Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice

Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. Mice were sensitized and intranasally challenged...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Phytomedicine (Stuttgart) 2019-03, Vol.55, p.238-248
Hauptverfasser: Bui, Thi Tho, Kwon, Da-Ae, Choi, Dae Woon, Jung, Sun Young, Lee, So-Young, Piao, Chun Hua, Hyeon, Eunjin, Fan, Yanjing, Yeon, Sung Hum, Son, Rak-Ho, Shon, Dong-Hwa, Song, Chang Ho, Shin, Hee Soon, Chai, Ok Hee
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 248
container_issue
container_start_page 238
container_title Phytomedicine (Stuttgart)
container_volume 55
creator Bui, Thi Tho
Kwon, Da-Ae
Choi, Dae Woon
Jung, Sun Young
Lee, So-Young
Piao, Chun Hua
Hyeon, Eunjin
Fan, Yanjing
Yeon, Sung Hum
Son, Rak-Ho
Shon, Dong-Hwa
Song, Chang Ho
Shin, Hee Soon
Chai, Ok Hee
description Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. Mice were sensitized and intranasally challenged with ovalbumin (OVA), the Th1/Th2-related cytokines and histopathology were examinated after RMFE treatments. Primary cell culture from spleen and NALT was performed to evaluate RMFE effect on Th1/Th2 responses. Four active components of RMFE were determined using HPLC and then tested the inhibition on Th2 response. Oral administration of RMFE inhibited the accumulation of eosinophils in nasal lavage fluid (NALF) and the nasal mucosa, goblet cells in the nasal epithelium, and mast cells in the respiratory region of the nasal cavity. Thus, the swelling of the nasal epithelium, nasal-associated lymphoid tissue (NALT), and lung tissue were ameliorated. Furthermore, the RMFE suppressed Th2-related cytokines, such as IL-4, IL-5, and IL-13 in NALF, NALT, and splenocytes, whereas the Th1-associated cytokine IL-12 was up-regulated by RMFE. We also revealed the active components of RMFE, such as ellagic acid, hyperoside, isoquercitrin, and miquelianin. They may inhibit IL-4 secretion in allergic responses. RMFE may have therapeutic potential for treating AR by modulating the relationships between Th1/Th2 responses. [Display omitted]
doi_str_mv 10.1016/j.phymed.2018.06.044
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2179445641</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0944711318302320</els_id><sourcerecordid>2179445641</sourcerecordid><originalsourceid>FETCH-LOGICAL-c362t-15bdba67f1b814f178ab5472d394c16ec6520a54f8f692087839d1eda5df595f3</originalsourceid><addsrcrecordid>eNp9kc-O0zAQxiMEYrsLb4CQj1yS2onjJBek3RWwSJWQUJG4WY493rqy4-I_FX0zHg-X7l45eTzzfR7P_KrqHcENwYSt981hd3KgmhaTscGswZS-qFaEkbHGU__zZbXCE6X1QEh3VV3HuMeY0GnAr6urDjM20q5fVX---ygAuWyT0daHEuuQZcoRwe8UhExILAqZFJH2OaCSMEdA0ruDX2ApaWEtHI1IgPxR2Dk7s9RmUVmC-lcLj0Yis2grnBPJhxMKEIs5QkTFV26P2Ypk_IK8RtsdWW93LTJuFlYsEooV3d1u7tYShZ1ZTDIROSPhTfVKCxvh7dN5U_34_Gl7_1Bvvn35en-7qWXH2lSTflazYIMm80ioJsMo5p4OreomKgkDyfoWi57qUbOpxeMwdpMioESvdD_1urupPlzePQT_K0NM3JkowZbPgc-Rt2QoW-4ZJUVKL1IZfIwBND8E40Q4cYL5mRnf8wszfmbGMeOFWbG9f-qQ53Pt2fQMqQg-XgRQ5jwaCDxKA2U3ygSQiStv_t_hL5Eqrnc</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2179445641</pqid></control><display><type>article</type><title>Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Bui, Thi Tho ; Kwon, Da-Ae ; Choi, Dae Woon ; Jung, Sun Young ; Lee, So-Young ; Piao, Chun Hua ; Hyeon, Eunjin ; Fan, Yanjing ; Yeon, Sung Hum ; Son, Rak-Ho ; Shon, Dong-Hwa ; Song, Chang Ho ; Shin, Hee Soon ; Chai, Ok Hee</creator><creatorcontrib>Bui, Thi Tho ; Kwon, Da-Ae ; Choi, Dae Woon ; Jung, Sun Young ; Lee, So-Young ; Piao, Chun Hua ; Hyeon, Eunjin ; Fan, Yanjing ; Yeon, Sung Hum ; Son, Rak-Ho ; Shon, Dong-Hwa ; Song, Chang Ho ; Shin, Hee Soon ; Chai, Ok Hee</creatorcontrib><description>Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. Mice were sensitized and intranasally challenged with ovalbumin (OVA), the Th1/Th2-related cytokines and histopathology were examinated after RMFE treatments. Primary cell culture from spleen and NALT was performed to evaluate RMFE effect on Th1/Th2 responses. Four active components of RMFE were determined using HPLC and then tested the inhibition on Th2 response. Oral administration of RMFE inhibited the accumulation of eosinophils in nasal lavage fluid (NALF) and the nasal mucosa, goblet cells in the nasal epithelium, and mast cells in the respiratory region of the nasal cavity. Thus, the swelling of the nasal epithelium, nasal-associated lymphoid tissue (NALT), and lung tissue were ameliorated. Furthermore, the RMFE suppressed Th2-related cytokines, such as IL-4, IL-5, and IL-13 in NALF, NALT, and splenocytes, whereas the Th1-associated cytokine IL-12 was up-regulated by RMFE. We also revealed the active components of RMFE, such as ellagic acid, hyperoside, isoquercitrin, and miquelianin. They may inhibit IL-4 secretion in allergic responses. RMFE may have therapeutic potential for treating AR by modulating the relationships between Th1/Th2 responses. [Display omitted]</description><identifier>ISSN: 0944-7113</identifier><identifier>EISSN: 1618-095X</identifier><identifier>DOI: 10.1016/j.phymed.2018.06.044</identifier><identifier>PMID: 30668435</identifier><language>eng</language><publisher>Germany: Elsevier GmbH</publisher><subject>Allergic rhinitis ; Animals ; Disease Models, Animal ; Eosinophils ; Fruit - chemistry ; Immunomodulation - immunology ; Inflammation - drug therapy ; Inflammation - immunology ; Mice ; Mice, Inbred BALB C ; Miquelianin ; Nasal epithelium ; Ovalbumin - adverse effects ; Plant Extracts - chemistry ; Plant Extracts - pharmacology ; Plant Extracts - therapeutic use ; Plants, Medicinal - chemistry ; Rhinitis, Allergic - chemically induced ; Rhinitis, Allergic - drug therapy ; Rhinitis, Allergic - immunology ; Rosa - chemistry ; Rosae Multiflorae fructus ; Th2 Cells - drug effects ; Th2 cytokines</subject><ispartof>Phytomedicine (Stuttgart), 2019-03, Vol.55, p.238-248</ispartof><rights>2018 Elsevier GmbH</rights><rights>Copyright © 2018 Elsevier GmbH. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-15bdba67f1b814f178ab5472d394c16ec6520a54f8f692087839d1eda5df595f3</citedby><cites>FETCH-LOGICAL-c362t-15bdba67f1b814f178ab5472d394c16ec6520a54f8f692087839d1eda5df595f3</cites><orcidid>0000-0003-2889-9743</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0944711318302320$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30668435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bui, Thi Tho</creatorcontrib><creatorcontrib>Kwon, Da-Ae</creatorcontrib><creatorcontrib>Choi, Dae Woon</creatorcontrib><creatorcontrib>Jung, Sun Young</creatorcontrib><creatorcontrib>Lee, So-Young</creatorcontrib><creatorcontrib>Piao, Chun Hua</creatorcontrib><creatorcontrib>Hyeon, Eunjin</creatorcontrib><creatorcontrib>Fan, Yanjing</creatorcontrib><creatorcontrib>Yeon, Sung Hum</creatorcontrib><creatorcontrib>Son, Rak-Ho</creatorcontrib><creatorcontrib>Shon, Dong-Hwa</creatorcontrib><creatorcontrib>Song, Chang Ho</creatorcontrib><creatorcontrib>Shin, Hee Soon</creatorcontrib><creatorcontrib>Chai, Ok Hee</creatorcontrib><title>Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice</title><title>Phytomedicine (Stuttgart)</title><addtitle>Phytomedicine</addtitle><description>Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. Mice were sensitized and intranasally challenged with ovalbumin (OVA), the Th1/Th2-related cytokines and histopathology were examinated after RMFE treatments. Primary cell culture from spleen and NALT was performed to evaluate RMFE effect on Th1/Th2 responses. Four active components of RMFE were determined using HPLC and then tested the inhibition on Th2 response. Oral administration of RMFE inhibited the accumulation of eosinophils in nasal lavage fluid (NALF) and the nasal mucosa, goblet cells in the nasal epithelium, and mast cells in the respiratory region of the nasal cavity. Thus, the swelling of the nasal epithelium, nasal-associated lymphoid tissue (NALT), and lung tissue were ameliorated. Furthermore, the RMFE suppressed Th2-related cytokines, such as IL-4, IL-5, and IL-13 in NALF, NALT, and splenocytes, whereas the Th1-associated cytokine IL-12 was up-regulated by RMFE. We also revealed the active components of RMFE, such as ellagic acid, hyperoside, isoquercitrin, and miquelianin. They may inhibit IL-4 secretion in allergic responses. RMFE may have therapeutic potential for treating AR by modulating the relationships between Th1/Th2 responses. [Display omitted]</description><subject>Allergic rhinitis</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Eosinophils</subject><subject>Fruit - chemistry</subject><subject>Immunomodulation - immunology</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - immunology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Miquelianin</subject><subject>Nasal epithelium</subject><subject>Ovalbumin - adverse effects</subject><subject>Plant Extracts - chemistry</subject><subject>Plant Extracts - pharmacology</subject><subject>Plant Extracts - therapeutic use</subject><subject>Plants, Medicinal - chemistry</subject><subject>Rhinitis, Allergic - chemically induced</subject><subject>Rhinitis, Allergic - drug therapy</subject><subject>Rhinitis, Allergic - immunology</subject><subject>Rosa - chemistry</subject><subject>Rosae Multiflorae fructus</subject><subject>Th2 Cells - drug effects</subject><subject>Th2 cytokines</subject><issn>0944-7113</issn><issn>1618-095X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-O0zAQxiMEYrsLb4CQj1yS2onjJBek3RWwSJWQUJG4WY493rqy4-I_FX0zHg-X7l45eTzzfR7P_KrqHcENwYSt981hd3KgmhaTscGswZS-qFaEkbHGU__zZbXCE6X1QEh3VV3HuMeY0GnAr6urDjM20q5fVX---ygAuWyT0daHEuuQZcoRwe8UhExILAqZFJH2OaCSMEdA0ruDX2ApaWEtHI1IgPxR2Dk7s9RmUVmC-lcLj0Yis2grnBPJhxMKEIs5QkTFV26P2Ypk_IK8RtsdWW93LTJuFlYsEooV3d1u7tYShZ1ZTDIROSPhTfVKCxvh7dN5U_34_Gl7_1Bvvn35en-7qWXH2lSTflazYIMm80ioJsMo5p4OreomKgkDyfoWi57qUbOpxeMwdpMioESvdD_1urupPlzePQT_K0NM3JkowZbPgc-Rt2QoW-4ZJUVKL1IZfIwBND8E40Q4cYL5mRnf8wszfmbGMeOFWbG9f-qQ53Pt2fQMqQg-XgRQ5jwaCDxKA2U3ygSQiStv_t_hL5Eqrnc</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Bui, Thi Tho</creator><creator>Kwon, Da-Ae</creator><creator>Choi, Dae Woon</creator><creator>Jung, Sun Young</creator><creator>Lee, So-Young</creator><creator>Piao, Chun Hua</creator><creator>Hyeon, Eunjin</creator><creator>Fan, Yanjing</creator><creator>Yeon, Sung Hum</creator><creator>Son, Rak-Ho</creator><creator>Shon, Dong-Hwa</creator><creator>Song, Chang Ho</creator><creator>Shin, Hee Soon</creator><creator>Chai, Ok Hee</creator><general>Elsevier GmbH</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2889-9743</orcidid></search><sort><creationdate>20190301</creationdate><title>Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice</title><author>Bui, Thi Tho ; Kwon, Da-Ae ; Choi, Dae Woon ; Jung, Sun Young ; Lee, So-Young ; Piao, Chun Hua ; Hyeon, Eunjin ; Fan, Yanjing ; Yeon, Sung Hum ; Son, Rak-Ho ; Shon, Dong-Hwa ; Song, Chang Ho ; Shin, Hee Soon ; Chai, Ok Hee</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-15bdba67f1b814f178ab5472d394c16ec6520a54f8f692087839d1eda5df595f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Allergic rhinitis</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Eosinophils</topic><topic>Fruit - chemistry</topic><topic>Immunomodulation - immunology</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - immunology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Miquelianin</topic><topic>Nasal epithelium</topic><topic>Ovalbumin - adverse effects</topic><topic>Plant Extracts - chemistry</topic><topic>Plant Extracts - pharmacology</topic><topic>Plant Extracts - therapeutic use</topic><topic>Plants, Medicinal - chemistry</topic><topic>Rhinitis, Allergic - chemically induced</topic><topic>Rhinitis, Allergic - drug therapy</topic><topic>Rhinitis, Allergic - immunology</topic><topic>Rosa - chemistry</topic><topic>Rosae Multiflorae fructus</topic><topic>Th2 Cells - drug effects</topic><topic>Th2 cytokines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bui, Thi Tho</creatorcontrib><creatorcontrib>Kwon, Da-Ae</creatorcontrib><creatorcontrib>Choi, Dae Woon</creatorcontrib><creatorcontrib>Jung, Sun Young</creatorcontrib><creatorcontrib>Lee, So-Young</creatorcontrib><creatorcontrib>Piao, Chun Hua</creatorcontrib><creatorcontrib>Hyeon, Eunjin</creatorcontrib><creatorcontrib>Fan, Yanjing</creatorcontrib><creatorcontrib>Yeon, Sung Hum</creatorcontrib><creatorcontrib>Son, Rak-Ho</creatorcontrib><creatorcontrib>Shon, Dong-Hwa</creatorcontrib><creatorcontrib>Song, Chang Ho</creatorcontrib><creatorcontrib>Shin, Hee Soon</creatorcontrib><creatorcontrib>Chai, Ok Hee</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Phytomedicine (Stuttgart)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bui, Thi Tho</au><au>Kwon, Da-Ae</au><au>Choi, Dae Woon</au><au>Jung, Sun Young</au><au>Lee, So-Young</au><au>Piao, Chun Hua</au><au>Hyeon, Eunjin</au><au>Fan, Yanjing</au><au>Yeon, Sung Hum</au><au>Son, Rak-Ho</au><au>Shon, Dong-Hwa</au><au>Song, Chang Ho</au><au>Shin, Hee Soon</au><au>Chai, Ok Hee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice</atitle><jtitle>Phytomedicine (Stuttgart)</jtitle><addtitle>Phytomedicine</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>55</volume><spage>238</spage><epage>248</epage><pages>238-248</pages><issn>0944-7113</issn><eissn>1618-095X</eissn><abstract>Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. Mice were sensitized and intranasally challenged with ovalbumin (OVA), the Th1/Th2-related cytokines and histopathology were examinated after RMFE treatments. Primary cell culture from spleen and NALT was performed to evaluate RMFE effect on Th1/Th2 responses. Four active components of RMFE were determined using HPLC and then tested the inhibition on Th2 response. Oral administration of RMFE inhibited the accumulation of eosinophils in nasal lavage fluid (NALF) and the nasal mucosa, goblet cells in the nasal epithelium, and mast cells in the respiratory region of the nasal cavity. Thus, the swelling of the nasal epithelium, nasal-associated lymphoid tissue (NALT), and lung tissue were ameliorated. Furthermore, the RMFE suppressed Th2-related cytokines, such as IL-4, IL-5, and IL-13 in NALF, NALT, and splenocytes, whereas the Th1-associated cytokine IL-12 was up-regulated by RMFE. We also revealed the active components of RMFE, such as ellagic acid, hyperoside, isoquercitrin, and miquelianin. They may inhibit IL-4 secretion in allergic responses. RMFE may have therapeutic potential for treating AR by modulating the relationships between Th1/Th2 responses. [Display omitted]</abstract><cop>Germany</cop><pub>Elsevier GmbH</pub><pmid>30668435</pmid><doi>10.1016/j.phymed.2018.06.044</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2889-9743</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0944-7113
ispartof Phytomedicine (Stuttgart), 2019-03, Vol.55, p.238-248
issn 0944-7113
1618-095X
language eng
recordid cdi_proquest_miscellaneous_2179445641
source MEDLINE; Elsevier ScienceDirect Journals
subjects Allergic rhinitis
Animals
Disease Models, Animal
Eosinophils
Fruit - chemistry
Immunomodulation - immunology
Inflammation - drug therapy
Inflammation - immunology
Mice
Mice, Inbred BALB C
Miquelianin
Nasal epithelium
Ovalbumin - adverse effects
Plant Extracts - chemistry
Plant Extracts - pharmacology
Plant Extracts - therapeutic use
Plants, Medicinal - chemistry
Rhinitis, Allergic - chemically induced
Rhinitis, Allergic - drug therapy
Rhinitis, Allergic - immunology
Rosa - chemistry
Rosae Multiflorae fructus
Th2 Cells - drug effects
Th2 cytokines
title Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T04%3A56%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Rosae%20multiflorae%20fructus%20extract%20and%20its%20four%20active%20components%20alleviate%20ovalbumin-induced%20allergic%20inflammatory%20responses%20via%20regulation%20of%20Th1/Th2%20imbalance%20in%20BALB/c%20rhinitis%20mice&rft.jtitle=Phytomedicine%20(Stuttgart)&rft.au=Bui,%20Thi%20Tho&rft.date=2019-03-01&rft.volume=55&rft.spage=238&rft.epage=248&rft.pages=238-248&rft.issn=0944-7113&rft.eissn=1618-095X&rft_id=info:doi/10.1016/j.phymed.2018.06.044&rft_dat=%3Cproquest_cross%3E2179445641%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2179445641&rft_id=info:pmid/30668435&rft_els_id=S0944711318302320&rfr_iscdi=true