Our Research

In our research group, we focus on the dynamics of toxic effects both over time and space within different endpoints ranging from gene expression and molecular changes to effects on different organs as well as the organism as a whole. We use advanced laboratory techniques to relate toxicants to genes, genes to pathways, and pathways to diseases. The unravelling of molecular mechanisms involved in the toxicity will further increase our understanding of disease processes and contribute to the scientific advancement in the toxicity studies.

Current Research Focus

Epigenetic effects of copper oxide nanoparticles leading to teratogenicity in zebrafish

Nano-copper oxides are a versatile inorganic material. As a result of their versatility, the immense applications and usage end up in the environment causing a concern for the lifespan of various beings. The ambiguities surround globally on the toxic effects of copper oxide nanoparticles (CuO-NPs). Hence, we endeavored to study the sub-lethal acute exposure effects on the developing zebrafish embryos. The 48 hpf LC50 value was about 64 ppm. The sub-lethal dose of 40 and 60 ppm led to the developmental anomalies in addition to oxidative stress in the developing embryos.


TEM image of CuO-NPs

Normal &  Malformed Larvae

Normal (Control) and malformed zebrafish larvae exposed to CuO-NPs. USB - Uninflated swim bladder, PCE - Pericardial edema, YSE - Yolk sac edema

With this valuable data, we are now exploring the epigenetic mechanisms involved in the induction of teratogenicity caused by CuO-NPs. The objectives are:

▢ Investigation of epigenetic modifications of DNA and changes in the transcriptome in CuO-NPs exposed zebrafish.
▢ Determination of microRNAs in teratogenicity induction in CuO-NPs exposed zebrafish.
▢ Elucidation of histone modifications (methylation, acetylation, and phoshorylation) in zebrafish on treatment with CuO-NPs.

Role of fisetin on the interrelationship between autophagy and apoptosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the one of the leading liver cancers in many countries and is the fifth most common cancer worldwide. Though HCC management has improved in recent years through the advances in prevention and treatment, it still requires the effective mechanism based approaches. When cancer cells are treated with different drugs, the interactions between autophagy and apoptosis will have profound effects on the outcome of the tumor cell. The cell may undergo autophagy by blocking apoptosis or by apoptosis when autophagy is inhibited. The discovery of cross link between the apoptosis machinery and autophagic machinery lead to a situation in better management of HCC.

Fisetin (3,7,3',4'- Tetrahydroxyflavone) is a plant secondary metabolite found in many fruits and vegetables such as tomatoes, onions, grapes, strawberry, persimmon, cucumber and apples which are regularly consumed in the human diet. This natural flavonoid reportedly exhibits antioxidant, neurotrophic, anti-inflammatory and anti-cancer effects. These properties necessitate fisetin to be further studied for its potential as a chemopreventive agent in HCC. Fisetin may afford chemopreventive as well as cancer chemotherapeutic effects against HCC. However, the effects of fisetin on HepG2 cells have not yet been investigated.


Proposed mechanism of fisetin on interrelationship between autophagy and apoptosis in hepatocellular carcinoma

In our lab, we investigate the effect of fisetin on apoptosis and autophagy in HepG2 cells with following objectives:

▢ Determination of the specific mode of action of fisetin on multiple signaling pathways leading to cell death using HepG2 cells.
▢ Establish the role of fisetin in apoptosis and autophagy signaling pathways.
▢ Exploration of the crosslink between apoptosis and autophagy on fisetin treated HepG2 cells.

Identifcation, validation, and analysis of molecular activators and antioxidant response elements in the Keap1-Nrf2-ARE pathway in zebrafish

The Keap1-Nrf2-ARE system serve as a permier defense mechanism to curb oxidative stress, thereby safeguard cells and organs. Nrf2 - the principal master regulator of the cellular defense system. The Keap1-Nrf2-ARE pathway is regulated by the Keap1-Nrf2 protein-protein interaction (PPI). Keap1 is a negative regulator of this pathway and in zebrafish, there are two types of Keap1: Keap1a and Keap1b. Recently, we identified top compounds that disrupts both Keap1a and Keap1b interaction with Nrf2. These potential can serve as safer Nrf2 activators due to their non-covalent disruption of Keap1-Nrf2 PPI.


Molecular activators that disrupt the interaction between Keap1a/b and Nrf2 in zebrafish

Nrf2 - a transcription factor which recognise specific DNA sequences upstream of the genes. These regulatory elements are called antioxidant response elements (ARE), which define outcome of gene expression. AREs are only a fraction of the total genome in zebrafish. Identifying these AREs is a daunting task. In the post-genomic era, deciphering the Nrf2 binding sites - AREs is an essential task that underlies and governs this Keap1-Nrf2-ARE pathway. Recently, we identified AREs in the genome of zebrafish through a pattern search algorithm and analyzed using computational tools available online. AREs are identified within 30 kb upstream from the transcription start site of antioxidant genes, mitochondrial genes, and all the known protein coding genes in the zebrafish genome. The findings revealed that TGAG/CNNNTC ARE motifs were found to be abundant than TCAG/CNNNGC ARE motifs in the antioxidant genes and in all protein coding genes of zebrafish. Our results help to understand the dynamic complexity of the Nrf2-ARE system in zebrafish.


Abundant AREs identified in zebrafish and their roles in the transcription of Nrf2-target genes

In order to disseminate and share the identified AREs in zebrafish. We have developed a database named, Zebrafish Antioxidant Response Element Database (ZFARED) www.zfared.buc.edu.in - an online open-access resource for AREs in zebrafish.


ZFARED: Zebrafish antioxidant response element database

Based on these discoveries, our lab is interested in understanding how Keap1-Nrf2-ARE signaling pathway regulates gene expression through following objectives:

▢ Identification and validation of compounds that disrupt the Keap1-Nrf2 PPI in vivo in zebrafish embryo/larva model.
▢ Functional characterization of identified AREs using molecular genetic approaches in zebrafish.

Research Grants

Ongoing Projects

▢ A grant of INR.46,19,000/- towards the project entitled, "Identification, validation, analysis and characterization of molecular activators and antioxidant response elements of Keap1/Nrf2/ARE signaling pathway in zebrafish" from March 2019 to March 2022 by Empowerment and Equity Opportunities for Excellence in Science, Department of Science and Technology – Science and Engineering Research Board, New Delhi.

Completed Projects

▢ A grant of INR.11,00,000/- toward the project entitled, “Role of fisetin on the interrelationship between autophagy and apoptosis in hepatocellular carcinoma” from March 2016 to March 2018 by Empowerment and Equity Opportunities for Excellence in Science, Department of Science and Technology – Science and Engineering Research Board, New Delhi.
▢ A grant of INR.20,20,000/- towards the project entitled, “Catecholaminergic activity enhancer compounds for performance enhancement in vitro and in vivo models” from April 2014 to March 2016 by Defence Research and Development Organization, New Delhi.
▢ A grant of INR.33,77,625/- towards the project entitled, “Elucidation the molecular of necroptosis in fluoride induced neurotoxicity: Therapeutic potential of Naringenin through Nf?B and Nrf2 signalling pathways” from December 2015 to December 2018 by Department of Science and Technology – Science and Engineering Research Board, New Delhi.
▢ A grant of INR.13,22,380/- towards the project entitled, “Effects of tamarind seed coat extract on fluoride induced apoptosis in MRC-9 cells” from February 2010 to January 2013 funded by University Grants Commission, New Delhi.

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