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Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition.

ABSTRACT: Bioactive fractions obtained from medicinal plants which have been used for the treatment of multiple diseases could exert their effects by targeting common pathways. Prior knowledge of their usage could allow us to identify novel molecular links. In this study, we explored the molecular basis of action of one such herbal formulation Cissampelos pareira L. (Cipa), used for the treatment of female hormone disorders and fever. Transcriptomic studies on MCF7 cell lines treated with Cipa extract carried out using Affymetrix arrays revealed a downregulation of signatures of estrogen response potentially modulated through estrogen receptor α (ERα). Molecular docking analysis identified 38 Cipa constituents that potentially bind (ΔG < - 7.5) with ERα at the same site as estrogen. The expression signatures in the connectivity map ( https://clue.io/; ) revealed high positive scores with translation inhibitors such as emetine (score: 99.61) and knockdown signatures of genes linked to the antiviral response such as ribosomal protein RPL7 (score: 99.92), which is a reported ERα coactivator. Further, gene knockdown experiments revealed that Cipa exhibits antiviral activity in dengue infected MCF7 cells potentially modulated through estrogen receptor 1. This approach reveals a novel pathway involving the ESR1-RPL7 axis which could be a potential target in dengue viral infection.

SUBMITTER: Haider M

PROVIDER: S-EPMC8505412 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition.

Haider Madiha M Dholakia Dhwani D Panwar Aleksha A Garg Parth P Gheware Atish A Singh Dayanidhi D Singhal Khushboo K Burse Shaunak A SA Kumari Surekha S Sharma Anmol A Ray Arjun A Medigeshi Guruprasad R GR Sharma Upendra U Prasher Bhavana B Mukerji Mitali M

Scientific reports 20211011 1

Bioactive fractions obtained from medicinal plants which have been used for the treatment of multiple diseases could exert their effects by targeting common pathways. Prior knowledge of their usage could allow us to identify novel molecular links. In this study, we explored the molecular basis of action of one such herbal formulation Cissampelos pareira L. (Cipa), used for the treatment of female hormone disorders and fever. Transcriptomic studies on MCF7 cell lines treated with Cipa extract car ...[more]

PMID: 34635729

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Project description:BackgroundViral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present. Herbal medicines have been a source of various antiviral compounds such as Oseltamivir, extracted using shikimic acid from star anise (Illicium verum) and Acyclovir from Carissa edulis are FDA (Food and Drug Administration) approved antiviral drugs. In this study, we dissect the anti-coronavirus infection activity of Cissampelos pareira L (Cipa) extract using an integrative approach.MethodsWe analysed the signature similarities between predicted antiviral agents and Cipa using the connectivity map ( https://clue.io/ ). Next, we tested the anti-SARS-COV-2 activity of Cipa in vitro. Molecular docking analyses of constituents of with key targets of SARS-CoV2 protein viz. spike protein, RNA‑dependent RNA‑polymerase (RdRp) and 3C‑like proteinase. was also performed. A three-way comparative analysis of Cipa transcriptome, COVID-19 BALF transcriptome and CMAP signatures of small compounds was also performed.ResultsSeveral predicted antivirals showed a high positive connectivity score with Cipa such as apcidin, emetine, homoharringtonine etc. We also observed 98% inhibition of SARS-COV-2 replication in infected Vero cell cultures with the whole extract. Some of its prominent pure constituents e.g. pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. Comparison of genes between BALF and Cipa showed an enrichment of biological processes like transcription regulation and response to lipids, to be downregulated in Cipa while being upregulated in COVID-19. CMAP also showed that Triciribine, torin-1 and VU-0365114-2 had positive connectivity with BALF 1 and 2, and negative connectivity with Cipa. Amongst all the tested compounds, Magnoflorine and Salutaridine exhibited the most potent and consistent strong in silico binding profiles with SARS-CoV2 therapeutic targets.

Project description:BackgroundIt is necessary to assess the cellular, molecular, and pathogenetic characteristics of COVID-19 and attention is required to understand highly effective gene targets and mechanisms. In this study, we suggest understandings into the fundamental pathogenesis of COVID-19 through gene expression analyses using the microarray data set GSE156445 publicly reachable at NIH/NCBI Gene Expression Omnibus database. The data set consists of MCF7 which is a human breast cancer cell line with estrogen, progesterone and glucocorticoid receptors. The cell lines treated with different quantities of Cissampelos pareira (Cipa). Cipa is a traditional medicinal plant which would possess an antiviral potency in preventing viral diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.MethodsUtilizing Biobase, GEOquery, gplots packages in R studio, the differentially expressed genes (DEGs) were identified. The gene ontology (GO) of pathway enrichments employed by utilizing DAVID and KEGG enrichment analyses were studied. We further constructed a human protein-protein interaction (PPI) network and performed, based upon that, a subnetwork module analysis for significant signaling pathways.ResultsThe study identified 418 differentially expressed genes (DEGs) using bioinformatics tools. The gene ontology of pathway enrichments employed by GO and KEGG enrichment analyses of down-regulated and up-regulated DEGs were studied. Gene expression analysis utilizing gene ontology and KEGG results uncovered biological and signaling pathways such as "cell adhesion molecules", "plasma membrane adhesion molecules", "synapse assembly", and "Interleukin-3-mediated signaling" which are mostly linked to COVID-19. Our results provide in silico evidence for candidate genes which are vital for the inhibition, adhesion, and encoding cytokine protein including LYN, IGFBP5, IL-1R1, and IL-13RA1 that may have strong biomarker potential for infectious diseases such as COVID-19 related therapy targets.

Dataset Information

Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition.

Publications

Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition.

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