Department of Biological Sciences
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Item Calcium chloride linked camel milk derived casein nanoparticles for the delivery of sorafenib in hepatocarcinoma cells(Tech Science Press, 2021-09) Dubey, Uma S.Sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma, is limited by its low oral bioavailability. To overcome this drawback, we have developed novel camel milk casein-derived nanoparticles as a drug delivery system. Camel milk casein is not only biocompatible on oral administration but is actually a dietary protein of pharmaceutical relevance. Casein is used because of its amphiphilic nature, self-assembling property, ability to show sustained release, and capability of encapsulating both hydrophilic and hydrophobic drugs. In this study, camel milk casein nanoparticles loaded with sorafenib were developed and characterized. Characterization of casein nanoparticles was done by dynamic light scattering (DLS), zeta potential analysis, scanning light microscopy (SEM), and FTIR. The drug content in nanoparticle and drug-protein binding studies were conducted by UV spectroscopy. The cytotoxicity and cellular uptake efficiency studies were performed in HepG2 cell lines. It was observed that the cytotoxic effect of sorafenib loaded camel milk casein nanoparticles was more than free sorafenib in HepG2 cells. This work suggests camel milk casein as a suitable drug delivery molecule for sorafenib. In the future, it may also be used in enhancing the efficacy and specific distribution of other water-insoluble anticancer drugs.Item Metal-free, visible-light-mediated synthesis of tetracyclic benzimidazole: regioselective c–h functionalization with in vitro and computational study of anti-breast cancer compounds(ACS, 2025-02) Murugesan, Sankaranarayanan; Mukherjee, SudeshnaGlobally, breast cancer is the leading cause of mortality. Within the field of antibreast cancer drug design by several compound docking studies, eight new N-containing nonsteroid tetracyclic derivatives have been synthesized via regioselective intramolecular C–H functionalization by visible light. The adopted methodology is highly efficient, green, and sustainable to unload a new pathway with excellent yield. It offers a rapid, low-cost, catalyst-free method for creating physiologically active molecules from easily accessible substrates. The synthesized substances were described using spectroscopic methods like HRMS, 1HNMR, 13CNMR, and XRD analysis. This study explores the cytotoxic potential of novel compounds against human MCF-7 breast cancer cells. This study includes in vitro experiments to assess the effect of our compounds on cells. These experiments include cytotoxicity assessment by cell cycle, apoptosis, MTT test analysis by flow cytometry, reactive oxygen species (ROS) production assessment, etc. Among the novel compounds, compound 2e exhibited the most potent cytotoxic activity, with an inhibitory concentration (IC50) of 40 nM, surpassing the efficacy of established drugs such as exemestane (IC50 24.97 micromolar) and tamoxifen (IC50 5.45 μM). Compound 2e also significantly induced apoptosis and cell cycle arrest in the G1 phase, increasing the apoptotic cell population to 65.97%. Additionally, the compound led to a marked rise in the level of ROS generation, implicating oxidative stress in its mechanism of action. Molecular docking and dynamic simulation further supported the vigorous anticancer activity of compound 2e, demonstrating its promise as an effective breast cancer treatment.Item G-Protein–Coupled Receptor Kinase Interacting Protein-1 Mediates Intima Formation by Regulating Vascular Smooth Muscle Proliferation, Apoptosis, and Migration(AHA Journals, 2013-02-21) Majumder, SyamantakThe G-protein–coupled receptor kinase interacting protein-1 (GIT1) is a scaffold protein that is important for phospholipase Cγ and extracellular signal-regulated kinase 1/2 signaling induced by angiotensin II and epidermal growth factor. Because GIT1 regulates signaling by several vascular smooth muscle cell (VSMC) growth factors, we hypothesized that intima formation would be inhibited by GIT1 depletion.Item Epigallocatechin gallate induced apoptosis in Sarcoma180 cells in vivo: Mediated by p53 pathway and inhibition in U1B, U4-U6 UsnRNAs expression(Springer, 2006-10-12) Mukherjee, SudeshnaThe aim of this study was to understand the mode of action of tea polyphenol epigallocatechin gallate (EGCG) in vivo. Swiss albino mice were treated i.p. with EGCG at two different doses i.e. 12-mg/kg body weight and 15-mg/kg body weight, for 7 days prior to inoculation of Sarcoma180 (S180) cells and continued for another 7 days. The growth of the S180, harvested 7 days after inoculation, was significantly reduced due to treatment with EGCG. The flowcytometric analysis of S180 cells, showed significant increase in apoptosis and reduction in the number of cells in G2/M phase of cell cycle due to treatment with EGCG. The induction of apoptosis has also been confirmed by the TUNEL and DNA fragmentation assays. Both RT-PCR and Western blot analysis showed significant up-regulation of p53 and bax, and down-regulation of bcl-2 and c-myc due to EGCG treatment. No changes in the expression pattern of p21, p27, bcl-xl, mdm2 and cyclin D1 were seen. Interestingly, there was significant down-regulation of spliceosomal uridylic acid rich small nuclear RNAs (UsnRNAs) U1B and U4-U6 due to EGCG treatment. This indicates that these UsnRNAs may be involved in the apoptosis process. Taken together, our study suggests that in vivo EGCG could induce apoptosis in S180 cells through alteration in G2/M phase of the cell cycle by up-regulation of p53, bax and down-regulation of c-myc, bcl-2 and U1B, U4-U6 UsnRNAs.Item Tea polyphenols can restrict benzo[a]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1(Elsiever, 2009-05) Mukherjee, SudeshnaThe modulatory influence of tea polyphenols (epigallocatechin gallate, epicatechin gallate and theaflavin) on benzo[a]pyrene (B[a]P)-induced lung carcinogenesis in mice was analyzed using histopathological and molecular parameters. Progression of lung lesions was restricted at the hyperplastic stage by tea polyphenols. A significant reduction in cellular proliferative index and an increase in apoptotic index were noted in the restricted lung lesions. High expression of H-ras, c-myc, cyclin D1 and p53 genes was seen at the inflammatory stage (9th week) and in subsequent premalignant lesions, but down-regulation of H-ras at the hyperplastic stage (17th week). Expression of bcl-2 was high in hyperplastic lesions, whereas the expression of mdm2 and bcl-xl increased only at the moderately dysplastic stage (36th week). The tea polyphenols inhibited inflammatory response in the lung lesions on the 9th week, when decreased expression of H-ras and c-myc and increased expression of bax were noted. Prolonged treatment (>9th week) with tea polyphenols resulted in changes in the expression of some additional genes, such as reduced expression of cyclin D1 (from the 17th week), bcl-2 (from the 26th week; mild dysplasia) and p21 (on the 36th week), and high expression of p53 (from the 17th week) and p27 (on the 36th week). These observations indicate that the tea polyphenols can restrict B[a]P-induced lung carcinogenesis by differential modulation of the expression of p53 and its associated genes such as bax, bcl-2, mdm2, p21 and p27, along with H-ras, c-myc and cyclin D1, at different time points.Item Evaluation of Apoptosis and Autophagy Inducing Potential of Berberis aristata, Azadirachta indica, and Their Synergistic Combinations in Parental and Resistant Human Osteosarcoma Cells(Frontiers, 2017) Chowdhury, Rajdeep; PAUL, Atish T.; Mukherjee, SudeshnaCancer is a multifactorial disease and hence can be effectively overcome by a multi-constituently therapeutic strategy. Medicinal plant extracts represent a perfect example of such stratagem. However, minimal studies have been done till date that portray the effect of extraction techniques on the phyto-constituent profile of plant extracts and its impact on anticancer activity. In the present study, we have evaluated the anticancer potential of methanolic extracts of Berberis aristata root and Azadirachta indica seeds prepared by various extraction techniques in human osteosarcoma (HOS) cells. Soxhlation extract of B. aristata (BAM-SX) and sonication extract of A. indica (AIM-SO) were most effective in inducing apoptosis in parental drug sensitive, as well as resistant cell type developed by repeated drug exposure. Generation of reactive oxygen species and cell cycle arrest preceded caspase-mediated apoptosis in HOS cells. Interestingly, inhibition of autophagy enhanced cell death suggesting the cytoprotective role of autophagy. Combination studies of different methanolic extracts of BAM and AIM were performed, among which, the combination of BAM-SO and AIM-SO (BAAISO) was found to show synergism (IC50 10.27 µg/ml) followed by combination of BAM-MC and AIM-MC (BAAIMC) with respect to other combinations in the ratio of 1:1. BAAISO also showed synergism when it was added to cisplatin-resistant HOS cells (HCR). Chromatographic profiling of BAM-SX and AIM-SO by high performance thin layer chromatography resulted in identification of berberine (Rf 0.55), palmitine (Rf 0.50) in BAM-SX and azadirachtin A (Rf 0.36), azadirachtin B (Rf 0.56), nimbin (Rf 0.80), and nimbolide (Rf 0.43) in AIM-SO. The cytotoxic sensitivity obtained can be attributed to the above compounds. Our results highlight the importance of extraction technique and subsequent mechanism of action of multi-constituential B. aristata and A. indica against both sensitive and drug refractory HOS cells.Item HnRNP E2 is downregulated in human oral cancer cells and the overexpression of hnRNP E2 induces apoptosis(Wiley, 2007) Chowdhury, RajdeepHuman hnRNP genes have been reported to be involved in human malignancies and several hnRNPs are promising biomarkers of lung, head and neck, colon, breast, and pancreatic cancers. The present study investigated the clinicopathologic and biological significance of hnRNP E2 gene expression in oral cancer. Human hnRNP E2 was significantly downregulated in oral cancer tissues compared to normal one (P < 0.0001) as determined by quantitative real-time reverse transcription PCR. The expression of hnRNP E2 is correlated with histology, being lower in moderate and poorly differentiated squamous cell carcinoma (SCC) compared to well-differentiated SCC. Transient transfection of hnRNP E2 in cancerous cell lines resulted in reduced cell viability and increased apoptotic nuclei. Compared to control transfectants, cells with higher expression showed an increase in the number of apoptotic cells by annexin-PI staining and an increase in caspase activity. The present study thus implicates downregulation of hnRNP E2 as a novel mechanism to enhance the resistance of cancer cells to apoptosis.Item Exploring the extensive crosstalk between the antagonistic cytokines- TGF-β and TNF-α in regulating cancer pathogenesis(Elsiever, 2021) Chowdhury, Rajdeep; Mukherjee, SudeshnaA plethora of cytokines are produced in the tumor microenvironment (TME) those play a vital role in cancer prognosis. Though it is completely contextual, cytokines produced from an inflammatory micro-environment can either modulate cancer progression at early stages of tumor development or in later stages cytokine derived cues can in turn control tumor cell invasion and metastasis. Therefore, understanding the crosstalk between the key cytokines regulating cancer prognosis is critical for the development of an effective therapy. In this regard, the role of transforming growth factor-beta (TGF-β) in cancer is controversially discussed in general inhibition of TGF-β promotes de novo tumorigenesis whereas paradoxically, TGF-β can promote malignancy in already established tumors. Another important cytokine, TNF-α have intense crosstalk with TGF-β from the fact that in a non-cancer context, TGF-β promotes fibrosis whereas TNF-α has anti-fibrotic activity. We have recently reported that TGF-β-induced differentiation of epithelial cells to mesenchymal type is suppressed by TNF-α through regulation of cellular homeostatic machinery- autophagy. Moreover, there are also rare reports of synergy between these two cytokines as well. The crosstalk between TGF-β and TNF-α is not only limited to regulating cancer cell differentiation and proliferation but also includes involvement in cell death. In this review, we hence summarize the molecular mechanisms by which these two important cytokines, TGF-β and TNF-α control cancer prognosis.Item Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicity(Elsiever, 2006) Deepa, P.R.The spectrum of the anti-apoptotic potential of heparin is currently under scrutiny in various tissues and under various pathological situations. In this study, the role of a low-molecular-weight heparin derivative (LMWH), certoparin in adriamycin-induced oxidative DNA damage has been evaluated in the cardiac and renal tissues. Two groups of male albino rats of the Wistar strain (140 ± 10 g) received a single intravenous injection of adriamycin (7.5 mg/kg), and one of them received low-molecular-weight heparin (Certoparin Sodium, 300 μg/day/rat s.c.) treatment, commencing on day 8, continued for a week. The nitrosative stress in ADR cytotoxicity is indicated by the 1.51-fold cardiac and 2.36-fold renal increase in reactive nitrogen species (RNS), while LMWH treatment restores normalcy (p < 0.001). The influence of LMWH on the pro-inflammatory and pro-apoptotic cytokine, TNF-α was studied. Renal and cardiac levels of TNF-α showed a significant rise (p < 0.001) in the ADR cytotoxic group, while the TNF-α values departed towards control levels in the LMWH treated group (p < 0.001). DNA damage indicated by the fragmentation pattern (agarose gel electrophoresis) and the significantly increased comet tail length (p < 0.001) observed after alkaline single cell gel electrophoresis confirmed the toxicity induced by ADR on DNA in the untreated group. In the LMWH-treated group, the observation of intact DNA band after agarose gel electrophoresis, and the finding of comet tail length being comparable with that of the control substantiated the protection rendered by the LMWH, certoparin. In short, the results suggest that the low-molecular-weight heparin derivative, certoparin exerts beneficial effects on the nitrosative status, and on the biological macromolecules as DNA and curtails the rise of the pro-apoptotic and pro-inflammatory cytokine, TNF-α in the cardiac and renal tissues.Item Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors(Elsiever, 2013) Deepa, P.R.Retinoblastoma (RB) is a malignant intra-ocular neoplasm that affects children (usually below the age of 5 years). In addition to conventional chemotherapy, novel therapeutic strategies that target metabolic pathways such as glycolysis and lipid metabolism are emerging. Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is over-expressed in retinoblastoma cancer. The present study evaluated the biochemical basis of FASN inhibition induced apoptosis in cultured Y79 RB cells. FASN inhibitors (cerulenin, triclosan and orlistat) significantly inhibited FASN enzyme activity (P < 0.05) in Y79 RB cells. This was accompanied by a decrease in palmitate synthesis (end-product depletion), and increased malonyl CoA levels (substrate accumulation). Differential lipid profile was biochemically estimated in neoplastic (Y79 RB) and non-neoplastic (3T3) cells subjected to FASN inhibition. The relative proportion of phosphatidyl choline to neutral lipids (triglyceride + total cholesterol) in Y79 RB cancer cells was found to be higher than the non-neoplastic cells, indicative of altered lipid distribution and utilization in tumor cells. FASN inhibitor treated Y79 RB and fibroblast cells showed decrease in the cellular lipids (triglyceride, cholesterol and phosphatidyl choline) levels. Apoptotic DNA damage induced by FASN inhibitors was accompanied by enhanced lipid peroxidation.