Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis

Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into f...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Phytotherapy research 2022-06, Vol.36 (6), p.2572-2582
Hauptverfasser: Zhang, Di, Chang, Shiquan, Li, Xin, Shi, Huimei, Jing, Bei, Chen, Zhenni, Lin, Yi, Zheng, Yachun, Qian, Guoqiang, Pan, Yuwei, Zhao, Guoping
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2582
container_issue 6
container_start_page 2572
container_title Phytotherapy research
container_volume 36
creator Zhang, Di
Chang, Shiquan
Li, Xin
Shi, Huimei
Jing, Bei
Chen, Zhenni
Lin, Yi
Zheng, Yachun
Qian, Guoqiang
Pan, Yuwei
Zhao, Guoping
description Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF‐α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF‐kB pathway. And paeoniflorin attenuated LPS‐induced Schwann cell apoptosis by decreasing the levels of TLR4, p‐NF‐kB, caspase3, cleaved‐caspase3, and cleaved‐caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.
doi_str_mv 10.1002/ptr.7472
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9320937</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2677576177</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4382-4d3d994bd021f6df7abbdd6ebb0e1a64733c69aafd8dfaa28ee79406d364d2323</originalsourceid><addsrcrecordid>eNp1kU2LFDEQhoMo7jgK_gJp8OKl13x1Z3IRZFk_YEHREbyFdFKxM_QkbdI9y5z946Zn12UVPBVVeXioyovQc4LPCcb09Tilc8EFfYBWBEtZk0awh2iFZUNqTjbfz9CTnHcYY0kxf4zOWMOlpAKv0K9tD0mPME_eVOAcmKmKrho1xODdEJMPVQyV6VPpTWViyFPyZvJl6MNuTscFn3qosvF6kQRIB6gOXp-mPvS-8ye8cF9Nf61D0cEwVHqM4xSzz0_RI6eHDM9u6xp9e3e5vfhQX316__Hi7VVtONvQmltmpeSdxZS41jqhu87aFroOA9EtF4yZVmrt7MY6rekGQEiOW8tabimjbI3e3HjHuduDNRCmpAc1Jr_X6aii9urvl-B79SMelGQUSyaK4NWtIMWfM-RJ7X1ebtEB4pwVbZtNy5vl99fo5T_oLs4plPMKJUQjWiLuCU2KOSdwd8sQrJZkVUlWLckW9MX95e_AP1EWoL4Brv0Ax_-K1Oftl5PwN1thsYg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2677576177</pqid></control><display><type>article</type><title>Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Zhang, Di ; Chang, Shiquan ; Li, Xin ; Shi, Huimei ; Jing, Bei ; Chen, Zhenni ; Lin, Yi ; Zheng, Yachun ; Qian, Guoqiang ; Pan, Yuwei ; Zhao, Guoping</creator><creatorcontrib>Zhang, Di ; Chang, Shiquan ; Li, Xin ; Shi, Huimei ; Jing, Bei ; Chen, Zhenni ; Lin, Yi ; Zheng, Yachun ; Qian, Guoqiang ; Pan, Yuwei ; Zhao, Guoping</creatorcontrib><description>Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF‐α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF‐kB pathway. And paeoniflorin attenuated LPS‐induced Schwann cell apoptosis by decreasing the levels of TLR4, p‐NF‐kB, caspase3, cleaved‐caspase3, and cleaved‐caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.</description><identifier>ISSN: 0951-418X</identifier><identifier>EISSN: 1099-1573</identifier><identifier>DOI: 10.1002/ptr.7472</identifier><identifier>PMID: 35499270</identifier><language>eng</language><publisher>Chichester, UK: John Wiley &amp; Sons, Ltd</publisher><subject>Addictions ; Apoptosis ; chronic constriction injury ; chronic neuralgia ; Constrictions ; Drugs ; Hyperalgesia ; Inflammation ; Interleukin 1 ; Interleukin 10 ; Interleukin 6 ; Lipopolysaccharides ; Nerves ; Neuralgia ; paeoniflorin ; Pain perception ; Schwann cells ; Sciatic nerve ; Sciatica ; TLR4 protein ; TLR4/NF‐kB ; Toll-like receptors ; Tumor necrosis factor</subject><ispartof>Phytotherapy research, 2022-06, Vol.36 (6), p.2572-2582</ispartof><rights>2022 The Authors. published by John Wiley &amp; Sons Ltd.</rights><rights>2022 The Authors. Phytotherapy Research published by John Wiley &amp; Sons Ltd.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4382-4d3d994bd021f6df7abbdd6ebb0e1a64733c69aafd8dfaa28ee79406d364d2323</citedby><cites>FETCH-LOGICAL-c4382-4d3d994bd021f6df7abbdd6ebb0e1a64733c69aafd8dfaa28ee79406d364d2323</cites><orcidid>0000-0002-8208-2323 ; 0000-0003-0885-8258 ; 0000-0003-1594-2378 ; 0000-0003-3888-9282 ; 0000-0002-3670-9877 ; 0000-0001-9026-5149 ; 0000-0001-9134-6573 ; 0000-0003-3036-1512 ; 0000-0002-5577-2329 ; 0000-0001-8040-8927</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fptr.7472$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fptr.7472$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35499270$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Di</creatorcontrib><creatorcontrib>Chang, Shiquan</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Shi, Huimei</creatorcontrib><creatorcontrib>Jing, Bei</creatorcontrib><creatorcontrib>Chen, Zhenni</creatorcontrib><creatorcontrib>Lin, Yi</creatorcontrib><creatorcontrib>Zheng, Yachun</creatorcontrib><creatorcontrib>Qian, Guoqiang</creatorcontrib><creatorcontrib>Pan, Yuwei</creatorcontrib><creatorcontrib>Zhao, Guoping</creatorcontrib><title>Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis</title><title>Phytotherapy research</title><addtitle>Phytother Res</addtitle><description>Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF‐α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF‐kB pathway. And paeoniflorin attenuated LPS‐induced Schwann cell apoptosis by decreasing the levels of TLR4, p‐NF‐kB, caspase3, cleaved‐caspase3, and cleaved‐caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.</description><subject>Addictions</subject><subject>Apoptosis</subject><subject>chronic constriction injury</subject><subject>chronic neuralgia</subject><subject>Constrictions</subject><subject>Drugs</subject><subject>Hyperalgesia</subject><subject>Inflammation</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 6</subject><subject>Lipopolysaccharides</subject><subject>Nerves</subject><subject>Neuralgia</subject><subject>paeoniflorin</subject><subject>Pain perception</subject><subject>Schwann cells</subject><subject>Sciatic nerve</subject><subject>Sciatica</subject><subject>TLR4 protein</subject><subject>TLR4/NF‐kB</subject><subject>Toll-like receptors</subject><subject>Tumor necrosis factor</subject><issn>0951-418X</issn><issn>1099-1573</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kU2LFDEQhoMo7jgK_gJp8OKl13x1Z3IRZFk_YEHREbyFdFKxM_QkbdI9y5z946Zn12UVPBVVeXioyovQc4LPCcb09Tilc8EFfYBWBEtZk0awh2iFZUNqTjbfz9CTnHcYY0kxf4zOWMOlpAKv0K9tD0mPME_eVOAcmKmKrho1xODdEJMPVQyV6VPpTWViyFPyZvJl6MNuTscFn3qosvF6kQRIB6gOXp-mPvS-8ye8cF9Nf61D0cEwVHqM4xSzz0_RI6eHDM9u6xp9e3e5vfhQX316__Hi7VVtONvQmltmpeSdxZS41jqhu87aFroOA9EtF4yZVmrt7MY6rekGQEiOW8tabimjbI3e3HjHuduDNRCmpAc1Jr_X6aii9urvl-B79SMelGQUSyaK4NWtIMWfM-RJ7X1ebtEB4pwVbZtNy5vl99fo5T_oLs4plPMKJUQjWiLuCU2KOSdwd8sQrJZkVUlWLckW9MX95e_AP1EWoL4Brv0Ax_-K1Oftl5PwN1thsYg</recordid><startdate>202206</startdate><enddate>202206</enddate><creator>Zhang, Di</creator><creator>Chang, Shiquan</creator><creator>Li, Xin</creator><creator>Shi, Huimei</creator><creator>Jing, Bei</creator><creator>Chen, Zhenni</creator><creator>Lin, Yi</creator><creator>Zheng, Yachun</creator><creator>Qian, Guoqiang</creator><creator>Pan, Yuwei</creator><creator>Zhao, Guoping</creator><general>John Wiley &amp; Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8208-2323</orcidid><orcidid>https://orcid.org/0000-0003-0885-8258</orcidid><orcidid>https://orcid.org/0000-0003-1594-2378</orcidid><orcidid>https://orcid.org/0000-0003-3888-9282</orcidid><orcidid>https://orcid.org/0000-0002-3670-9877</orcidid><orcidid>https://orcid.org/0000-0001-9026-5149</orcidid><orcidid>https://orcid.org/0000-0001-9134-6573</orcidid><orcidid>https://orcid.org/0000-0003-3036-1512</orcidid><orcidid>https://orcid.org/0000-0002-5577-2329</orcidid><orcidid>https://orcid.org/0000-0001-8040-8927</orcidid></search><sort><creationdate>202206</creationdate><title>Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis</title><author>Zhang, Di ; Chang, Shiquan ; Li, Xin ; Shi, Huimei ; Jing, Bei ; Chen, Zhenni ; Lin, Yi ; Zheng, Yachun ; Qian, Guoqiang ; Pan, Yuwei ; Zhao, Guoping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4382-4d3d994bd021f6df7abbdd6ebb0e1a64733c69aafd8dfaa28ee79406d364d2323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Addictions</topic><topic>Apoptosis</topic><topic>chronic constriction injury</topic><topic>chronic neuralgia</topic><topic>Constrictions</topic><topic>Drugs</topic><topic>Hyperalgesia</topic><topic>Inflammation</topic><topic>Interleukin 1</topic><topic>Interleukin 10</topic><topic>Interleukin 6</topic><topic>Lipopolysaccharides</topic><topic>Nerves</topic><topic>Neuralgia</topic><topic>paeoniflorin</topic><topic>Pain perception</topic><topic>Schwann cells</topic><topic>Sciatic nerve</topic><topic>Sciatica</topic><topic>TLR4 protein</topic><topic>TLR4/NF‐kB</topic><topic>Toll-like receptors</topic><topic>Tumor necrosis factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Di</creatorcontrib><creatorcontrib>Chang, Shiquan</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Shi, Huimei</creatorcontrib><creatorcontrib>Jing, Bei</creatorcontrib><creatorcontrib>Chen, Zhenni</creatorcontrib><creatorcontrib>Lin, Yi</creatorcontrib><creatorcontrib>Zheng, Yachun</creatorcontrib><creatorcontrib>Qian, Guoqiang</creatorcontrib><creatorcontrib>Pan, Yuwei</creatorcontrib><creatorcontrib>Zhao, Guoping</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Phytotherapy research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Di</au><au>Chang, Shiquan</au><au>Li, Xin</au><au>Shi, Huimei</au><au>Jing, Bei</au><au>Chen, Zhenni</au><au>Lin, Yi</au><au>Zheng, Yachun</au><au>Qian, Guoqiang</au><au>Pan, Yuwei</au><au>Zhao, Guoping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis</atitle><jtitle>Phytotherapy research</jtitle><addtitle>Phytother Res</addtitle><date>2022-06</date><risdate>2022</risdate><volume>36</volume><issue>6</issue><spage>2572</spage><epage>2582</epage><pages>2572-2582</pages><issn>0951-418X</issn><eissn>1099-1573</eissn><abstract>Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF‐α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF‐kB pathway. And paeoniflorin attenuated LPS‐induced Schwann cell apoptosis by decreasing the levels of TLR4, p‐NF‐kB, caspase3, cleaved‐caspase3, and cleaved‐caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.</abstract><cop>Chichester, UK</cop><pub>John Wiley &amp; Sons, Ltd</pub><pmid>35499270</pmid><doi>10.1002/ptr.7472</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-8208-2323</orcidid><orcidid>https://orcid.org/0000-0003-0885-8258</orcidid><orcidid>https://orcid.org/0000-0003-1594-2378</orcidid><orcidid>https://orcid.org/0000-0003-3888-9282</orcidid><orcidid>https://orcid.org/0000-0002-3670-9877</orcidid><orcidid>https://orcid.org/0000-0001-9026-5149</orcidid><orcidid>https://orcid.org/0000-0001-9134-6573</orcidid><orcidid>https://orcid.org/0000-0003-3036-1512</orcidid><orcidid>https://orcid.org/0000-0002-5577-2329</orcidid><orcidid>https://orcid.org/0000-0001-8040-8927</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0951-418X
ispartof Phytotherapy research, 2022-06, Vol.36 (6), p.2572-2582
issn 0951-418X
1099-1573
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9320937
source Wiley Online Library Journals Frontfile Complete
subjects Addictions
Apoptosis
chronic constriction injury
chronic neuralgia
Constrictions
Drugs
Hyperalgesia
Inflammation
Interleukin 1
Interleukin 10
Interleukin 6
Lipopolysaccharides
Nerves
Neuralgia
paeoniflorin
Pain perception
Schwann cells
Sciatic nerve
Sciatica
TLR4 protein
TLR4/NF‐kB
Toll-like receptors
Tumor necrosis factor
title Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T11%3A45%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Therapeutic%20effect%20of%20paeoniflorin%20on%20chronic%20constriction%20injury%20of%20the%20sciatic%20nerve%20via%20the%20inhibition%20of%20Schwann%20cell%20apoptosis&rft.jtitle=Phytotherapy%20research&rft.au=Zhang,%20Di&rft.date=2022-06&rft.volume=36&rft.issue=6&rft.spage=2572&rft.epage=2582&rft.pages=2572-2582&rft.issn=0951-418X&rft.eissn=1099-1573&rft_id=info:doi/10.1002/ptr.7472&rft_dat=%3Cproquest_pubme%3E2677576177%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2677576177&rft_id=info:pmid/35499270&rfr_iscdi=true