An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication

Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of sever...

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Autores principales:	Lirun Zhou, Lei Bao, Yaxin Wang, Mengping Chen, Yingying Zhang, Zihan Geng, Ronghua Zhao, Jing Sun, Yanyan Bao, Yujing Shi, Rongmei Yao, Shanshan Guo, Xiaolan Cui
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	geniposide influenza A virus RNA polymerase calcium signaling pathway CAMKII Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/c655c26f2af54fe898a683ee273c1310
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spelling	oai:doaj.org-article:c655c26f2af54fe898a683ee273c13102021-11-19T07:50:50ZAn Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication1663-981210.3389/fphar.2021.755796https://doaj.org/article/c655c26f2af54fe898a683ee273c13102021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.755796/fullhttps://doaj.org/toc/1663-9812Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of several strains of the influenza virus. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the mechanism of geniposide on influenza A virus (IAV). The potential targets and signaling pathways of geniposide in the IAV infection were predicted using network pharmacology analysis. According to the result of network pharmacology analysis, we validated the calcium signaling pathway induced by IAV and investigated the effect of geniposide extracted from Gardenia jasminoides J.Ellis on this pathway. The primary Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways KEGG enrichment analysis indicated that geniposide has a multi-target and multi-pathway inhibitory effect against influenza, and one of the mechanisms involves calcium signaling pathway. In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.Lirun ZhouLei BaoYaxin WangMengping ChenYingying ZhangZihan GengRonghua ZhaoJing SunYanyan BaoYujing ShiRongmei YaoShanshan GuoXiaolan CuiFrontiers Media S.A.articlegeniposideinfluenza A virusRNA polymerasecalcium signaling pathwayCAMKIITherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	geniposide influenza A virus RNA polymerase calcium signaling pathway CAMKII Therapeutics. Pharmacology RM1-950
spellingShingle	geniposide influenza A virus RNA polymerase calcium signaling pathway CAMKII Therapeutics. Pharmacology RM1-950 Lirun Zhou Lei Bao Yaxin Wang Mengping Chen Yingying Zhang Zihan Geng Ronghua Zhao Jing Sun Yanyan Bao Yujing Shi Rongmei Yao Shanshan Guo Xiaolan Cui An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
description	Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of several strains of the influenza virus. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the mechanism of geniposide on influenza A virus (IAV). The potential targets and signaling pathways of geniposide in the IAV infection were predicted using network pharmacology analysis. According to the result of network pharmacology analysis, we validated the calcium signaling pathway induced by IAV and investigated the effect of geniposide extracted from Gardenia jasminoides J.Ellis on this pathway. The primary Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways KEGG enrichment analysis indicated that geniposide has a multi-target and multi-pathway inhibitory effect against influenza, and one of the mechanisms involves calcium signaling pathway. In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.
format	article
author	Lirun Zhou Lei Bao Yaxin Wang Mengping Chen Yingying Zhang Zihan Geng Ronghua Zhao Jing Sun Yanyan Bao Yujing Shi Rongmei Yao Shanshan Guo Xiaolan Cui
author_facet	Lirun Zhou Lei Bao Yaxin Wang Mengping Chen Yingying Zhang Zihan Geng Ronghua Zhao Jing Sun Yanyan Bao Yujing Shi Rongmei Yao Shanshan Guo Xiaolan Cui
author_sort	Lirun Zhou
title	An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
title_short	An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
title_full	An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
title_fullStr	An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
title_full_unstemmed	An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
title_sort	integrated analysis reveals geniposide extracted from gardenia jasminoides j.ellis regulates calcium signaling pathway essential for influenza a virus replication
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c655c26f2af54fe898a683ee273c1310
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An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication

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