Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species

The ethnomedicinal plant Curatella americana L. (Dilleniaceae) is a common shrub in the Brazilian cerrado, in which crude extract showed antifungal activity in a preliminary study. In this work, the antifungal and cytotoxic properties of the crude extract, fractions, and isolated compounds from C. a...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Evidence-based complementary and alternative medicine 2015-01, Vol.2015 (2015), p.1-9
Hauptverfasser: Nakamura, Celso Vataru, Dias Filho, Benedito Prado, Palazzo de Mello, João Carlos, Santos, Patrícia Regina, Mendes de Toledo, Cleyton Eduardo, Ueda-Nakamura, Tânia
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 9
container_issue 2015
container_start_page 1
container_title Evidence-based complementary and alternative medicine
container_volume 2015
creator Nakamura, Celso Vataru
Dias Filho, Benedito Prado
Palazzo de Mello, João Carlos
Santos, Patrícia Regina
Mendes de Toledo, Cleyton Eduardo
Ueda-Nakamura, Tânia
description The ethnomedicinal plant Curatella americana L. (Dilleniaceae) is a common shrub in the Brazilian cerrado, in which crude extract showed antifungal activity in a preliminary study. In this work, the antifungal and cytotoxic properties of the crude extract, fractions, and isolated compounds from C. americana were evaluated against the standard yeast strains Candida albicans, C. tropicalis, and C. parapsilosis, clinical isolates, and fluconazole-resistant strains. The combinatory effects between subfractions and isolated compounds and effects on cell morphology, virulence factors, and exogenous ergosterol were also evaluated. The MIC obtained against the Candida species including fluconazole-resistant strain ranged from 15.3 to 31.3 µg/mL for crude extract, 3.9 to 15.6 µg/mL for ethyl acetate fraction, and 7.8 to 31.3 µg/mL for subfractions. The isolated compounds identified as 4′-O-methyl-catechin, epicatechin-3-O-gallate, and 4′-O-methyl-catechin-3-O-gallate showed lower antifungal activity than the crude extract and fractions (MIC ranging from 31.3 to 125.0 µg/mL). The addition of exogenous ergosterol to yeast culture did not interfere in the antifungal activity of the extract and its fractions. Synergistic antifungal activity was observed between subfractions and isolated compounds. The effects on virulence factors and the different mechanisms of action compared to fluconazole and nystatin suggest that this ethnomedicinal plant may be an effective alternative treatment for candidiasis.
doi_str_mv 10.1155/2015/673962
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4548135</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1710654623</sourcerecordid><originalsourceid>FETCH-LOGICAL-c463t-70194f8c7fc4dea2b454e40409d8d71b3b3de243966ba0745108c1c3d85a5eeb3</originalsourceid><addsrcrecordid>eNqNkk1v1DAQhiMEoqVw4o4scSkf29qOHScXpLK0gLQSlQCJmzWxJ1uXxE7thI8fwv_Fy5ZV4QKnGcmP3_E7foviIaNHjEl5zCmTx5Uqm4rfKvaZEmwheF3f3vXq015xL6VLSnmjlLpb7PGqFEo1dL_4ceIn181-DT05j2HEODlMJHRkGWeL5PTbFMFM6Tk521QXfG7BW3I-R9c5tGQZhjHM3ibSxTCQlxA__7o-R5iw74HAgNEZ8EBWR-Twlet79A4MAj4hsAbn00SWWdJZIO9HNHn-_eJOB33CB9f1oPh4dvph-Waxevf67fJktTCiKqeFoqwRXW1UZ4RF4K2QAgUVtLG1Vawt29IiF3kzVQtUCclobZgpbS1BIrblQfFiqzvO7YDWoM9uez1GN0D8rgM4_eeJdxd6Hb7oPKhmpcwCh9cCMVzNmCY9uGQ2tj2GOWmmuKoaJjP8b5TRSoqKlxl9_Bd6Gebo8yYyRRuef1o2mXq2pUwMKUXsdu9mVG-SoTfJ0NtkZPrRTas79ncUMvB0C1w4b-Gr-z81zAh2cAPOeqIpfwLMo8r_</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1709296259</pqid></control><display><type>article</type><title>Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species</title><source>PubMed (Medline)</source><source>Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><source>PubMed Central Open Access</source><creator>Nakamura, Celso Vataru ; Dias Filho, Benedito Prado ; Palazzo de Mello, João Carlos ; Santos, Patrícia Regina ; Mendes de Toledo, Cleyton Eduardo ; Ueda-Nakamura, Tânia</creator><contributor>van Vuuren, Sandy</contributor><creatorcontrib>Nakamura, Celso Vataru ; Dias Filho, Benedito Prado ; Palazzo de Mello, João Carlos ; Santos, Patrícia Regina ; Mendes de Toledo, Cleyton Eduardo ; Ueda-Nakamura, Tânia ; van Vuuren, Sandy</creatorcontrib><description>The ethnomedicinal plant Curatella americana L. (Dilleniaceae) is a common shrub in the Brazilian cerrado, in which crude extract showed antifungal activity in a preliminary study. In this work, the antifungal and cytotoxic properties of the crude extract, fractions, and isolated compounds from C. americana were evaluated against the standard yeast strains Candida albicans, C. tropicalis, and C. parapsilosis, clinical isolates, and fluconazole-resistant strains. The combinatory effects between subfractions and isolated compounds and effects on cell morphology, virulence factors, and exogenous ergosterol were also evaluated. The MIC obtained against the Candida species including fluconazole-resistant strain ranged from 15.3 to 31.3 µg/mL for crude extract, 3.9 to 15.6 µg/mL for ethyl acetate fraction, and 7.8 to 31.3 µg/mL for subfractions. The isolated compounds identified as 4′-O-methyl-catechin, epicatechin-3-O-gallate, and 4′-O-methyl-catechin-3-O-gallate showed lower antifungal activity than the crude extract and fractions (MIC ranging from 31.3 to 125.0 µg/mL). The addition of exogenous ergosterol to yeast culture did not interfere in the antifungal activity of the extract and its fractions. Synergistic antifungal activity was observed between subfractions and isolated compounds. The effects on virulence factors and the different mechanisms of action compared to fluconazole and nystatin suggest that this ethnomedicinal plant may be an effective alternative treatment for candidiasis.</description><identifier>ISSN: 1741-427X</identifier><identifier>EISSN: 1741-4288</identifier><identifier>DOI: 10.1155/2015/673962</identifier><identifier>PMID: 26347790</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Candida albicans ; Chromatography ; Curatella americana ; Dilleniaceae ; Drugs ; Flowers &amp; plants ; Fractions ; Fungal infections ; Herbal medicine ; Laboratories ; Medical research ; Metabolism ; Studies</subject><ispartof>Evidence-based complementary and alternative medicine, 2015-01, Vol.2015 (2015), p.1-9</ispartof><rights>Copyright © 2015 Cleyton Eduardo Mendes de Toledo et al.</rights><rights>Copyright © 2015 Cleyton Eduardo Mendes de Toledo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2015 Cleyton Eduardo Mendes de Toledo et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-70194f8c7fc4dea2b454e40409d8d71b3b3de243966ba0745108c1c3d85a5eeb3</citedby><cites>FETCH-LOGICAL-c463t-70194f8c7fc4dea2b454e40409d8d71b3b3de243966ba0745108c1c3d85a5eeb3</cites><orcidid>0000-0002-9911-7369</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548135/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548135/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26347790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>van Vuuren, Sandy</contributor><creatorcontrib>Nakamura, Celso Vataru</creatorcontrib><creatorcontrib>Dias Filho, Benedito Prado</creatorcontrib><creatorcontrib>Palazzo de Mello, João Carlos</creatorcontrib><creatorcontrib>Santos, Patrícia Regina</creatorcontrib><creatorcontrib>Mendes de Toledo, Cleyton Eduardo</creatorcontrib><creatorcontrib>Ueda-Nakamura, Tânia</creatorcontrib><title>Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species</title><title>Evidence-based complementary and alternative medicine</title><addtitle>Evid Based Complement Alternat Med</addtitle><description>The ethnomedicinal plant Curatella americana L. (Dilleniaceae) is a common shrub in the Brazilian cerrado, in which crude extract showed antifungal activity in a preliminary study. In this work, the antifungal and cytotoxic properties of the crude extract, fractions, and isolated compounds from C. americana were evaluated against the standard yeast strains Candida albicans, C. tropicalis, and C. parapsilosis, clinical isolates, and fluconazole-resistant strains. The combinatory effects between subfractions and isolated compounds and effects on cell morphology, virulence factors, and exogenous ergosterol were also evaluated. The MIC obtained against the Candida species including fluconazole-resistant strain ranged from 15.3 to 31.3 µg/mL for crude extract, 3.9 to 15.6 µg/mL for ethyl acetate fraction, and 7.8 to 31.3 µg/mL for subfractions. The isolated compounds identified as 4′-O-methyl-catechin, epicatechin-3-O-gallate, and 4′-O-methyl-catechin-3-O-gallate showed lower antifungal activity than the crude extract and fractions (MIC ranging from 31.3 to 125.0 µg/mL). The addition of exogenous ergosterol to yeast culture did not interfere in the antifungal activity of the extract and its fractions. Synergistic antifungal activity was observed between subfractions and isolated compounds. The effects on virulence factors and the different mechanisms of action compared to fluconazole and nystatin suggest that this ethnomedicinal plant may be an effective alternative treatment for candidiasis.</description><subject>Candida albicans</subject><subject>Chromatography</subject><subject>Curatella americana</subject><subject>Dilleniaceae</subject><subject>Drugs</subject><subject>Flowers &amp; plants</subject><subject>Fractions</subject><subject>Fungal infections</subject><subject>Herbal medicine</subject><subject>Laboratories</subject><subject>Medical research</subject><subject>Metabolism</subject><subject>Studies</subject><issn>1741-427X</issn><issn>1741-4288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkk1v1DAQhiMEoqVw4o4scSkf29qOHScXpLK0gLQSlQCJmzWxJ1uXxE7thI8fwv_Fy5ZV4QKnGcmP3_E7foviIaNHjEl5zCmTx5Uqm4rfKvaZEmwheF3f3vXq015xL6VLSnmjlLpb7PGqFEo1dL_4ceIn181-DT05j2HEODlMJHRkGWeL5PTbFMFM6Tk521QXfG7BW3I-R9c5tGQZhjHM3ibSxTCQlxA__7o-R5iw74HAgNEZ8EBWR-Twlet79A4MAj4hsAbn00SWWdJZIO9HNHn-_eJOB33CB9f1oPh4dvph-Waxevf67fJktTCiKqeFoqwRXW1UZ4RF4K2QAgUVtLG1Vawt29IiF3kzVQtUCclobZgpbS1BIrblQfFiqzvO7YDWoM9uez1GN0D8rgM4_eeJdxd6Hb7oPKhmpcwCh9cCMVzNmCY9uGQ2tj2GOWmmuKoaJjP8b5TRSoqKlxl9_Bd6Gebo8yYyRRuef1o2mXq2pUwMKUXsdu9mVG-SoTfJ0NtkZPrRTas79ncUMvB0C1w4b-Gr-z81zAh2cAPOeqIpfwLMo8r_</recordid><startdate>20150101</startdate><enddate>20150101</enddate><creator>Nakamura, Celso Vataru</creator><creator>Dias Filho, Benedito Prado</creator><creator>Palazzo de Mello, João Carlos</creator><creator>Santos, Patrícia Regina</creator><creator>Mendes de Toledo, Cleyton Eduardo</creator><creator>Ueda-Nakamura, Tânia</creator><general>Hindawi Publishing Corporation</general><general>Hindawi Limited</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7T5</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M2M</scope><scope>M2O</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>M7N</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9911-7369</orcidid></search><sort><creationdate>20150101</creationdate><title>Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species</title><author>Nakamura, Celso Vataru ; Dias Filho, Benedito Prado ; Palazzo de Mello, João Carlos ; Santos, Patrícia Regina ; Mendes de Toledo, Cleyton Eduardo ; Ueda-Nakamura, Tânia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-70194f8c7fc4dea2b454e40409d8d71b3b3de243966ba0745108c1c3d85a5eeb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Candida albicans</topic><topic>Chromatography</topic><topic>Curatella americana</topic><topic>Dilleniaceae</topic><topic>Drugs</topic><topic>Flowers &amp; plants</topic><topic>Fractions</topic><topic>Fungal infections</topic><topic>Herbal medicine</topic><topic>Laboratories</topic><topic>Medical research</topic><topic>Metabolism</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakamura, Celso Vataru</creatorcontrib><creatorcontrib>Dias Filho, Benedito Prado</creatorcontrib><creatorcontrib>Palazzo de Mello, João Carlos</creatorcontrib><creatorcontrib>Santos, Patrícia Regina</creatorcontrib><creatorcontrib>Mendes de Toledo, Cleyton Eduardo</creatorcontrib><creatorcontrib>Ueda-Nakamura, Tânia</creatorcontrib><collection>الدوريات العلمية والإحصائية - e-Marefa Academic and Statistical Periodicals</collection><collection>معرفة - المحتوى العربي الأكاديمي المتكامل - e-Marefa Academic Complete</collection><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>ProQuest Psychology Journals</collection><collection>ProQuest Research Library</collection><collection>Research Library (Corporate)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Evidence-based complementary and alternative medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakamura, Celso Vataru</au><au>Dias Filho, Benedito Prado</au><au>Palazzo de Mello, João Carlos</au><au>Santos, Patrícia Regina</au><au>Mendes de Toledo, Cleyton Eduardo</au><au>Ueda-Nakamura, Tânia</au><au>van Vuuren, Sandy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species</atitle><jtitle>Evidence-based complementary and alternative medicine</jtitle><addtitle>Evid Based Complement Alternat Med</addtitle><date>2015-01-01</date><risdate>2015</risdate><volume>2015</volume><issue>2015</issue><spage>1</spage><epage>9</epage><pages>1-9</pages><issn>1741-427X</issn><eissn>1741-4288</eissn><abstract>The ethnomedicinal plant Curatella americana L. (Dilleniaceae) is a common shrub in the Brazilian cerrado, in which crude extract showed antifungal activity in a preliminary study. In this work, the antifungal and cytotoxic properties of the crude extract, fractions, and isolated compounds from C. americana were evaluated against the standard yeast strains Candida albicans, C. tropicalis, and C. parapsilosis, clinical isolates, and fluconazole-resistant strains. The combinatory effects between subfractions and isolated compounds and effects on cell morphology, virulence factors, and exogenous ergosterol were also evaluated. The MIC obtained against the Candida species including fluconazole-resistant strain ranged from 15.3 to 31.3 µg/mL for crude extract, 3.9 to 15.6 µg/mL for ethyl acetate fraction, and 7.8 to 31.3 µg/mL for subfractions. The isolated compounds identified as 4′-O-methyl-catechin, epicatechin-3-O-gallate, and 4′-O-methyl-catechin-3-O-gallate showed lower antifungal activity than the crude extract and fractions (MIC ranging from 31.3 to 125.0 µg/mL). The addition of exogenous ergosterol to yeast culture did not interfere in the antifungal activity of the extract and its fractions. Synergistic antifungal activity was observed between subfractions and isolated compounds. The effects on virulence factors and the different mechanisms of action compared to fluconazole and nystatin suggest that this ethnomedicinal plant may be an effective alternative treatment for candidiasis.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>26347790</pmid><doi>10.1155/2015/673962</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-9911-7369</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1741-427X
ispartof Evidence-based complementary and alternative medicine, 2015-01, Vol.2015 (2015), p.1-9
issn 1741-427X
1741-4288
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4548135
source PubMed (Medline); Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; PubMed Central Open Access
subjects Candida albicans
Chromatography
Curatella americana
Dilleniaceae
Drugs
Flowers & plants
Fractions
Fungal infections
Herbal medicine
Laboratories
Medical research
Metabolism
Studies
title Antifungal Properties of Crude Extracts, Fractions, and Purified Compounds from Bark of Curatella americana L. (Dilleniaceae) against Candida Species
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T19%3A49%3A39IST&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=Antifungal%20Properties%20of%20Crude%20Extracts,%20Fractions,%20and%20Purified%20Compounds%20from%20Bark%20of%20Curatella%20americana%20L.%20(Dilleniaceae)%20against%20Candida%20Species&rft.jtitle=Evidence-based%20complementary%20and%20alternative%20medicine&rft.au=Nakamura,%20Celso%20Vataru&rft.date=2015-01-01&rft.volume=2015&rft.issue=2015&rft.spage=1&rft.epage=9&rft.pages=1-9&rft.issn=1741-427X&rft.eissn=1741-4288&rft_id=info:doi/10.1155/2015/673962&rft_dat=%3Cproquest_pubme%3E1710654623%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=1709296259&rft_id=info:pmid/26347790&rfr_iscdi=true