Year of Publication Publication Type Title

2020

Journal Article

A. Sreekumar, Navaneeth, P., Suneesh, P. Vasu, Dr. Bipin G. Nair, and Dr. Satheesh Babu T. G., “A graphite pencil electrode with electrodeposited Pt-CuO for nonenzymatic amperometric sensing of glucose over a wide linear response range”, Microchimica Acta, vol. 187, p. 113, 2020.[Abstract]


A disposable nonenzymatic glucose sensor was obtained by pulsed electrodeposition of Pt-CuO on a graphite pencil electrode (GPE). The morphology of the modified GPE was studied using SEM, and the chemical composition of the coating was examined by EDAX and XRD. The electrochemical response of the modified GPE was compared with individual copper- and platinum-modified GPEs. The electrodeposition parameters were optimized with respect to the electrocatalytic activity of the deposits towards glucose oxidation. Best operated at a working potential of 0.6 V vs. Ag/AgCl, the sensor has a sensitivity of 2035 μA mM−1 cm−2, a 0.1 μM detection limit and a wide linear response range that extends up to 25 mM. It is highly selective for glucose in the presence of various exogenous and endogenous interfering species. Eventhough the requirement of alkaline medium for sensing is a limitation, easy fabrication procedure, very high sensitivity and selectivity, wide analytical range, and disposable sensor characteristics show potential application towards blood glucose determination.

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2020

Journal Article

A. K. Ravi, Navaneeth, P., Suneesh, P. Vasu, Dr. Bipin G. Nair, and Dr. Satheesh Babu T. G., “Manganese dioxide based electrochemical sensor for the detection of nitro-group containing organophosphates in vegetables and drinking water samples”, Journal of Electroanalytical Chemistry, p. 113841, 2020.[Abstract]


The widespread use of organophosphates in agricultural farms for pest control has raised serious concerns over the quality of food and water available to the common public. As an effort to fabricate a sensitive, selective, cost-effective and non-toxic sensor to detect nitro-group containing organophosphates in and vegetable washings, a simple manganese dioxide based sensor was developed. α-Manganese dioxide nano-rods were electrodeposited on platinum disk electrode (MnO2/Pt) and is employed to detect 4-nitrophenyl phosphate (4-NPP). 4-NPP is a model compound that well represents widely used nitro-group containing organophosphates such methyl parathion, parathion, fenitrothion, methyl paraoxon and paraoxon in aqueous medium. Determination of 4-NPP at nanomolar levels was achieved using the fabricated sensor using cyclic voltammetry. The developed sensor was found to show a linear response in the concentration range 100 nM to 900 nM with a Limit of Detection (LOD) of 10 nM and a high sensitivity of 11.68 μA μM−1. The sensor showed good selectivity against many of common inorganic ions and two of the major organophosphates: Quinalphos and Dimethoate but the selectivity is poor among other nitro-group containing aromatics.

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2020

Journal Article

V. S. Vargis, Vasu, S. P., Sree, R. J., Dr. Bipin G. Nair, and Dr. Satheesh Babu T. G., “Peroxidase Labeled Antibody Conjugated Gold Nanoparticles for Ultrasensitive Voltammetric Immunosensing”, IEEE Sensors Journal, vol. 20, pp. 1142-1149, 2020.[Abstract]


An electrochemical immunosensing platform capable of detecting Immunoglobulin G (IgG) concentration as low as femtograms was developed based on signal amplification strategy. The immunosensing platform was fabricated using self-assembled monolayers (SAM) of 11- mercaptoundecanoic acid (MUDA) on a gold disc electrode. The covalent immobilization of antibody was achieved through the bonding of a carboxyl group of MUDA and amino group of antibody using [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide] (EDC) and N-hydroxysuccinimide (NHS) chemistry. The formation of SAM and antibody immobilization was analyzed using cyclic voltammetry and electrochemical impedance spectroscopy. The gold nanoparticles conjugated with horseradish peroxidase-labeled secondary antibodies were used as nanolabels, to increase the sensitivity and catalytic efficiency of the immunosensor. The sandwich immunocomplex formed on the electrode surface produced an electrocatalytic response through the reduction of hydrogen peroxide in the presence of thionin. The fabricated immunosensor exhibited two linear ranges that included IgG concentrations of 10 fg mL−1 to 0.1 ng mL−1 and 0.1 to 100 ng mL−1 respectively.

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2020

Conference Proceedings

Anupama Binoy, Divya Nedungadi, Damu Sunilkumar, Dr. Bipin G. Nair, and Dr. Nandita Mishra, “Role of AIF in Plumbagin induced Paraptosis-A caspase independent cell death in MDA-MB-231 cancer cells”, 39th Annual Conference of Indian Association for Cancer Research (IACR-2020): “Leading the Fight against Cancer”, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India, February 5-7. 2020.

2020

Conference Proceedings

Sanu K Shaji, Damu Sunilkumar, Dr. Geetha Kumar, and Dr. Bipin G. Nair, “Systematic understanding of anti-tumor mechanisms of tamarixetin through network and experimental analyses”, 39th Annual Conference of Indian Association for Cancer Research (IACR-2020): “Leading the Fight against Cancer”, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India, February 5-7. 2020.

2020

Journal Article

S. Khatun, Biswas, S., Anupama Binoy, Podder, A., Dr. Nandita Mishra, and Bhuniya, S., “Highly chemoselective turn-on fluorescent probe for ferrous (Fe2+) ion detection in cosmetics and live cells”, Journal of Photochemistry and Photobiology B: Biology, vol. 209, p. 111943, 2020.[Abstract]


In modern society, the use of cosmetics has increased extensively; unfortunately, so-called several toxic metal salts are present as the colorant or filler in cosmetics. The ferrous ion (Fe2+) is one of the metal ions used in cosmetics as a colorant. Ferrous ion (Fe2+) is a vital component in live cells. Considering the adverse effect of high doses of ferrous ions in cosmetics and live cells, we developed a turn-on fluorescent probe PFe(II) for quantitative estimation of ferrous ion (Fe2+) in cosmetics and monitoring of labile ferrous (Fe2+) ion in live cells. The fluorescent probe PFe(II) showed a visual color change from colorless to orange in the presence of ferrous ion (Fe2+) in the cosmetics. We observed that UV-absorption increased at 390 nm upon incubation with ferrous ion (Fe2+). The probe PFe(II) has provided quantitative information on ferrous ion (Fe2+) in various cosmetics, kajol, lip balm, face foundation, mascara, eyeliner, lipliner, face makeup, sindoor, lipstick, nail polish in ppm level through the fluorescence signaling at 460 nm.The probe PFe(II) provided information on labile Fe2+ ion pool via a fluorescence imaging. It is a new addition to the diagnostic inventory for detecting ferrous ion in live cells and cosmetics.

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2020

Journal Article

A. Vijayakumar, Madhavan*, A., Chinchu Bose, Pandurangan Nanjan, Kokkal, S. S., Veedu, A. P., Megha Prasad, Dr. Sanjay Pal, and Dr. Bipin G. Nair, “Potent Chitin Synthase Inhibitors from Plants”, Current Bioactive Compounds, vol. 16, no. 1, 2020.[Abstract]


Background: Chitin is the main component of fungal, protozoan and helminth cell wall. Theyhelp to maintain the structural and functional characteristics of these organisms. The chitin wall is dynamicand is repaired, rearranged and synthesized as the cells develop. Active synthesis can be noticedduring cytokinesis, laying of primary septum, maintenance of lateral cell wall integrity and hyphal tipgrowth. Chitin synthesis involves coordinated action of two enzymes namely, chitin synthase (that laysnew cell wall) and chitinase (that removes the older ones). Since chitin synthase is conserved in differenteukaryotic microorganisms that can be a ‘soft target’ for inhibition with small molecules. Whenchitin synthase is inhibited, it leads to the loss of viability of cells owing to the self- disruption of thecell wall by existing chitinase.Methods: In the described study, small molecules from plant sources were screened for their ability tointerfere with hyphal tip growth, by employing Hyphal Tip Burst assay (HTB). Aspergillus niger wasused as the model organism. The specific role of these small molecules in interfering with chitin synthesiswas established with an in-vitro method. The enzyme required was isolated from Aspergillus nigerand its activity was deduced through a novel method involving non-radioactively labelled substrate. Theactivity of the potential lead molecules were also checked against Candida albicans and Caenorhabditiselegans. The latter was adopted as a surrogate for the pathogenic helminths as it shares similarity withregard to cell wall structure and biochemistry. Moreover, it is widely studied and the methodologies arewell established.Results: Out of the 11 compounds and extracts screened, 8 were found to be prospective. They werealso found to be effective against Candida albicans and Caenorhabditis elegans.Conclusion: Purified Methyl Ethyl Ketone (MEK) Fraction1 (F1) of Coconut (Cocos nucifera) ShellExtract (COSE) was found to be more effective against Candida albicans with an IC50 value of 3.04μg/mL and on L4 stage of Caenorhabditis elegans with an IC50 of 77.8 μg/mL.

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2020

Journal Article

Hemalatha Sasidharakurup and Dr. Shyam Diwakar, “Computational modelling of TNFα related pathways regulated by neuroinflammation, oxidative stress and insulin resistance in neurodegeneration”, Applied Network Science, vol. 5, no. 1, p. 72, 2020.[Abstract]


Computational and mathematical modelling towards understanding the structure and dynamics of biological systems has significantly impacted on translational neuroscience to face novel approaches toward neurological disorders such as Alzheimer’s (AD) and Parkinson’s disease (PD). In this study, a computational model of AD and PD have been modelled using biochemical systems theory, and shows how Tumour Necrosis Factor alpha (TNF훼) regulated neuroinflammation, oxidative stress and insulin pathways can dysregulate its downstream signalling cascade that lead to neurodegeneration observed in AD and PD. The experimental data for initial conditions for this model and validation of the model was based on data reported in literature. In simulations, elevations in the aggregations of major proteins involved in the pathology of AD and PD including amyloid beta, alpha synuclein, tau have been modelled. Abnormal aggregation of these proteins and hyperphosphorylation of tau were observed in the model. This aggregation may lead to developing Lewy bodies, fibrils, plaques and tangles inside neurons that trigger apoptosis. An increase in the concentrations of TNF훼 and glutamate during diseased conditions was noted in the model. Accumulation of these proteins may be related to the feedback mechanism of TNF훼 that initiates its own release and the production of excess glutamate. This could lead to the prolonged activation of microglia that result in death of surrounding neurons. With the elevation in reactive oxygen species, oxidative stress also increased. Simulations suggest insulin may be an important factor identifying neurodegeneration in AD and PD, through its action along with the neuroinflammation and oxidative stress. Low insulin level was noticed in the diseased condition due to abnormal protein aggregation that leads to TNFα release. Given the role towards better design of real experiments, accumulation of oligomers of mutated proteins in AD and PD activating microglia and secreting TNFα along with other cytokines map to oxidative stress that led to cell death.

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2020

Journal Article

E. Peñas-LLedó, Terán, E., Sosa-Macías, M., Galaviz-Hernández, C., Gil, J. - P., Nair, S., Dr. Shyam Diwakar, Hernández, I., Lara-Riegos, J., Ramírez-Roa, R., Verde, gnacio, Tarazona-Santos, E., Molina-Guarneros, J., Moya, G., ägo, L., and Adrian Llerena, “Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings”, Conclusions From the Council for International Organizations of Medical Sciences–Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting, Clinical Therapeutics, vol. 42, no. 8, pp. 1595-1610, 2020.[Abstract]


Purpose
The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics.
Methods
A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted.
Findings
The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common.
Implications
The main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

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2020

Journal Article

Dr. Krishnashree Achuthan, Prof. Prema Nedungadi, Kolil, V. Kani, Dr. Shyam Diwakar, and Raghu Raman, “Innovation Adoption and Diffusion of Virtual Laboratories”, International Journal of Online and Biomedical Engineering (IJOE), vol. 16, no. 9, 2020.[Abstract]


Educational technology such as Virtual laboratories (VLs) are being perceived as sustainable solutions to growing concerns related to laboratory skill training i.e. delivering quality laboratory education to a large number of students due to shortage of infrastructure and access especially in developing nations. With these VLs being an innovation for engineering education, the study of its diffusion in higher educational institutions is critical for gauging its impact. This study examines the five variables of Rogers Diffusion of Innovations theory in determining how VLs have changed or modified users through its adoption. The involvement of early adopters participating through a program called Nodal centers and their innovation decision stages are addressed. The study also analyzed the change agents as the nodal centers for diffusing the innovation in teaching and learning processes. Virtual laboratory adoption by users (n=43600) over 30 months was surveyed and factors of diffusion were reported. Similar scoring in assessment factors suggested relative advantage, technology acceptance, intention of use and relevance of trialability were pertinent in users' perception of VLs. Social hubs among higher education institutions promoted early adoption through better engagement of students.

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2020

Journal Article

Drishya G., Dr. Jyotsna Nambiar, Sanu K. Shaji, Muralidharan Vanuopadath, A., A., Abishek, K., Ashna, A., Ayesha Sherif, Catherine Joseph, Divya P., Damu Sunilkumar, Chinchu Bose, Dr. Sobha V. Nair, S. Sudarslal, Dr. Geetha Kumar, S., L., and Dr. Bipin G. Nair, “RECK and TIMP-2 mediate inhibition of MMP-2 and MMP-9 by Annona muricata”, Journal of Biosciences, vol. 45, no. 1, p. 89, 2020.[Abstract]


Up-regulation of MMP-2 and MMP-9 plays a significant role in promoting cancer progression by degrading the components of the extracellular matrix, thereby enhancing the migration of tumor cells. Although the anti-proliferative and apoptotic effect of Annona muricata is well established, its effect on MMP-2 and MMP-9, a major target in several types of cancers, has not been studied. Powdered samples of various parts of A. muricata like fruit, stem, seed, and twig extracted using aqueous methanol showed significant dose-dependent inhibition of MMP-2 and MMP-9 in a highly metastatic fibrosarcoma cell line, HT1080. Additionally, these extracts also up-regulated the expression of several endogenous inhibitors of MMP-2 and MMP-9 like REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2). Furthermore, primary cells developed from tumor tissues obtained from patients not exposed to chemotherapy, also exhibited similar results. Remarkably, the inhibition of MMP-2 and MMP-9 observed was tumor specific, with the A. muricata fruit extract showing only 2% inhibition in cells obtained from normal tissues, when compared to 60% inhibition observed in cells obtained from tumor samples. The present study elucidates a novel mechanism by which A. muricata extracts selectively exhibit their anti-cancer activity in tumor cells by down-regulating MMP-2 and MMP-9 that are important biomarkers in cancer.

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2020

Journal Article

Divya Nedungadi, Anupama Binoy, Nanjan Pandurangan, Dr. Bipin G. Nair, and Dr. Nandita Mishra, “Proteasomal dysfunction and ER stress triggers 2′‐hydroxy‐retrochalcone‐induced paraptosis in cancer cells”, Cell Biology International, 2020.[Abstract]


Chalcones are biologically active class of compounds, known for their anticancer activities. Here we show for the first time that out of the six synthetic derivatives of chalcone tested, 2′‐hydroxy‐retrochalcone (HRC) was the most effective in inducing extensive cytoplasmic vacuolation mediated death called paraptosis in malignant breast and cervical cancer cells. The cell death by HRC is found to be nonapoptotic in nature due to the absence of DNA fragmentation, PARP cleavage, and phosphatidylserine externalization. It was also found to be nonautophagic as there was an increase in the levels of autophagic markers LC3I, LC3II and p62. Immunofluorescence with the endoplasmic reticulum (ER) marker protein calreticulin showed that the cytoplasmic vacuoles formed were derived from the ER. This ER dilation was due to ER stress as evidenced from the increase in polyubiquitinated proteins, Bip and CHOP. Docking studies revealed that HRC could bind to the Thr1 residue on the active site of the chymotrypsin‐like subunit of the proteasome. The inhibition of proteasomal activity was further confirmed by the fluorescence based assay of the chymotrypsin‐like subunit of the 26S proteasome. The cell death by HRC was also triggered by the collapse of mitochondrial membrane potential and depletion of ATP. Pretreatment with thiol antioxidants and cycloheximide were able to inhibit this programmed cell death. Thus our data suggest that HRC can effectively kill cancer cells via paraptosis, an alternative death pathway and can be a potential lead molecule for anticancer therapy.

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2020

Journal Article

A. Alangode, Karthika Rajan, and Dr. Bipin G. Nair, “Snake antivenom: Challenges and alternate approaches”, Biochemical Pharmacology, vol. 181, p. 114135, 2020.[Abstract]


Snake envenomation is still a serious threat to many countries in the world. The only mainstay treatment depends on the administration of animal derived immunoglobulin based antivenom. Significant limitations to these antivenoms are a challenge in the treatment of snake envenomation. Many alternate approaches have been explored to overcome the limitations of antivenom. Exploring alternate approaches like use of bioactive components from plant sources, use of peptide and small molecule inhibitors are some aspects taken towards improving the current limitations of antivenom therapy. However, all these alternate approaches also have many drawbacks which should be improved by more in vitro and in vivo experiments. Here, we review some of the limitations of current antivenom therapy and developments as well as drawbacks of these alternate treatment strategies.

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2020

Journal Article

A. Pathak, Venugopal, P., Dr. Bipin G. Nair, Suneesh, P. Vasu, and Babu, T. G. Satheesh, “Facile pH-sensitive optical detection of pathogenic bacteria and cell imaging using multi-emissive nitrogen-doped carbon dots”, Microchemical Journal, vol. 159, p. 105324, 2020.[Abstract]


Rapid detection of lethal pathogens is critical to abate the mortality rate of patients suffering from infectious diseases. Herein, we report a pH-sensitive detection of the pathogenic bacteria using multicolor emissive Nitrogen-doped Carbon Dots (NtCD) synthesized by a one-step hydrothermal method. The unique pH-sensitive interaction of NtCD with bacteria was best studied at pH 2. NtCD was competent to detect several pathogenic bacteria such as; Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis) and Proteus vulgaris (P. vulgaris). The fluorescence spectral investigations of NtCD revealed the excitation dependent emission property with a red-shift. It shows an intense photoluminescent (PL) emission at λex/λem = 340/435 nm. The calculated quantum yield of NtCD was 27.2%. It also possesses multicolor emission at different excitation wavelengths. TEM analysis displayed the uniform spherical morphology of NtCD particles with an average hydrodynamic diameter of 3.11 ± 0.75 nm. The zeta potential of NtCD was measured as −8.4 mV at pH 2. The interaction between NtCD and bacteria was explained on the basis of their zeta potential values. The PL emission response of NtCD tagged bacteria was investigated at λex = 340 nm. It was potentially tagging to both E. coli and S. aureus but with a better response towards E. coli cells. The human squamous epithelial cells (SEC) were deployed as a fitting substitute for achieving NtCD-mammalian cell imaging. Both NtCD tagged bacterial cells and SEC exhibited multicolor emission as well. Mechanistic implications of pH-dependent PL emission property of NtCD and its bacterial interaction were discussed extensively.

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2020

Journal Article

S. Chouhan, Singh, S., Athavale, D., Ramteke, P., Vanuopadath, M., Dr. Bipin G. Nair, Nair, S. Sadasivan, and Bhat, M. Kumar, “Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucosedependent alterations in reactive oxygen species, P-glycoprotein and DKK4.”, J Biosci, vol. 45, 2020.[Abstract]


Altered glucose uptake and metabolism is the key characteristic of cancer cells including hepatocellular carcinoma (HCC). However, role of glucose availability in chemotherapeutic outcome of HCC is unclear. The present study investigates the effect of glucose facilitated sensitization of HCC cells towards doxorubicin (DOX) and sorafenib (SORA). In HCC cells, we observed that hyperglycemic culture condition (HG) is associated with increased sensitivity towards DOX and SORA. P-glycoprotein (P-gp), a transporter involved in drug efflux, was elevated in HCC cells in NG, rendering them less susceptible to DOX and SORA. Further, this study demonstrated that knockdown of dickkopf protein 4 (DKK4), a Wnt antagonist protein, causes enhanced glucose uptake and reduction in P-gp level rendering HCC cells in NG sensitive to DOX and SORA. Moreover, HG elevates the level of intracellular reactive oxygen species (ROS), which regulates P-gp. Alteration in intracellular ROS did not directly affect regulation of DKK4 in HCC cells. Functional assays suggest that alterations in DKK4 and P-gp level in HCC cells are dependent on glucose availability and changes in ROS level because of enhanced glucose utilization, respectively. Collectively, the present study highlights direct involvement of glucose-induced ROS, DKK4 and P-gp in altering the sensitivity of HCC cells towards DOX and SORA.

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2020

Journal Article

K. K. Mangalaparthi, Patel, K., Khan, A. A., Manoharan, M., Karunakaran, C., Murugan, S., Gupta, R., Gupta, R., Khanna-Gupta, A., Chaudhuri, A., Kumar, P., Dr. Bipin G. Nair, Kumar, R. V., Prasad, T. S. Keshava, Chatterjee, A., Pandey, A., and Gowda, H., “Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort.”, Front Oncol, vol. 10, p. 1457, 2020.[Abstract]


Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as , and were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in ---, and - gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.

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2020

Journal Article

V. N. Puttamallesh, Deb, B., Gondkar, K., Jain, A., Dr. Bipin G. Nair, Pandey, A., Chatterjee, A., Gowda, H., and Kumar, P., “Quantitative Proteomics of Urinary Bladder Cancer Cell Lines Identify UAP1 as a Potential Therapeutic Target”, Genes, vol. 11, no. 7, p. 763, 2020.[Abstract]


Bladder carcinoma (BC) incidence and mortality rates are increasing worldwide. The development of novel therapeutic strategies is required to improve clinical management of this cancer. Aberrant protein expression may lead to cancer initiation and progression. Therefore, the identification of these potential protein targets and limiting their expression levels would provide alternative treatment options. In this study, we utilized a liquid-chromatography tandem mass spectrometry-based global proteomics approach to identify differentially expressed proteins in bladder cancer cell lines. A total of 3913 proteins were identified in this study, of which 479 proteins were overexpressed and 141 proteins were downregulated in 4 out of 6 BC cell lines when compared with normal human urothelial cell line (TERT-NHUC). We evaluated the role of UDP-N-acetylhexosamine pyrophosphorylase (UAP1) in bladder cancer pathogenesis. The silencing of UAP1 led to reduction in proliferation, invasion, colony formation and migration capability of bladder cancer cell lines. Thus, our study reveals UAP1 as a promising therapeutic target for bladder cancer.

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2020

Journal Article

Muralidharan Vanuopadath, Shaji, S. Korumadath, Dileepkumar Raveendran, Dr. Bipin G. Nair, and Sudarslal Sadasivan Nair, “Delineating the venom toxin arsenal of Malabar pit viper (Trimeresurus malabaricus) from the Western Ghats of India and evaluating its immunological cross-reactivity and in vitro cytotoxicity”, International Journal of Biological Macromolecules, vol. 148, pp. 1029 - 1045, 2020.[Abstract]


The venom protein components of Malabar pit viper (Trimeresurus malabaricus) were identified by combining SDS-PAGE and ion-exchange chromatography pre-fractionation techniques with LC-MS/MS incorporating Novor and PEAKS-assisted de novo sequencing strategies. Total 97 proteins that belong to 16 protein families such as L-amino acid oxidase, metalloprotease, serine protease, phospholipase A2, 5′-nucleotidase, C-type lectins/snaclecs and disintegrin were recognized from the venom of a single exemplar species. Of the 97 proteins, eighteen were identified through de novo approaches. Immunological cross-reactivity assessed through ELISA and western blot indicate that the Indian antivenoms binds less effectively to Malabar pit viper venom components compared to that of Russell's viper venom. The in vitro cell viability assays suggest that compared to the normal cells, MPV venom induces concentration dependent cell death in various cancer cells. Moreover, crude venom resulted in chromatin condensation and apoptotic bodies implying the induction of apoptosis. Taken together, the present study enabled in dissecting the venom proteome of Trimeresurus malabaricus and revealed the immuno-cross-reactivity profiles of commercially available Indian polyvalent antivenoms that, in turn, is expected to provide valuable insights on the need in improving antivenom preparations against its bite.

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2020

Conference Proceedings

Jayalekshmi H., “Essential oils modulate antibiotic mediated persister cell formation of P. aeruginosa”, International Webinar on Phytochemistry 2020’ organized by Kerala Academy of Sciences. 2020.

2020

Journal Article

Muralidharan Vanuopadath, Shaji, S. Korumadath, Dileepkumar Raveendran, Nair, B. Gopalakris, and Nair, udarslalSadasivan, “Delineating the venom toxin arsenal of Malabar pit viper (Trimeresurus malabaricus) from the Western Ghats of India and evaluating its immunological cross-reactivity and in vitro cytotoxicity.”, Int J Biol Macromol, vol. 148, pp. 1029-1045, 2020.[Abstract]


The venom protein components of Malabar pit viper (Trimeresurus malabaricus) were identified by combining SDS-PAGE and ion-exchange chromatography pre-fractionation techniques with LC-MS/MS incorporating Novor and PEAKS-assisted de novo sequencing strategies. Total 97 proteins that belong to 16 protein families such as L-amino acid oxidase, metalloprotease, serine protease, phospholipase A, 5'-nucleotidase, C-type lectins/snaclecs and disintegrin were recognized from the venom of a single exemplar species. Of the 97 proteins, eighteen were identified through de novo approaches. Immunological cross-reactivity assessed through ELISA and western blot indicate that the Indian antivenoms binds less effectively to Malabar pit viper venom components compared to that of Russell's viper venom. The in vitro cell viability assays suggest that compared to the normal cells, MPV venom induces concentration dependent cell death in various cancer cells. Moreover, crude venom resulted in chromatin condensation and apoptotic bodies implying the induction of apoptosis. Taken together, the present study enabled in dissecting the venom proteome of Trimeresurus malabaricus and revealed the immuno-cross-reactivity profiles of commercially available Indian polyvalent antivenoms that, in turn, is expected to provide valuable insights on the need in improving antivenom preparations against its bite.

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2020

Journal Article

V. M., D., R., B.G., N., and , “Evaluating the Immunological cross-reactivity of Indian polyvalent antivenoms towards the venom of Hypnalehypnale (hump-nosed pit viper) from the Western Ghats”, bioRxiv, 2020.[Abstract]


Hypnale hypnale (hump-nosed pit viper) is a venomous pit viper species found in the Western 24 Ghats of India and Sri Lanka. Due to the severe life-threatening envenomation effects induced by 25 its venom components, Hypnale hypnale has been classified under ‘category 1’ of medically 26 important snake species by the World Health Organization. Since there are no specific antivenoms 27 available to combat its envenomation in India, the only option available is to administer Indian 28 polyvalent antivenoms. However, the cross-neutralization potential of the commercially available 29 polyvalent antivenoms on Indian Hypnale hypnale venom has not been explored so far. In the 30 current study, in vitro immunological cross-reactivity of Hypnale hypnale venom towards various 31 Indian polyvalent antivenoms were assessed using end point titration ELISA and Western blotting. 32 A three to four-fold increase in EC50 values were obtained for Hypnale hypnale venom towards all 33 the antivenoms tested. Observation of minimal binding specificities towards low and high 34 molecular mass venom proteins are suggestive of the fact that commercially available polyvalent 35 antivenoms failed to detect and bind to the antigenic epitopes of considerable number of proteins 36 present in Hypnale hypnale venom. This highlights the importance of including Hypnale hypnale 37 venom in the immunization mixture while raising antivenoms.

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2020

Journal Article

Akshay P., S., S., Rajesh, R., and Geena Prasad, “Portable and efficient graphene-oxide based multistage filtration unit for water purification”, Materials Today: Proceedings, 10th International Conference on Materials Manufacturing and Characterization, Mathura, Uttar Pradesh, India, vol. 26, pp. 2344 - 2350, 2020.[Abstract]


In recent times, ensuring availability of adequate supply of potable water for its citizens is of great concern for nations across the globe. Water purification is a matter of high immediacy in developing countries, where enough supply of clean drinking water is unavailable. Globally, in consideration of the water-related diseases, assurance of an affordable, scalable water treatment infrastructure is of paramount significance. Many states in India face are confronted by scarcity of safe water and pollution, evoked mainly by anthropogenic activities. Majority of the population is unable to either access or afford safe drinking water. More than 60% of this population rely on groundwater for the purpose of drinking alone and on surface waters for all other purposes. In this era of high-water necessity, the aim of this paper is to develop a handy personal, water purifier, which is a ubiquitous, cost-effective access to healthy potable water for humans. This portable water purifier is a multi-stage filter constituted of a fabric filter, graphene-oxide coated sand filter, vetiver grass filter, and a UV filtration system. Water quality test show drastic reductions in the total dissolved solids (TDS), hardness, chloride and calcium ions. Implementation of this filtration unit in water-stressed countries is expected to serve as an efficient and affordable appliance for daily consumption of water.

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2020

Journal Article

Y. Kimata, Leturcq, M., and Dr. Rajaguru Aradhya, “Emerging roles of metazoan cell cycle regulators as coordinators of the cell cycle and differentiation”, FEBS Letters, vol. 594, 2020.[Abstract]


In multicellular organisms, cell proliferation must be tightly coordinated with other developmental processes to form functional tissues and organs. Despite significant advances in our understanding of how the cell cycle is controlled by conserved cell‐cycle regulators (CCRs), how the cell cycle is coordinated with cell differentiation in metazoan organisms and how CCRs contribute to this process remain poorly understood. Here, we review the emerging roles of metazoan CCRs as intracellular proliferation‐differentiation coordinators in multicellular organisms. We illustrate how major CCRs regulate cellular events that are required for cell fate acquisition and subsequent differentiation. To this end, CCRs employ diverse mechanisms, some of which are separable from those underpinning the conventional cell‐cycle‐regulatory functions of CCRs. By controlling cell‐type‐specific specification/differentiation processes alongside the progression of the cell cycle, CCRs enable spatiotemporal coupling between differentiation and cell proliferation in various developmental contexts in vivo. We discuss the significance and implications of this underappreciated role of metazoan CCRs for development, disease and evolution.

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2020

Book Chapter

Dr. Rajaguru Aradhya and Jagla, K., “Insulin-dependent Non-canonical Activation of Notch in Drosophila: A Story of Notch-Induced Muscle Stem Cell Proliferation”, in Notch Signaling in Embryology and Cancer: Molecular Biology of Notch Signaling, vol. 1227, J. Reichrath and Reichrath, S., Eds. Cham: Springer International Publishing, 2020, pp. 131–144.[Abstract]


Notch plays multiple roles both in development and in adult tissue homeostasis. Notch was first identified in Drosophila in which it has then been extensively studied. Among the flag-ship Notch functions we could mention its capacity to keep precursor and stem cells in a nondifferentiated state but also its ability to activate cell proliferation that in some contexts could led to cancer. In general, both these functions involve, canonical, ligand-dependent Notch activation. However, a ligand-independent Notch activation has also been described in a few cellular contexts. Here, we focus on one of such contexts, Drosophila muscle stem cells, called AMPs, and discuss how insulin-dependent noncanonical activation of Notch pushes quiescent AMPs to proliferation.

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2020

Journal Article

Dr. Parvathy Venugopal, Veyssière, H., Couderc, J. - L., Richard, G., Vachias, C., and Mirouse, V., “Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster”, MC Dev Biol, vol. 20, no. 1, p. 10, 2020.[Abstract]


Scaffold proteins support a variety of key processes during animal development. Mutant mouse for the MAGUK protein Discs large 5 (Dlg5) presents a general growth impairment and moderate morphogenetic defects.

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2019

Journal Article

P. Ponnachan, Vinod, V., Pullanhi, U., Varma, P., Singh, S., Biswas, R., and Kumar, A., “Antifungal activity of octenidine dihydrochloride and ultraviolet-C light against multidrug-resistant Candida auris.”, J Hosp Infect, vol. 102, no. 1, pp. 120-124, 2019.[Abstract]


Outbreaks due to multidrug-resistant Candida auris have emerged as a large threat to modern medicine. Since skin colonization and environmental contamination have been identified as a precursor for outbreaks, we evaluated the antifungal activity of ultraviolet-C light using mercury vapour lamp with a peak emission of 254 ± 2 nm and octenidine dihydrochloride against C. auris clinical isolates. Octenidine dihydrochloride was found effective at significantly lower concentrations (0.00005-0.0004%) than those currently used in the clinical setting (0.05-0.1%). Scanning electron microscopy images show destruction of the organism within 6 h of exposure to 0.0005% octenidine dihydrochloride. Ultraviolet-C light could kill all C. auris with 15 min exposure.

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2019

Journal Article

J. Advani, Verma, R., Chatterjee, O., Balaya, R. Devasahaya, Najar, M. Altaf, Ravishankara, N., Suresh, S., Pachori, P. Kumar, Gupta, U. D., Pinto, S. M., Chauhan, D. S., Tripathy, S. Prasad, Gowda, H., and Prasad, T. S. Keshava, “Rise of Clinical Microbial Proteogenomics: A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC22.”, OMICS, vol. 23, no. 1, pp. 1-16, 2019.[Abstract]


Nontuberculous mycobacterial (NTM) species present a major challenge for global health with serious clinical manifestations ranging from pulmonary to skin infections. Multiomics research and its applications toward clinical microbial proteogenomics offer veritable potentials in this context. For example, the Mycobacterium abscessus, a highly pathogenic NTM, causes bronchopulmonary infection and chronic pulmonary disease. The rough variant of the M. abscessus UC22 strain is extremely virulent and causes lung upper lobe fibrocavitary disease. Although several whole-genome next-generation sequencing studies have characterized the genes in the smooth variant of M. abscessus, a reference genome sequence for the rough variant was generated only recently and calls for further clinical applications. We carried out whole-genome sequencing and proteomic analysis for a clinical isolate of M. abscessus UC22 strain obtained from a pulmonary tuberculosis patient. We identified 5506 single-nucleotide variations (SNVs), 63 insertions, and 76 deletions compared with the reference genome. Using a high-resolution LC-MS/MS-based approach (liquid chromatography tandem mass spectrometry), we obtained protein coding evidence for 3601 proteins, representing 71% of the total predicted genes in this genome. Application of proteogenomic approach further revealed seven novel protein-coding genes and enabled refinement of six computationally derived gene models. We also identified 30 variant peptides corresponding to 16 SNVs known to be associated with drug resistance. These new observations offer promise for clinical applications of microbial proteogenomics and next-generation sequencing, and provide a resource for future global health applications for NTM species.

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2019

Journal Article

Nidheesh Melethadathil, Dr. Bipin G. Nair, Dr. Shyam Diwakar, and Jaap Heringa, “Mining inter-relationships in online scientific articles and its visualization: Natural language processing for systems biology modeling”, International Journal of Online Engineering, vol. 15, no. 2, pp. 39-59, 2019.[Abstract]


With the rapid growth in the numbers of scientific publications in domains such as neuroscience and medicine, visually interlinking documents in online databases such as PubMed with the purpose of indicating the context of a query results can improve the multi-disciplinary relevance of the search results. Translational medicine and systems biology rely on studies relating basic sciences to applications, often going through multiple disciplinary domains. This paper focuses on the design and development of a new scientific document visualization platform, which allows inferring translational aspects in biosciences within published articles using machine learning and natural language processing (NLP) methods. From online databases, this software platform effectively extracted relationship connections between multiple subdomains within neuroscience derived from abstracts related to user query. In our current implementation, the document visualization platform employs two clustering algorithms namely Suffix Tree Clustering (STC) and LINGO. Clustering quality was improved by mapping top-ranked cluster labels derived from an UMLS-Metathesaurus using a scoring function. To avoid non-clustered documents, an iterative scheme, called auto-clustering was developed and this allowed mapping previously uncategorized documents during the initial grouping process to relevant clusters. The efficacy of this document clustering and visualization platform was evaluated by expert-based validation of clustering results obtained with unique search terms. Compared to normal clustering, auto-clustering demonstrated better efficacy by generating larger numbers of unique and relevant cluster labels. Using this implementation, a Parkinson's disease systems theory model was developed and studies based on user queries related to neuroscience and oncology have been showcased as applications. © 2019 Kassel University Press GmbH.

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2019

Conference Paper

Asha R. Pai, Parvathy,, and Dr. Bipin G. Nair, “Biosynthesis of ZnO@Ag from Gracinia Cambogia linn and its structural Characterisation using XPS (Poster)”, in 5th International conference on Nanoscience and Nanotechnology-ICONN 2019, 2019.

2019

Journal Article

Asha R. Pai and Dr. Bipin G. Nair, “Synthesis and characterisation of Sb-doped ZrO2 and TiO2 nanoparticles”, International Journal of Microstructure and Materials Properties, vol. 14, no. 3, pp. 286-298, 2019.[Abstract]


The present study aims at the synthesis and structural characterisation of Sb-doped titania and zirconia nanoparticles using a modified precipitation synthesis method. The produced nanoparticles were characterised using various techniques such as UV-Visible spectroscopy, Scanning electron microscopy, Transmission electron microscopy and Dynamic light scattering. The crystallite sizes were obtained to be <20 nm for Sb-doped ZrO2 and <10 nm for Sb-Doped TiO2 which was very evident from the Transmission electron microscope images. The hydrodynamic sizes in the range of 100 nm using Dynamic light scattering method were also evaluated for the assessment for biological application. The optical band gap was found out to be 3.21 eV for Sb-Doped TiO2 and 3.87 eV for Sb-doped ZrO2.

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2019

Journal Article

C. Nutakki, Radhakrishnan, S., Dr. Bipin G. Nair, and Dr. Shyam Diwakar, “Modeling fMRI BOLD signals and temporal mismatches in the cerebellar cortex”, CSI Transactions on ICT, 2019.[Abstract]


To understand brain activity relating neurons to circuits to learning and behavior, we explored a bottom-up computational reconstruction of population signals arising from cerebellum granular layer. As a first implementation, using bio-realistic computational models of cerebellum granule cell, in vivo spike train patterns were computed and then translated into functional Magnetic Resonance Imaging, Blood Oxygen-Level Dependent (BOLD) signals. The BOLD response was generated from averaged activity arising from center-surround organization modeled by using excitatory-inhibitory ratios related to experimental data. The averaged responses were converted to BOLD signals using the balloon and modified Windkessel models. Although both models generated BOLD responses corresponding to neural activity, the temporal mismatch was attributed to the response by the delayed compliance parameter in the Windkessel model. The modeling suggests that experimental variability observed in the cerebellar micro-zones could be related to compliance chances, activation patterns and number of neurons. Although detailed neuro-vasculature information was not modeled, the advantage in this methodology is that cerebellar cortex may allow seemingly linear transformations of underlying spiking that could be then used to validate network reconstructions.

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2019

Journal Article

K. Naidu Bobba, Anupama Binoy, Koo, S., Nedungadi, D., Podder, A., Sharma, A., Dr. Nandita Mishra, Kim, J. Seung, and Bhuniya, S., “Direct readout protonophore induced selective uncoupling and dysfunction of individual mitochondria within cancer cells”, Chemical Communications, vol. 55, no. 45, pp. 6429-6432, 2019.[Abstract]


Concurrently, manipulation of mitochondrial activity and its monitoring have enormous significance in cancer therapy and diagnosis. In this context, a fluorescent probe MitoDP has been developed for validating H2S mediated protonophore (2,4-dinitrophenol, DNP) induced mitochondrial membrane potential change, ROS formation and ATP depletion in cancer cells. The extent of protonophore activation for mitochondrial dysfunction is monitored through fluorescence signalling at 450 nm. The current study provides a proof for the concept of endogenous H2S-mediated controlled and spatial release of bioactive agents, or toxins specifically in mitochondria of cancer cells.

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2019

Journal Article

Divya Nair, Muralidharan Vanuopadath, Balasubramanian, A., Iyer, A., Ganesh, S., Anil, A. Nair, Vikraman, V., Pillai, P., Chinchu Bose, Dr. Bipin G. Nair, Pai, J. Gopalakris, and Nair, S. Sadasivan, “Phlorotannins from Padina tetrastromatica: structural characterisation and functional studies”, Journal of Applied Phycology, pp. 1–11, 2019.[Abstract]


In this study, LC–MS/MS-based structural characterisation of phlorotannins from Padina tetrastromatica, a marine brown macroalga collected from South-West coastal region of Kerala, and its bioactivities are presented. The tandem mass spectrometric data revealed a series of phlorotannins with degree of polymerisation ranging from 2 to 18. The characteristic neutral loss of tandem mass spectra further confirmed that these molecules belong to fucophlorethol class of phlorotannins. DPPH assay of the HPLC-purified, phlorotannin-enriched fraction possesses significant free radical-scavenging activity. Cell viability assay indicated that phlorotannin concentration ranging from 1.5 to 50.0&nbsp;μg&nbsp;mL−1 is non-toxic to THP-1 cell lines. Anti-inflammatory assay performed through gelatin zymography confirmed that phlorotannins ameliorated high-glucose-induced pro-MMP-9 expression in a dose-dependent manner whereas the level of pro-MMP-2 remains unaltered. The antimicrobial assays carried out using both the crude and HPLC-purified phlorotannin fraction showed its anti-MRSA potential.

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2019

Journal Article

K. Gondkar, Patel, K., Krishnappa, S., Patil, A., Dr. Bipin G. Nair, Meenakshisundaram, G., Tan, T. Zea, and Kumar, P., “E74 like ETS transcription factor 3 (ELF3) is a negative regulator of epithelial- mesenchymal transition in bladder carcinoma”, Cancer Biomarkers, pp. 1-10, 2019.[Abstract]


Background: Transcription factors are commonly deregulated in various cancers. Here, we evaluated role of ELF3 in pathogenesis of bladder carcinoma (BCa). Materials and methods: We confirmed ELF3 expression pattern in BCa cell lines using western blot; and in different grades of tumors using Immunohistochemistry. Cell invasion assay was employed to demonstrate potential role of ELF3 in EMT. Results and conclusion: ELF3 showed selective expression in low-grade cell lines and tumor tissues. Overexpression of ELF3 in mesenchymal cell line UMUC3 resulted in reduced invasion and decreased expression of mesenchymal markers. We observe association of low ELF3 expression with increased risk and overall poor survival using publicly available data. ELF3-modulated reversal of EMT might be a useful strategy in the treatment of bladder cancer.

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2019

Journal Article

S. SK, D, S., K, M., G, K., and Dr. Bipin G. Nair, “Analysis of microarray data for identification of key microRNAs signature in glioblastoma multiforme”, Oncology Letters, 2019.

2019

Journal Article

Anupama Binoy, Divya Nedungadi, Katiyar, N., Chinchu Bose, Dr. Sahadev Shankarappa, Dr. Bipin G. Nair, and Dr. Nandita Mishra, “Plumbagin induces paraptosis in cancer cells by disrupting the sulfhydryl homeostasis and proteasomal function”, Chemico-Biological Interactions, p. 108733, 2019.[Abstract]


Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.

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2019

Journal Article

A. Choorakott Pushkaran, Vinod, V., Muralidharan Vanuopadath, Sudarslal S, Shantikumar V Nair, Vasudevan, A. Kumar, Dr. Raja Biswas, and Dr. Gopi Mohan C., “Combination of Repurposed Drug Diosmin with Amoxicillin-Clavulanic acid Causes Synergistic Inhibition of Mycobacterial Growth”, Scientific Reports, vol. 9, no. 1, 2019.[Abstract]


Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in Mycobacterium tuberculosis (Mtb). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in Mtb cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against Mycobacterium marinum as compared to individual drugs. Scanning electron microscopy study of M. marinum treated with AMC-DIO and AMC-DMT showed marked cellular leakage. M. marinum infected Drosophila melanogaster fly model showed an increased fly survival of 60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced in vitro antimicrobial activity of AMC-DIO was validated against Mtb H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB. © 2019, The Author(s).

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2019

Journal Article

K. Gondkar, Patel, K., Krishnappa, S., Patil, A., Dr. Bipin G. Nair, Sundaram, G. Meenakshi, Zea, T. Tuan, and Kumar, P., “E74 like ETS transcription factor 3 (ELF3) is a negative regulator of epithelial- mesenchymal transition in bladder carcinoma.”, Cancer Biomark, 2019.[Abstract]


<p><b>BACKGROUND: </b>Transcription factors are commonly deregulated in various cancers. Here, we evaluated role of ELF3 in pathogenesis of bladder carcinoma (BCa).</p>

<p><b>MATERIALS AND METHODS: </b>We confirmed ELF3 expression pattern in BCa cell lines using western blot; and in different grades of tumors using Immunohistochemistry. Cell invasion assay was employed to demonstrate potential role of ELF3 in EMT.</p>

<p><b>RESULTS AND CONCLUSION: </b>ELF3 showed selective expression in low-grade cell lines and tumor tissues. Overexpression of ELF3 in mesenchymal cell line UMUC3 resulted in reduced invasion and decreased expression of mesenchymal markers. We observe association of low ELF3 expression with increased risk and overall poor survival using publicly available data. ELF3-modulated reversal of EMT might be a useful strategy in the treatment of bladder cancer.</p>

More »»

2019

Journal Article

K. N. Bobba, Binoy, A., Koo, S., Nedungadi, D., Podder, A., Sharma, A., Mishra, N., Kim, J. S., and Bhuniya, S., “Direct readout protonophore induced selective uncoupling and dysfunction of individual mitochondria within cancer cells”, Chemical Communications, vol. 55, pp. 6429-6432, 2019.[Abstract]


Concurrently, manipulation of mitochondrial activity and its monitoring have enormous significance in cancer therapy and diagnosis. In this context, a fluorescent probe MitoDP has been developed for validating H2S mediated protonophore (2,4-dinitrophenol, DNP) induced mitochondrial membrane potential change, ROS formation and ATP depletion in cancer cells. The extent of protonophore activation for mitochondrial dysfunction is monitored through fluorescence signalling at 450 nm. The current study provides a proof for the concept of endogenous H2S-mediated controlled and spatial release of bioactive agents, or toxins specifically in mitochondria of cancer cells. © 2019 The Royal Society of Chemistry. More »»

2019

Journal Article

V. Sara Vargis, Priya, C. Jayachandr, Surendran, H., Vasu, S. Punathil, Dr. Bipin G. Nair, Gopalakrishnan, T., and Dr. Satheesh Babu T. G., “Gold Nanoparticles Decorated Reduced Graphene Oxide Nanolabel for Voltammetric Immunosensing.”, IET Nanobiotechnol, vol. 13, no. 2, pp. 107-113, 2019.[Abstract]


This study describes the development and testing of a simple and novel enzyme-free nanolabel for the detection and signal amplification in a sandwich immunoassay. Gold nanoparticles decorated reduced graphene oxide (rGOAu) was used as the nanolabel for the quantitative detection of human immunoglobulin G (HIgG). The rGOAu nanolabel was synthesised by one pot chemical reduction of graphene oxide and chloroauric acid using sodium borohydride. The pseudo-peroxidase behaviour of rGOAu makes the nanolabel unique from other existing labels. The immunosensing platform was fabricated using self-assembled monolayers of 11-mercaptoundecanoic acid (11-MUDA) on a gold disc electrode. The covalent immobilisation of antibody was achieved through the bonding of the carboxyl group of 11-MUDA and the amino group of the antibody using chemical linkers [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide] and -hydroxysuccinimide. The fabricated immunosensor exhibited a linear range that included HIgG concentrations of 62.5-500 ng ml. The sensor was also used for the testing of HIgG in the blood sample.

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2019

Journal Article

R. Banerjee, Shine, O., Rajachandran, V., Krishnadas, G., Minnick, M. F., Paul, S., and Sujay Chattopadhyay, “Gene Duplication and Deletion, not Horizontal Transfer, Drove Intra-Species Mosaicism of Bartonella Henselae”, Genomics, 2019.[Abstract]


Bartonella henselae is a facultative intracellular pathogen that occurs worldwide and is responsible primarily for cat-scratch disease in young people and bacillary angiomatosis in immunocompromised patients. The principal source of genome-level diversity that contributes to B. henselae's host-adaptive features is thought to be horizontal gene transfer events. However, our analyses did not reveal the acquisition of horizontally-transferred islands in B. henselae after its divergence from other Bartonella. Rather, diversity in gene content and genome size was apparently acquired through two alternative mechanisms, including deletion and, more predominantly, duplication of genes. Interestingly, a majority of these events occurred in regions that were horizontally transferred long before B. henselae's divergence from other Bartonella species. Our study indicates the possibility that gene duplication, in response to positive selection pressures in specific clones of B. henselae, might be linked to the pathogen's adaptation to arthropod vectors, the cat reservoir, or humans as incidental host-species.

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2019

Journal Article

A. K. Thomas, Preetha, S., Omanakuttan, A., Vidyullata, L., Ashokan, A., Rajachandran, V., and Sujay Chattopadhyay, “Mutational Convergence Acts as a Major Player in Adaptive Parallel Evolution of Shigella Spp”, Sci Rep, vol. 9, no. 1, p. 3252, 2019.[Abstract]


Shigella spp., emerging from multiple origins of Escherichia coli, poses a significant health threat as a causative agent of bacillary dysentery. While multiple serotypes of four different species have evolved via independent lineages, Shigella spp. are designated as a single pathotype, primarily because of their common mode of pathogenesis. Convergent horizontal transfer events have so far been attributed to the commonalities in the evolution of virulence across diverse lineages. However, the role of mutational convergence in such parallel evolution is not yet well understood. Here we have carried out a genome-wide analysis of Shigella strains from all four species to detect the core genes (i.e. the ones present in all analyzed strains) acquiring convergent mutations of evolutionarily recent origin. Simulation studies show non-neutral accumulation of these convergent mutations across species, suggesting their adaptive role in the evolution of Shigella virulence. S. dysenteriae strain 197, representing highly virulent type 1 (Sd1) clone, carries excessively high number of core genes with recent convergent mutations compared to other analyzed strains. We propose that this high frequency of adaptive convergence in S. dysenteriae strain 197 could be linked to recent re-emergence of the Sd1 clone and its increased resistance to antimicrobials.

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2019

Journal Article

Divya Nedungadi, Anupama Binoy, Vinod, V., Muralidharan Vanuopadath, Sudarslal Sadasivan Nair, Dr. Bipin G. Nair, and Dr. Nandita Mishra, “Ginger extract activates caspase independent paraptosis in cancer cells via ER stress, mitochondrial dysfunction, AIF translocation and DNA damage”, Nutrition and Cancer, pp. 1-13, 2019.[Abstract]


AbstractThe rhizome of ginger (Zingiber officinale) a common culinary agent is also known for its medicinal activity. We have earlier reported that pure 6-shogaol, an important component of ginger induces paraptosis in triple negative breast cancer (MDA-MB-231) and non small cell lung (A549) cancer cells. However, the chemopreventive potential of the whole ginger extract in food remains to be elucidated. Here, we demonstrate for the first time that ginger extract (GE) triggers similar anticancer activity/paraptosis against the same cell lines but through different molecular mechanisms. Q-TOF LC-MS analysis of the extract showed the presence of several other metabolites along with 6-shogaol and 6-gingerol. GE induces cytoplasmic vacuolation through ER stress and dilation of the ER. Drastic decrease in the mitochondrial membrane potential and ATP production along with the excess generation of ROS contributed to mitochondrial dysfunction. Consequently, GE caused the translocation of apoptosis inducing factor to the nucleus leading to the fragmentation of DNA. Taken together, these show a novel mechanism for ginger extract induced cancer cell death that can be of potential interest for cancer preventive strategies.

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2019

Journal Article

Damu Sunilkumar, Drishya G., Chandrasekharan, A., Shaji, S. K., Chinchu Bose, Jossart, J., J. Jefferson P. Perry, Dr. Nandita Mishra, Dr. Geetha Kumar, and Dr. Bipin G. Nair, “Oxyresveratrol drives caspase-independent apoptosis-like cell death in MDA-MB-231 breast cancer cells through the induction of ROS.”, Biochem Pharmacol, p. 113724, 2019.[Abstract]


Earlier studies from our laboratory have demonstrated that Oxyresveratrol (OXY), a hydroxyl-substituted stilbene, exhibits potent inhibition of human melanoma cell proliferation. The present study defines a cytotoxic effect of OXY on the highly chemo-resistant, triple-negative human breast cancer cell line MDA-MB-231. OXY-mediated cell death resulted in accumulation of cells at the sub-G1 phase of the cell cycle, induced chromatin condensation, DNA fragmentation, phosphatidylserine externalization and PARP cleavage, indicative of apoptosis. Interestingly, morphology and cell viability studies with the pan-caspase inhibitor, QVD-OPH revealed that OXY-induced cell death was caspase-independent.Docking studies also showed that OXY can bind to the S1 site of caspase-3, and could also exert an inhibitory effect on this executioner caspase. The immunoblot analysis demonstrating the absence of caspase cleavage during cell death further confirmed these findings. OXY was also observed to induce the production of reactive oxygen species, which caused the depolarization of the mitochondrial membrane resulting in translocation of Apoptosis Inducing Factor (AIF) into the nucleus. Pretreatment of the cells with N-Acetyl Cysteine antioxidant prevented cell death resulting from OXY treatment. Thus, OXY initiates ROS-mediated, apoptosis-like cell death, involving mitochondrial membrane depolarization, translocation of AIF into the nucleus, and DNA fragmentation, resulting in caspase-independent cell death in MDA-MB-231 cells. The cytotoxicity manifested by OXY was also observed in 3D cell culture models and primary cells, thereby providing a basis for the utilization of OXY as a novel template for the future design of anticancer therapeutics.

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2019

Journal Article

S. K. Shaji, Damu Sunilkumar, V., M. N., Geetha B. Kumar, and Dr. Bipin G. Nair, “Analysis of microarray data for identification of key microRNA signatures in glioblastoma multiforme”, Oncol Lett, vol. 18, no. 2, pp. 1938-1948, 2019.[Abstract]


Glioblastoma multiforme (GBM) is one of the most malignant types of glioma known for its reduced survival rate and rapid relapse. Previous studies have shown that the expression patterns of different microRNAs (miRNA/miR) play a crucial role in the development and progression of GBM. In order to identify potential miRNA signatures of GBM for prognostic and therapeutic purposes, we downloaded and analyzed two expression data sets from Gene Expression Omnibus profiling miRNA patterns of GBM compared with normal brain tissues. Validated targets of the deregulated miRNAs were identified using MirTarBase, and were mapped to Search Tool for the Retrieval of Interacting Genes/Proteins, Database for Annotation, Visualization and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes databases in order to construct interaction networks and identify enriched pathways of target genes. A total of 6 miRNAs were found to be deregulated in both expression datasets studied. Pathway analysis demonstrated that most of the target genes were enriched in signaling cascades connected to cancer development, such as 'Pathways in cancer', 'Focal adhesion' and 'PI3K-Akt signaling pathway'. Of the five target genes that were enriched in the glioblastoma pathway, in the WikiPathway database, both HRas proto-oncogene, GTPase and MET proto-oncogene, receptor tyrosine kinase target genes of hsa-miR-139-5p, were found to be significantly associated with patient survival. The present study may thus form the basis for further exploration of hsa-miR-139-5p, not only as a therapeutic agent, but also as a diagnostic biomarker for GBM as well as a predictive marker for patient survival.

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2019

Journal Article

R. P. Edachana, Kumaresan, A., Balasubramanian, V., Thiagarajan, R., Dr. Bipin G. Nair, and Dr. Satheesh Babu T. G., “Paper-based device for the colorimetric assay of bilirubin based on in-situ formation of gold nanoparticles”, Microchimica Acta, vol. 187, p. 60, 2019.[Abstract]


A paper-based colorimetric assay for the determination of bilirubin has been developed. The method is based on the in-situ reduction of chloroauric acid to form gold nanoparticles. A chromatographic paper was patterned using a wax printer. Chloroauric acid was drop-cast onto the reagent zone. In the presence of bilirubin, gold(III) ions are reduced and form gold nanoparticles. This leads to a color change from yellow to purple. The intensity of the purple color (peak at 530&nbsp;nm) increases with bilirubin concentration in the 5.0 to 1000&nbsp;mg&nbsp;L−1 range. The detection limit is 1.0&nbsp;mg&nbsp;L−1. For the quantification of bilirubin, images were captured using a digital camera, and data were processed with the help of machine learning-based supervised prediction using Random Forest classification. The method was applied to the determination of bilirubin in urine samples. The spiked urine samples exhibit more than 95% recovery.

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2019

Journal Article

V. Vijayanandh, Aarathi Pradeep, Suneesh, P. V., and Dr. Satheesh Babu T. G., “Design and simulation of passive micromixers with ridges for enhanced efficiency”, IOP Conference Series: Materials Science and Engineering, vol. 577, p. 012106, 2019.[Abstract]


Uniform and rapid mixing between various streams in a microfluidic device is essential for the development of device involving reaction between multiple streams. In this work, microfluidic channels of various geometries were designed and their fluid flow patterns were analyzed to optimize complete mixing of different fluids. The designs were modified by incorporating different types of ridges (square, curved and triangular shaped) in the microfluidic channels. Numerical analysis of the designs was carried out using COMSOL Multiphysics 4.3a. The extent of mixing in each of the design was calculated and the optimized design was fabricated using photolithography followed by soft lithography. The performance of the developed micromixer was studied using colored solutions and it was found to be in good agreement with the simulated results.

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2019

Patent

Raveendran, Jeethu,, Raj,, S., V., Pradeep, A., Vasu, S. P., Stanley, J., Nair, B., Thiagarajan, R., and Dr. Satheesh Babu T. G., “Lab on a Chip Device for Multi-Analyte Detection and a Method of Fabrication Thereof”, U.S. Patent 16/1829132019.[Abstract]


The disclosure provides for a lab-on-a-chip (LOC) device and a method of fabrication thereof. Additionally, a system and a method for point of care testing of multiple biomarkers such as glucose, cholesterol, creatinine, uric acid, and bilirubin is provided. The microfluidic assembly consists of three layers in which the top and the middle layers are made up of polydimethylsiloxane (PDMS) and the bottom layer with polyethylene terephthalate (PET). The device integrates screen printed non-enzymatic electrochemical sensors in the bottom layer for simultaneous detection of glucose, cholesterol, creatinine, uric acid, and bilirubin. A hand held potentiostat with readout enables readout for the point of care application of integrated sensing device. The device developed has potential to revamp healthcare by providing access to affordable technology for better management a diabetes and related complications at every door step.

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2019

Journal Article

K. Dhara and Dr. Satheesh Babu T. G., “Electrochemical Nonenzymatic Detection of Hydrogen Peroxide at Pd Nanoparticles-Reduced Graphene Oxide Nanocomposite”, Sensor Letters, vol. 17, pp. 283-289, 2019.[Abstract]


A highly sensitive nonenzymatic hydrogen peroxide (H2O2) sensor was fabricated using palladium nanoparticles decorated reduced graphene oxide (Pd/rGO) nanocomposite. The Pd/rGO nanocomposite was prepared by single-step chemical reduction method. Nanocomposite was characterized by Raman spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and high-resolution transmission electron microscopy (HRTEM). Screen printed electrodes (SPE) were fabricated, and the Pd/rGO nanocomposite was cast on the working electrode of the SPE. The Pd/rGO/SPE was electrochemically characterized by linear sweep voltammetry (LSV) and amperometry. The sensor exhibited extremely high electrocatalytic activity to H2O2 in neutral medium (pH = 7.4) with a wide linear range (from 10 μM to 4 mM), and very high sensitivity of 2104 μA mM–1 cm–2. The lower limit of detection found to be 0.5 μM. The Pd/rGO/SPE sensor demonstrated excellent features such as good reproducibility, long-term stability, and selectivity.

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2019

Journal Article

Dr. Geetha Kumar, Dr. Bipin G. Nair, J. Perry, J. P., and Martin, D. B. C., “Recent insights into natural product inhibitors of matrix metalloproteinases”, Med. Chem. Commun., vol. 10, pp. 2024-2037, 2019.[Abstract]


Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders. The outcomes of initial clinical trials with the first generation of MMP inhibitors proved disappointing. However, our growing understanding of the complexities of the MMP function in disease, and an increased understanding of MMP protein architecture and control of activity now provide new opportunities and avenues to develop MMP-focused therapies. Natural products that affect MMP activities have been of strong interest as templates for drug discovery, and for their use as chemical tools to help delineate the roles of MMPs that still remain to be defined. Herein, we highlight the most recent discoveries of structurally diverse natural product inhibitors to these proteases.

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