Swati Srivastava

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4' benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations.

Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer’s disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A–B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer.

Identification and analysis of miRNAs and their targets in ginger using bioinformatics approach.

MicroRNAs (miRNAs) are a large family of endogenous small RNAs derived from the non-protein coding genes. miRNA regulates the gene expression at the post-transcriptional level and plays an important role in plant development. Zingiber officinale is an important medicinal plant having numerous therapeutic properties. Its bioactive compound gingerol and essential oil posses important pharmacological and physiological activities. In this study, we used a homology search based computational approach for identifying miRNAs in Z. officinale. A total of 16 potential miRNA families (miR167, miR407, miR414, miR5015, miR5021, miR5644, miR5645, miR5656, miR5658, miR5664, miR827, miR838, miR847, miR854, miR862 and miR864) were predicted in ginger. Phylogenetic and conserved analyses were performed for predicted miRNAs. Thirteen miRNA families were found to regulate 300 target transcripts and play an important role in cell signaling, reproduction, metabolic process and stress. To understand the miRNA mediated gene regulatory control and to validate miRNA target predictions, a biological network was also constructed. Gene ontology and pathway analyses were also done. miR5015 was observed to regulate the biosynthesis of gingerol by inhibiting phenyl ammonia lyase (PAL), a precursor enzyme in the biosynthesis of gingerol. Our results revealed that most of the predicted miRNAs were involved in the regulation of rhizome development. miR5021, miR854 and miR838 were identified to regulate the rhizome development and the essential oil biosynthesis in ginger.

Identification of miRNAs and their targets involved in the secondary metabolic pathways of Mentha spp.

The endogenous, small and non-coding functional microRNAs govern the regulatory system of gene expression and control the growth and development of the plants. Mentha spp. are well known herbs for its flavor, fragrance and medicinal properties. In the present study, we used a computational approach to identify miRNAs and their targets involved in different secondary metabolic pathways of Mentha spp. Additionally, phylogenetic and conservation analysis were also done for the predicted miRNAs. Eleven miRNAs families were identified from Mentha spp., out of which five miRNA families were reported for the first time from Lamiaceae. Overall, 130 distinct target transcripts were predicted for eight miRNAs families. All the predicted targets regulated by predicted miRNAs control the reproduction, signaling, stimulus response, developmental and different metabolic process. miRNA mediated gene regulatory network was also constructed on the basis of hybridized minimum free energy of identified miRNAs and their targets. The study revealed that the gene regulatory system of essential oil biosynthesis may be governed by miR156, miR414 and miR5021 in mint family. Furthermore, three miRNA candidates (miR156, miR5021, and miR5015b) were observed to be involved in trichome development also. This is the first in-silico study describing miRNAs and their role in the regulation of secondary metabolic pathways in Mentha spp.

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.

Curcumin and β-caryophellene attenuate cadmium quantum dots induced oxidative stress and lethality in Caenorhabditis elegans model system

Curcumin (CUR) and β-caryophellene (BCP) are well known bioactive phytomolecules which are known to reduce oxidative stress in living organisms. Therefore, the present study was envisaged to explore the possible effects of CUR and BCP in suppression of cadmium quantum dots (CdTe QDs) induced toxicity in Caenorhabditis elegans. CdTe QD are luminescent nanoparticles extensively exploited for in vivo imaging, but long term bioaccumulation confer deleterious effects on living organisms. The 24-h LC50 and LC100 of CdTe QD were found to be 18.40 μg/ml and 100 μg/ml respectively. The CdTe QD exposure elevated HSP-16.2 expression mediating induction of the stress response. The CdTe QD lethality was due to increment in ROS and decline in SOD and GST expression. The present study demonstrates improved survival in BCP (50 μM) and CUR (20 μM) treated worms by over 60% (P<0.01) and 50% (P<0.029) in CdTe QD (100 μg/ml) exposed worms. Furthermore, BCP and CUR attenuate oxidative stress triggered by QD. The present study for the first time demonstrates CdTe QD toxicity remediation via BCP and CUR. The future investigations can unravel underlying protective effects of phytomolceules for remediating cyotoxicolgical effects of QDs.

Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer’s disease

AbstractBACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimers disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer’s disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstractNaphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β.

Comparative Study of Withanolide Biosynthesis-Related miRNAs in Root and Leaf Tissues of Withania somnifera

Withania somnifera, popularly known as Indian ginseng, is one of the most important medicinal plants. The plant is well studied in terms of its pharmaceutical activities and genes involved in biosynthetic pathways. However, not much is known about the regulatory mechanism of genes responsible for the production of secondary metabolites. The idea was to identify miRNA transcriptome responsible for the regulation of withanolide biosynthesis, specifically of root and leaf tissues individually. The transcriptome data of in vitro culture of root and leaf tissues of the plant was considered for miRNA identification. A total of 24 and 39 miRNA families were identified in root and leaf tissues, respectively. Out of these, 15 and 27 miRNA families have shown their involvement in different biological functions in root and leaf tissues, respectively. We report here, specific miRNAs and their corresponding target genes for corresponding root and leaf tissues. The target genes have also been analyzed for their role in withanolide metabolism. Endogenous root-miR5140, root-miR159, leaf-miR477, and leaf-miR530 were reported for regulation of withanolide biosynthesis.

A bioinformatics study of miRNAs and their regulating targets in Curcuma longa (turmeric)

microRNAs are small, endogenous, noncoding RNA, work at post-transcriptional level and control the gene regulation in animals and plants. Turmeric is an Asian medicinal plant known for its medicinal properties. The present work focused on identification of the miRNAs take part in the developmental process of turmeric. Eight miRNA families (miR156, miR157, miR159, miR170, miR171, miR319, miR396 and miR5015) were identified by using bioinformatics approach. Phylogenetic analysis of selective miRNAs was performed. Six miRNA families were observed to regulate eighty-six target transcripts. Our results further indicated their role in binding, reproduction, stress and other developmental process. Gene annotation and pathway analysis illustrate the biological function of the targets regulated by the putative miRNAs. Involvement of miR156 and miR5015 in the regulation of rhizome development was also observed. Other miRNAs were found to be involved in the growth and developmental process of turmeric. To the best of our knowledge, this is the first report on miRNA prediction and regulation in turmeric.

Verminoside mediates life span extension and alleviates stress in Caenorhabditis elegans

Abstract The discovery of bioactive molecules modulating aging in living organism promotes development of natural therapeutics for curing age-related afflictions. The progression in age-related disorders can be attributed to increment in intracellular reactive oxygen species (ROS) and oxidative stress level. To this end, we isolated an iridoid verminoside (VMS) from Stereospermum suaveolens (Roxb.) DC. and evaluated its effect on Caenorhabditis elegans. The present study delineates VMS-mediated alteration of intracellular ROS, oxidative stress, and life span in C. elegans. The different tested doses of VMS (5 μM, 25 μM, and 50 μM) were able to enhance ROS scavenging and extend mean life span in C. elegans. The maximal life span extension was observed in 25 μM VMS, that is, 20.79% (P < 0.0001) followed by 9.84% (P < 0.0001) in 5 μM VMS and 8.54% (P < 0.0001) in 50 μM VMS. VMS was able to alleviate juglone-induced oxidative stress and enhanced thermotolerance in worms. The stress-modulating and ROS-scavenging potential of VMS was validated by increment in mean survival by 29.54% (P < 0.0001) in VMS-treated oxidative stress hypersensitive mev-1 mutant strain. Furthermore, VMS modulates expression of DAF-16 (a FoxO transcription factor) promoting stress resistance and longevity. Altogether, our results suggest that VMS attenuates intracellular ROS and stress (oxidative and thermal) level promoting longevity. The longevity and stress modulation can be attributed to VMS-mediated alterations in daf-16 expression which regulates insulin signaling pathway. This study opens doors for development of phytomolecule-based therapeutics for prolonging life span and managing age-related severe disorders.

In-silico analysis of marker genes from gene expression data of solanaceous plants responsible for various abiotic stresses

Understanding the responses of plant against any environmental condition requires the expression analysis of transcriptome data. The present work focused on identifying the group of genes of Solanum tuberosum, differentially expressed in different abiotic stresses. The public database has assessed for the gene expression data in response to cold, heat and salt stresses, respectively. Furthermore, the common genes considered as marker genes, responding to all three abiotic conditions were analysed. The gene ontology classification of the marker genes and their visualisation in metabolic pathway was also analysed. The genes responsible for kunitz-type protease inhibitor precursor were found to be up-regulated, whereas the genes encoding lipid transfer protein showed down-regulation. These marker genes may be studied for further validation to see their role in stress responses to the medicinally important plants of solanaceae family.