Department of Biological Sciences
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Item Dual drug loaded vitamin D3 nanoparticle to target drug resistance in cancer(RSC, 2014) Chowdhury, RajdeepOvercoming drug resistance is one of the most challenging problems in cancer chemotherapy. Drug cocktails can overcome the drug resistance. However, multiple drug combinations lead to multifold increment of off-target toxicity, as well as the delivery of the required therapeutic amount of combined drugs remains problematic. To address these problems, we have developed a sub 200 nm vitamin D3 nanoparticle, which can contain a rational combination of dual drugs (PI103 and cisplatin or doxorubicin or proflavine). The size, shape and morphology of these dual drug containing vitamin D3 nanoparticles were characterized by DLS, FESEM, AFM and TEM. The nanoparticles released the dual drugs in high quantity at pH = 5.5 compared to pH = 7.4 in a slow and sustained manner over 72 h with stability over 15 days at 37 °C, as well as 4 °C. These dual drug loaded nanoparticles induced increased cell death in human hepatocellular carcinoma, Hep3B cells at 24 h compared to monotherapy; moreover, they were effective against cisplatin-resistant cells (Hep3B-R) as well. VitD3–PI103–CDDP-NP and vitD3–PI103–Dox-NP showed cytotoxicity by inducing apoptosis through DNA damage. Furthermore, vitD3–PI103–CDDP-NP showed considerably improved efficacy in 5-fluorouracil (5-FU) resistant Hep3B–5FU-R cells; its activity was even better compared to 5-FU. Finally, vitD3–PI103–proflavine-NP internalized into Hep3B-R cells considerably faster (within 3 minutes) compared to Hep3B cells, as visualized by fluorescent microscopy. Therefore, these dual drug loaded nanoparticles can successfully overcome the trauma of drug resistance and have the potential to be applied into the clinics for improved cancer therapeutics.Item Fast Microwave Assisted Synthesis of Pyranopyrazole Derivatives as New Anticancer Agents(Bentham Science, 2016) Chowdhury, Rajdeep; Shukla, ParitoshA series of compounds having the pyranopyrazole pharmacophore were synthesised by the traditional method and then by an unreported rapid four-component microwave assisted method. The microwave strategy required substantially shorter reaction times as compared to the traditional method. The prepared molecules were tested in-vitro for their cytotoxic activity against the Hep3B cancer cell lines. The activity results were subsequently rationalized for a quick structure-activity relationship leading to the conclusion that the presence of certain heteroatom substituents at a 3-position of the pharmacophore may be crucial for anticancer potency.Item Chitosan-encapsulated ZnS : M (M: Fe3+ or Mn2+) quantum dots for fluorescent labelling of sulphate-reducing bacteria(IAS, 2016) Chowdhury, Rajdeep; MAZUMDER, SonalChitosan-encapsulated Mn2+andFe^{3+}−dopedZnScolloidalquantumdots(QDs)weresynthesizedusingchemicalprecipitationmethod.Thoughtherearemanyreportsonbio−imagingapplicationsofZnSQDs,thepresentstudyfocussedonthenewtypeofmicrobial−inducedcorrosivebacteriaknownassulphate−reducingbacteria,Thiobacillusnovellus.Sulphate−reducingbacteriacanobtainenergybyoxidizingorganiccompoundswhilereducingsulphatestohydrogensulphide.Thiscancreateaprobleminengineeringindustries.Whenmetalsareexposedtosulphatecontainingwater,waterandmetalinteractsandcreatesalayerofmolecularhydrogenonthemetalsurface.Sulphate−reducingbacteriathenoxidizethehydrogenwhilecreatinghydrogensulphide,whichcontributestocorrosionforinstance,inpipelinesofoilandgasindustries.Inthisstudy,detectionandlabellingofsulphate−reducingbacteriaisdemonstratedusingfluorescentQDs.ChitosancappedZnSQDsweresynthesizedusingdopantsatdifferentdopingconcentrations.UV–Visspectroscopy,XRDandFTIRcharacterizationsweredonetoidentifytheopticalbandgapenergy,crystalplanesanddeterminethepresenceofcappingagent,respectively.Themorphologyandtheaverageparticlesizeof3.5\pm 0.2$ nm were analysed using TEM which substantiated UV–Vis and XRD results. Photoluminescence spectroscopy detected the bacteria attachment to the QDs by showing significant blue shift in bacteria conjugated ZnS QDs. Fluorescence microscopy confirmed the fluorescent labelling of QDs to Thiobacillus novellus bacteria cells making them ideal for bio-labelling applications.Item The dynamic role of autophagy and MAPK signaling in determining cell fate under cisplatin stress in osteosarcoma cell(Plos One, 2017) Chowdhury, Rajdeep; Mukherjee, SudeshnaOsteosarcoma (OS) is an aggressive bone malignancy commonly observed in children and adolescents. Sub-optimal therapy for years has irretrievably compromised the chances of OS patient survival; also, lack of extensive research on this rare disease has hindered therapeutic development. Cisplatin, a common anti-tumor drug, is currently an integral part of treatment regime for OS along with methotrexate and doxorubicin. However, toxicity issues associated with combination module impede OS therapy. Also, despite the proven benefits of cisplatin, acquisition of resistance remains a concern with cisplatin-based therapy. This prompted us to investigate the molecular effects of cisplatin exposure and changes associated with acquired resistance in OS cells. Cisplatin shock was found to activate MAPK signaling and autophagy in OS cells. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. A crosstalk between JNK and autophagy was observed. Maximal sensitivity to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Cisplatin resistant cells were further developed by repetitive drug exposure followed by clonal selection. The resistant cells showed an altered signaling circuitry upon cisplatin exposure. Our results provide valuable cues to possible molecular alterations that can be considered for development of improved therapeutic strategy against osteosarcomaItem Understanding cancer complexome using networks, spectral graph theory and multilayer framework(Springer Nature, 2017) Chowdhury, RajdeepCancer complexome comprises a heterogeneous and multifactorial milieu that varies in cytology, physiology, signaling mechanisms and response to therapy. The combined framework of network theory and spectral graph theory along with the multilayer analysis provides a comprehensive approach to analyze the proteomic data of seven different cancers, namely, breast, oral, ovarian, cervical, lung, colon and prostate. Our analysis demonstrates that the protein-protein interaction networks of the normal and the cancerous tissues associated with the seven cancers have overall similar structural and spectral properties. However, few of these properties implicate unsystematic changes from the normal to the disease networks depicting difference in the interactions and highlighting changes in the complexity of different cancers. Importantly, analysis of common proteins of all the cancer networks reveals few proteins namely the sensors, which not only occupy significant position in all the layers but also have direct involvement in causing cancer. The prediction and analysis of miRNAs targeting these sensor proteins hint towards the possible role of these proteins in tumorigenesis. This novel approach helps in understanding cancer at the fundamental level and provides a clue to develop promising and nascent concept of single drug therapy for multiple diseases as well as personalized medicine.Item Aggregation induced emission’ active iridium(iii) complexes with applications in mitochondrial staining(RSC, 2017) Chowdhury, Rajdeep; Laskar, Inamur RahamanTwo new bis-cyclometalated iridium(III) complexes, [Ir(F2ppy)2(L)] and [Ir(ppy)2(L)], where F2ppy = 2-(2′,4′-difluoro)phenylpyridine, ppy = 2-phenylpyridine and L = 1,2-((pyridin-2-ylimino)methyl)phenol, have been designed and synthesized by a convenient route. We have univocally characterized their structure by 1H NMR, 19F NMR, HRMS and SXRD. Both complexes exhibit strong ‘Aggregation Induced Emission (AIE)’ activity, which has been investigated using spectroscopy measurements, ab initio quantum chemical calculations and by analysing their crystal packing. One of the complexes has been shown to have a potential application as a non-toxic bio-imaging probe for mitochondrial staining.Item Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies(Bentham Science, 2019) Chowdhury, Rajdeep; Shukla, Paritosh; Sharma, AshokBackground: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.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 Design, in silico modeling, biodistribution study of rutin and quercetin loaded stable human hair keratin nanoparticles intended for anticancer drug delivery(IOP, 2018) Chowdhury, Rajdeep; Murugesan, SankaranarayananCurrent drug development using functional polymers is one of the major tasks for enhancing effectiveness and reducing the side effects in cancer therapeutics. To achieve this immense goal, human hair keratin and model drugs rutin-quercetin (Ru-Qr) were chosen to formulate nanoparticles (NPs). Drug delivery is a core path to produce significant biological activity, and in this connection, the current study was designed to produce highly stable Ru-Qr NPs and their characterization such as the encapsulation of Ru-Qr, the nature, molecular shape, particle size, stability and polydispersity index by Fourier transform infrared spectroscopy, x-ray diffraction, scanning electron microscopy, transmission electron microscopy and Zetasizer analyzer. Based on a literature report, the drug targets 521P and 5P21 were chosen to perform in silico study. The observed in silico study reports showed the strong interaction of NPs and binding pockets of H-Ras P21 proto-oncogene. In this respect, the importance of NPs prompted us to study the biodistribution and in vitro anticancer activity by using cancer cell lines. The investigation of biodistribution showed that it penetrated after 3 d of injection, up to 14% in the liver, 18% in the kidneys, 8% in the spleen, 3% in the heart and 0% in the brain. At 50 μg ml−1 concentration, the NPs displayed 78.02% viability in the normal liver cell line and 95.60% cytotoxicity in the HeLa cell line. The obtained results showed the active NPs enhancing controlled, site-specific drug delivery and they can serve as a novel nanodrug in the management of cancer.Item Exploring the Hidden Potential of Benzothiazole Based Schiff base “AIE and ESIPT” active for pH Sensing, Intracellular Imaging and Ultrasensitive & Selective detection of Aluminium (Al3+).(RSC, 2018) Chowdhury, Rajdeep; Laskar, Inamur RahamanThe Analyst is an international journal concerned with the development and application of analytical and bioanalytical techniques. The journal is published monthly, and also includes critical, tutorial and mini-reviews on selected topics of interest to analytical scientists. Occasional special issues are also published. The Analyst publishes full papers and urgent communications on all aspects of the theory and practice of analytical science, both fundamental and applied, including bioanalysis (including biospecific assays), chromatography and electrophoresis, mass spectrometry, electrochemistry, sensors, imaging techniques, sampling and sample handling, chemometrics/statistics, atomic and molecular spectroscopy and all other areas related to measurement science.