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

Despite the existing therapies and lack of receptors such as HER-2, estrogen receptor and progesterone receptor, triple-negative breast cancer is one of the most aggressive subtypes of breast cancer. TNBCs are known for their highly aggressive metastatic behavior and typically migrate to brain and bone for secondary site propagation. Many diseases share similar molecular pathology exposing new avenues in molecular signaling for engendering innovative therapies. Generation of newer therapies and novel drugs are time consuming associated with very high resources. In order to provide personalized or precision medicine, drug repositioning will contribute in a cost-effective manner. In our study, we have repurposed and used a neoteric combination of two drug molecules namely, fluvoxamine and tivozanib, to target triple-negative breast cancer growth and progression. Our combination regime significantly targets two diverse but significant pathways in TNBCs. Subsequent analysis on migratory, invasive, and angiogenic properties showed the significance of our repurposed drug combination. Molecular array data resulted in identifying the specific and key players participating in cancer progression when the drug combination was used. The innovative combination of fluvoxamine and tivozanib reiterates the use of drug repositioning for precision medicine and subsequent companion diagnostic development. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

World University root node

(SoNS) School of Natural Sciences

Molecular and Cellular Biochemistry

Intuitive repositioning of an anti-depressant drug in combination with tivozanib: precision medicine for breast cancer therapy

Hijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics. © 2021, The Author(s).

Fulltext

Cell Death Discovery

Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies. © Copyright © 2021 Sharma, Mir and Galande.

Frontiers in Genetics

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

The article describes the non-genetic roles of DNA molecule and its applications in diagnostic and therapeutic fields such as in biosensors, barcodes, nanomachines, biochips, probes, and DNA scaffolds. © 2021, Indian Academy of Sciences.

Resonance

DNA: More Than Just a Genetic Material

Climate changes and environmental stresses have a consequential association with crop plant growth and yield, meaning it is necessary to cultivate crops that have tolerance toward the changing climate and environmental disturbances such as water stress, temperature fluctuation, and salt toxicity. Recent studies have shown that trans-acting regulatory elements, including microRNAs (miRNAs) and transcription factors (TFs), are emerging as promising tools for engineering naive improved crop varieties with tolerance for multiple environmental stresses and enhanced quality as well as yield. However, the interwoven complex regulatory function of TFs and miRNAs at transcriptional and post-transcriptional levels is unexplored in Oryza sativa. To this end, we have constructed a multiple abiotic stress responsive TF-miRNA-gene regulatory network for O. sativa using a transcriptome and degradome sequencing data meta-analysis approach. The theoretical network approach has shown the networks to be dense, scale-free, and small-world, which makes the network stable. They are also invariant to scale change where an efficient, quick transmission of biological signals occurs within the network on extrinsic hindrance. The analysis also deciphered the existence of communities (cluster of TF, miRNA, and genes) working together to help plants in acclimatizing to multiple stresses. It highlighted that genes, TFs, and miRNAs shared by multiple stress conditions that work as hubs or bottlenecks for signal propagation, for example, during the interaction between stress-responsive genes (TFs/miRNAs/other genes) and genes involved in floral development pathways under multiple environmental stresses. This study further highlights how the fine-tuning feedback mechanism works for balancing stress tolerance and how timely flowering enable crops to survive in adverse conditions. This study developed the abiotic stress-responsive regulatory network, APRegNet database (http://lms.snu.edu.in/APRegNet), which may help researchers studying the roles of miRNAs and TFs. Furthermore, it advances current understanding of multiple abiotic stress tolerance mechanisms. © Copyright © 2021 Sharma, Upadhyay, Bhattacharya and Singh.

Mathematics

Abiotic Stress-Responsive miRNA and Transcription Factor-Mediated Gene Regulatory Network in Oryza sativa: Construction and Structural Measure Study

Chemotherapy is a general treatment procedure for cancer. The diversity in cancer incidence and the failure of therapy due to chemoresistance lead to increased cancer-related deaths. Therefore, new drugs with fewer secondary complications targeting diverse pathways are the need of the hour. Geranyl isovalerate (GIV), one of the active ingredients of ethyl acetate fraction of Argyreia nervosa is routinely used as a food flavoring agent. In this study, we found that GIV also exhibits anticancer activity when tested against the HCT116 cell line. It influenced the viability of the cells in a dose- and time-dependent manner. We examined whether GIV could induce oxidative stress and affect the mitochondrial membrane potential, thereby leading to apoptosis induction. Moreover, GIV could suppress the expression of antiapoptotic genes, such as BCl2 and PARP, and induce the expression of proapoptotic genes, such as Caspase 3 and 9. This is the first study demonstrating the anticancer activity of GIV and providing evidence for its mechanism of action. In conclusion, this study proposes GIV as a potential lead or supplementary molecule in treating and preventing colorectal cancer (CRC). Based on our findings, we conclude that GIV may be a viable lead or supplementary molecule for treating and preventing CRC. © Copyright © 2021 Rasool, Sharma, Anand, Magani and Tantravahi.

Frontiers in Pharmacology

Evaluation of the Anticancer Properties of Geranyl Isovalerate, an Active Ingredient of Argyreia nervosa Extract in Colorectal Cancer Cells

Background: Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. Methods: The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Results: Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Conclusion: Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum. © 2021, The Author(s).

Chemistry

Malaria Journal

Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum

In the present paper Global Positioning System (GPS) as well as Very Low Frequency (VLF) measurements at multi-stations have been used to analyze ionospheric anomalies related with major earthquake (Mw = 7.4) of South West Banten (Lampung Area), Indonesia. The earthquake occurred on 02 August 2019 at 19:03:21 LT (epicenter at geog. lat = 07.22° S, long. 104.83º E, depth 10 km). Tremors due to the earthquakes were felt in Jakarta, Bandung, and several parts of Java and Sumatra and more than 160,000 people were exposed and estimated release of energy to this earthquake (EQ) was 278 GWh. In this paper statistical analysis of the GPS-TEC data clearly supports the presence of earthquake signature in the form of anomalous perturbations in total electron content (TEC). Analysis found the presence of ionospheric perturbations 0–5 days before and after the main shock of the earthquake. The anomalous perturbations in the TEC were observed from few days to few hours prior to the main shock of the earthquake. Perturbations in TEC have been found to depend on the distance as well as direction of observation point from the epicentre. In general ionospheric perturbations after the EQ at all the stations are found larger than that before the EQ. VLF signal analysis using night-time fluctuation method indicates a significant increase in VLF amplitude before couple of days of EQ. Probable mechanisms behind these perturbations associated with EQ have also been discussed. © 2021, Akadémiai Kiadó.

Acta Geodaetica et Geophysica

Ionospheric perturbations observed due to Indonesian Earthquake (Mw = 7.4) using GPS and VLF measurements at multi-stations

<p>The sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria.&nbsp;Erythrocytes, the host for asexual stage of Plasmodium, are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) that catalyzed its biosynthesis from sphingosine (Sph). Since, Plasmodium lacks SphK homologous protein it can be envisaged that it co-opts sphingolipids from both intraerythrocytic as well as extracellular pools for its growth and development. Herein, by sphingosine-NBD probing, we report that infected erythrocytes imports Sph from extracellular pool, which is converted to S1P and thereby taken by P. falciparum. Next, by targeting of the SphK through specific inhibitor N,N-Dimethylsphingosine DMS, we show a reduction in erythrocyte endogenous S1P pool and SphK-phosphorylation that led to inhibition in growth and development of ring stage P. falciparum. Owing to the role of S1P in erythrocyte glycolysis we analyzed uptake of NBD-Glucose and production of lactate in DMS treated and untreated plasmodium. DMS treatment led to decreased glycolysis in Plasmodium. Interestingly the host free Plasmodium did not show any effect on glycolysis with DMS treatment indicating its host-mediated effect. Further to understand the in-vivo anti-plasmodial effects of exogenous and endogenous erythrocyte S1P level, Sphingosine-1-phosphate lyase (S1PL) inhibitor (THI), S1P and SphK-1 inhibitor (DMS), were used in Plasmodium berghei ANKA (PbA) mice model. DMS treatment led to reduction of endogenous S1P conferred significant decrease in parasite load, whereas the plasma level S1P modulated by (THI) and exogenous S1P have no effect on growth of Plasmodium. This suggested erythrocyte endogenous S1P pool is important for Plasmodium growth whereas the plasma level S1P has no effect. Altogether, this study provides insight on cellular processes regulated by S1P in&nbsp;P. falciparum&nbsp;and highlights the novel mechanistically distinct molecular target i.e. SphK-1. © 2021, The Author(s).</p>

Scientific Reports

Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum

Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. P. falciparum harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death, including Annexin/PI positivity, depolarized the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rationale for the design of adjunct therapies against severe malaria.