Life Sciences

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity. © 2022

World University root node

(SoNS) School of Natural Sciences

Journal of Organometallic Chemistry

Evaluation of anticancer activity of ferrocene based benzothiazole and β-ketooxothioacetal

Cancer is the second most common cause of deaths worldwide after noncommunicable diseases. Hepatocellular carcinoma (HCC) is the fourth most deadly type of cancer worldwide. The reasons for this high rate of mortality are linked to the heterogeneity of HCC, late detection, and development of resistance to therapies. This chapter focuses on drug resistance in HCC. This chapter briefly explains the molecular signaling pathways and their role in drug resistance. This chapter further discusses cancer stem cells, stem cell markers, signaling pathways and transcription factors that regulate stem cell-mediated drug resistance in HCC. © 2022 Elsevier Inc. All rights reserved.

Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma, Volume 2: Diagnosis, Therapeutic Targets, and Molecular Mechanisms

Molecular signaling and its role in drug resistance in hepatocellular carcinomas

Microsatellites, also termed as simple sequence repeats, are repetitive tracts in a DNA sequence, typically consisting of one to six nucleotides. These repeats are found in all genomes and play key roles in phylogeny and species identification. Microsatellites are highly polymorphic, and their length may differ from species to species. There are several online resources dedicated to mitochondria; however, comprehensive information is not available about the length variation of mitochondrial microsatellites. Therefore, to explore it between species among a genus, we have developed a database named pSATdb (polymorphic microSATellites database; https://lms.snu.edu.in/pSATdb/). pSATdb contains 28,710 perfect microsatellites identified across 5,976 mitochondrial genome (mt-genome) sequences from 1,576 genera which includes 1,535 (5,846 mt-genome) and 41 (130 mt-genome) genera of Metazoa and Viridiplantae, respectively. pSATdb is the only database which provides genus-wise information about the length variation of mitochondrial microsatellites. Because of the emerging role of microsatellites in genomics studies, the identified common, polymorphic, and unique microsatellites stored in pSATdb will be effectively useful in various studies including genetic diversity, mapping, marker-assisted selection, and comparative population studies. © 2022 Kumar et al.

Fulltext

Life Science Alliance

pSATdb: a database of mitochondrial common, polymorphic, and unique microsatellites

Wound healing is a complex phenomenon that requires coordination of numerous molecular and cellular changes to facilitate timely and efficient repair of the damaged tissue. Although many of these molecular pathways have been detailed, others remain to be elucidated. In the present work, we show for the first time, roles for the acetyltransferase TIP60 and nuclear receptor transcription factor PXR in this process, participating in wound healing by altering actin dynamics and cellular motility. We found that in response to wound-injury, TIP60 induces rapid formation of filopodia at the wounded cell front, leading to enhanced cell migration and faster closure of the wound. Further, qPCR analysis revealed heightened expression of Cdc42 and ROCK1 genes, key regulators involved in filopodia formation and actin reorganization, exclusively in TIP60-PXR-expressing cells upon wound-induction. We also performed ChIP assays to confirm the context-specific binding of TIP60 on the ROCK1 promoter and demonstrated that the TIP60 chromodomain is essential for loading of the TIP60–PXR complex onto the chromatin. Results from immunoprecipitation assays revealed that during the wounded condition, TIP60 alters the chromatin microenvironment by specifically acetylating histones H2B and H4, thereby modulating the expression of target genes. Overall, findings of this study show that TIP60 is a novel regulator of the wound healing process by regulating the expression of wound repair-related genes. © 2022 The Authors

Journal of Biological Chemistry

TIP60 acts as a regulator of genes involved in filopodia formation and cell migration during wound healing

Mitochondria and endoplasmic reticulum (ER) remain closely tethered by contact sites to maintain unhindered biosynthetic, metabolic, and signalling functions. Apart from its constituent proteins, contact sites localize ER-unfolded protein response (UPR) sensors like Ire1 and PERK, indicating the importance of ER-mitochondria communication during stress. In the mitochondrial sub-compartment-specific proteotoxic model of yeast, Saccharomyces cerevisiae, we show that an intact ER-UPR pathway is important in stress tolerance of mitochondrial intermembrane space (IMS) proteotoxic stress, while disrupting the pathway is beneficial during matrix stress. Deletion of IRE1 and HAC1 leads to accumulation of misfolding-prone proteins in mitochondrial IMS indicating the importance of intact ER-UPR pathway in enduring mitochondrial IMS proteotoxic stresses. Although localized proteotoxic stress within mitochondrial IMS does not induce ER-UPR, its artificial activation helps cells to better withstand the IMS proteotoxicity. Furthermore, overexpression of individual components of ER-mitochondria contact sites is found to be beneficial for general mitochondrial proteotoxic stress, in an Ire1-Hac1-independent manner. © 2022, The Author(s) under exclusive licence to [Cell Stress Society International.

Cell Stress and Chaperones

Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress

The GroEL/ES chaperonin cavity surface charge properties, especially the negative charges, play an important role in its capacity to assist intracavity protein folding. Remarkably, the larger fraction of GroEL/ES negative charges are not conserved among different bacterial species, resulting in a large variation in negative-charge density in the GroEL/ES cavity across prokaryotes. Intriguingly, eukaryotic GroEL/ES homologs have the lowest negative-charge density in the chaperonin cavity. This prompted us to investigate if GroEL's chaperoning mechanism changed during evolution. Using a model in vivo GroEL/ES substrate, we show that the ability of GroEL/ES to buffer entropic traps in the folding pathway of its substrate was partially dependent upon the negativecharge density inside its cavity. While this activity of GroEL/ES was found to be essential for Escherichia coli, it has been perfected in some organisms and diminished in others. However, irrespective of their charges, all the tested homologs retained their ability to regulate polypeptide chain collapse and remove enthalpic traps from folding pathways. The ability of these GroEL/ES homologs to buffer mutational variations in a model substrate correlated with their negative-charge density. Thus, Hsp60/10 chaperonins in different organisms may have changed to accommodate a different spectrum of mutations on their substrates. © 2022 National Academy of Sciences. All rights reserved.

Proceedings of the National Academy of Sciences of the United States of America

Conserved and divergent chaperoning effects of Hsp60/10 chaperonins on protein folding landscapes

Drought stress limits plant growth, resulting in a significant yield loss in chickpea. The diversification in genome sequence and selective sweep of allele(s) in different genotypes of a crop plant may play an important role in the determination of agronomic traits, including drought stress response. We investigated, via whole genome resequencing, the DNA polymorphisms between two sets of chickpea genotypes with contrasting drought stress responses (3 drought-sensitive vs. 6 drought-tolerant). In total, 36,406 single nucleotide polymorphisms (SNPs) and 3407 insertions or deletions (InDels) differentiating drought-sensitive and drought-tolerant chickpea genotypes were identified. Interestingly, most (91%) of these DNA polymorphisms were located in chromosomes 1 and 4. The genes harboring DNA polymorphisms in their promoter and/or coding regions and exhibiting differential expression under control and/or drought stress conditions between/within the drought-sensitive and tolerant genotypes were found implicated in the stress response. Furthermore, we identified DNA polymorphisms within the cis-regulatory motifs in the promoter region of abiotic stress-related and QTL-associated genes, which might contribute to the differential expression of the candidate drought-responsive genes. In addition, we revealed the effect of nonsynonymous SNPs on mutational sensitivity and stability of the encoded proteins. Taken together, we identified DNA polymorphisms having relevance in drought stress response and revealed candidate genes to engineer drought tolerance in chickpea. © 2021 Scandinavian Plant Physiology Society.

Physiologia Plantarum

Genome-wide discovery of DNA polymorphisms via resequencing of chickpea cultivars with contrasting response to drought stress

We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 linear chain, but not higher, along with a carboxyl/ester group showed a similar anti-leishmanial effect. Ergosterol depletion was the major cause of CA-mediated cell death. Molecular docking and molecular dynamic simulation studies indicated the enzyme mevalonate kinase (MevK) of the ergosterol biosynthesis pathway as a possible target of CA. Enzyme assays with purified recombinant MevK and CA/CA analogs confirmed the target with a competitive inhibition pattern. Using biochemical and biophysical studies; strong binding interaction between MevK and CA/CA analogs was established. Further, using parasites with overexpressed MevK and proteomics studies of CA-treated parasites the direct role of MevK as the target was validated. We established the mechanism of the antileishmanial effect of CA, a natural product, against VL where toxicity and drug resistance with current chemotherapeutics demand an alternative. This is the first report on the identification of an enzymatic target with kinetic parameters and mechanistic insights against any organism for a natural medium-chain FA. © 2022, The Author(s).

Scientific Reports

Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Th17 cells are essential for protection against extracellular pathogens, but their aberrant activity can cause autoimmunity. Molecular mechanisms that dictate Th17 cell-differentiation have been extensively studied using mouse models. However, species-specific differences underscore the need to validate these findings in human. Here, we characterized the human-specific roles of three AP-1 transcription factors, FOSL1, FOSL2 and BATF, during early stages of Th17 differentiation. Our results demonstrate that FOSL1 and FOSL2 co-repress Th17 fate-specification, whereas BATF promotes the Th17 lineage. Strikingly, FOSL1 was found to play different roles in human and mouse. Genome-wide binding analysis indicated that FOSL1, FOSL2 and BATF share occupancy over regulatory regions of genes involved in Th17 lineage commitment. These AP-1 factors also share their protein interacting partners, which suggests mechanisms for their functional interplay. Our study further reveals that the genomic binding sites of FOSL1, FOSL2 and BATF harbour hundreds of autoimmune disease-linked SNPs. We show that many of these SNPs alter the ability of these transcription factors to bind DNA. Our findings thus provide critical insights into AP-1-mediated regulation of human Th17-fate and associated pathologies. © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

Nucleic Acids Research

A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation

Bisphenol A (BPA) is a known endocrine disruptor with estrogen-like effects, which causes damage to human organs. BPA can affect the immune, reproductive, and neuroendocrine systems and is also carcinogenic. Herein, highly selective electrochemical sensing of BPA using H+-exchanged α-MnO2 in water under room conditions was developed. H+-exchanged α-MnO2 was synthesized via ion exchange. The synthesized material was characterized using an X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS), which confirms a successful synthesis of 1-D H+-exchanged α-MnO2. A nano-enabled, label-free electrochemical sensor was fabricated by employing synthesized materials. The sensor prominently showed high sensitivity of 0.64 kΩ/nM/mm2 and a lower limit of detection (LoD) of 16 nM. The equivalent Randel circuit was modeled for electron transfer kinetics evaluation. Additionally, the shelf life analysis confirmed the stability and reproducibility of the designed sensor over 30 days. Moreover, the sensor is highly selective toward BPA against other organic compounds. So, H+-exchanged α-MnO2-based BPA sensor provides a feasible and novel avenue to detect BPA in water under ambient conditions for health safety purposes. © 2001-2012 IEEE.