qRT-PCR. Results We found that metformin inhibited the growth, proliferation and clonogenic potential of the breast cancer-derived cells tested. ROS levels were found to be significantly reduced by metformin and, concomitantly, superoxide dismutase (SOD) isoforms were found to be upregulated. Mitochondrial dysfunction was observed in metformin treated cells, indicating apoptosis. In metastatic MDA-MB-231 cells, migration was found to be suppressed by metformin through deregulation of the matrix metalloproteinases MMP-2 and MMP-9. The oncogenic microRNAs miR-21 and miR-155 were found to be downregulated by metformin, which may be correlated with the suppression of cell proliferation and/or migration. Conclusions Our data indicate that metformin may play a pivotal role in modulating the anti-oxidant system, including the SOD machinery, in breast cancer-derived cells. Our observations were validated by in silico analyses, indicating a close interaction between SOD and metformin. We also found that metformin may inhibit breast cancer-derived cell proliferation through apoptosis induction via the mitochondrial pathway. Finally, we found that metformin may modulate the pro-apoptotic Bax, anti-apoptotic Bcl-2, MMP-2, MMP-9, miR-21 and miR-155 expression levels. These findings may be instrumental for the clinical management and/or (targeted) treatment of breast cancer.Item Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles(2012) Singh, R.P.; Ramarao, P.Silver nanoparticles (Ag NPs) are used in consumer products and wound dressings due to their antimicrobial properties. However, in addition to toxic effects on microbes, Ag NPs can also induce stress responses as well as cytotoxicity in mammalian cells. We observed that Ag NPs are efficiently internalized via scavenger receptor-mediated phagocytosis in murine macrophages. Confocal and electron microscopy analysis revealed that internalized Ag NPs localize in the cytoplasm. Ag NPs cause mitochondrial damage, induce apoptosis and cell death. These effects were abrogated in presence of Ag ion-reactive, thiol-containing compounds suggesting the central of Ag ions in Ag NP toxicity. Quantitative image analysis revealed that intracellular dissolution of Ag NPs occurs about 50 times faster than in water. In conclusion, we demonstrate for the first time that Ag NPs are internalized by scavenger receptors, trafficked to cytoplasm and induce toxicity by releasing Ag ions. ? 2012 Elsevier Ireland Ltd.Item Geminin a multi task protein involved in cancer pathophysiology and developmental process: A review(Elsevier B.V., 2016) Kushwaha, Prem Prakash; Rapalli, Krishna Chaitanya; Kumar, ShashankDNA replicates in a timely manner with each cell division. Multiple proteins and factors are involved in the initiation of DNA replication including a dynamic interaction between Cdc10-dependent transcript (Cdt1) and Geminin (GMNN). A conformational change between GMNN-Cdt1 heterotrimer and heterohexamer complex is responsible for licensing or inhibition of the DNA replication. This molecular switch ensures a faithful DNA replication during each S phase of cell cycle. GMNN inhibits Cdt1-mediated minichromosome maintenance helicases (MCM) loading onto the chromatin-bound origin recognition complex (ORC) which results in the inhibition of pre-replication complex assembly. GMNN modulates DNA replication by direct binding to Cdt1, and thereby alters its stability and activity. GMNN is involved in various stages of development such as pre-implantation, germ layer formation, cell commitment and specification, maintenance of genome integrity at mid blastula transition, epithelial to mesenchymal transition during gastrulation, neural development, organogenesis and axis patterning. GMNN interacts with different proteins resulting in enhanced hematopoietic stem cell activity thereby activating the development-associated genes' transcription. GMNN expression is also associated with cancer pathophysiology and development. In this review we discussed the structure and function of GMNN in detail. Inhibitors of GMNN and their role in DNA replication, repair, cell cycle and apoptosis are reviewed. Further, we also discussed the role of GMNN in virus infected host cells. ? 2016 Elsevier B.V. and Soci?t? Fran?aise de Biochimie et Biologie Mol?culaire (SFBBM)Item Ganoderma lucidum targeting lung cancer signaling: A review(SAGE Publications Ltd, 2017) Gill, Balraj Singh; Navgeet; Kumar, Sanjeev; Gill, B.S.; Navgeet, Kumar, S.Lung cancer causes huge mortality to population, and pharmaceutical companies require new drugs as an alternative either synthetic or natural targeting lung cancer. The conventional therapies cause side effects, and therefore, natural products are used as a therapeutic candidate in lung cancer. Chemical diversity among natural products highlights the impact of evolution and survival of fittest. One such neglected natural product is Ganoderma lucidum used for promoting health and longevity for a longer time. The major bioconstituents of G. lucidum are mainly terpenes, polysaccharides, and proteins, which were explored for various activities ranging from apoptosis to autophagy. The bioconstituents of G. lucidum activate plasma membrane receptors and initiate various downstream signaling leading to nuclear factor-?B, phosphoinositide 3-kinase, Akt, and mammalian target of rapamycin in cancer. The bioconstituents regulate the expression of various genes involved in cell cycle, immune response, apoptosis, and autophagy in lung cancer. This review highlights the inextricable role of G. lucidum and its bioconstituents in lung cancer signaling for the first time. ? The Author(s) 2017.