A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells

In this study, Moringa oleifera flower extract and a trypsin inhibitor (MoFTI) isolated from it were evaluated for anti-protozoal activity against Trypanosoma cruzi and cytotoxicity to mammalian cells. The presence of flavonoids was remarkable in the HPLC fingerprints of the extract at 254 and 360 n...

Full description

Saved in:
Bibliographic Details
Published in:Natural product research 2018-12, Vol.32 (24), p.2940-2944
Main Authors: Pontual, Emmanuel V., Pires-Neto, Divar F., Fraige, Karina, Higino, Taciana M. M., Carvalho, Belany E. A., Alves, Neyla M. P., Lima, Thâmarah A., Zingali, Russolina B., Coelho, Luana C. B. B., Bolzani, Vanderlan S., Figueiredo, Regina C. B. Q., Napoleão, Thiago H., Paiva, Patrícia M. G.
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cercopithecus aethiops
chagas disease
Cytotoxicity
Flavonoids
Flavonoids - analysis
Flowers - chemistry
High-performance liquid chromatography
Liquid chromatography
Lysis
Macrophages
Macrophages, Peritoneal - drug effects
Mammalian cells
Mammals
Mice
Moringa oleifera
Moringa oleifera - chemistry
Peptides
Peritoneum
Plant Extracts - chemistry
Plant Extracts - pharmacology
protease inhibitor
Protozoa
Selectivity
Toxicity
Trypanocidal Agents - pharmacology
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
trypomastigote
Trypomastigotes
Trypsin
Trypsin inhibitors
Trypsin Inhibitors - isolation & purification
Trypsin Inhibitors - pharmacology
Vero cells
Vero Cells - drug effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013
cites cdi_FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013
container_end_page 2944
container_issue 24
container_start_page 2940
container_title Natural product research
container_volume 32
creator Pontual, Emmanuel V.
Pires-Neto, Divar F.
Fraige, Karina
Higino, Taciana M. M.
Carvalho, Belany E. A.
Alves, Neyla M. P.
Lima, Thâmarah A.
Zingali, Russolina B.
Coelho, Luana C. B. B.
Bolzani, Vanderlan S.
Figueiredo, Regina C. B. Q.
Napoleão, Thiago H.
Paiva, Patrícia M. G.
description In this study, Moringa oleifera flower extract and a trypsin inhibitor (MoFTI) isolated from it were evaluated for anti-protozoal activity against Trypanosoma cruzi and cytotoxicity to mammalian cells. The presence of flavonoids was remarkable in the HPLC fingerprints of the extract at 254 and 360 nm. Amino acid sequences of peptides derived from in-gel digestion of MoFTI were determined. Both the extract and MoFTI caused lysis of T. cruzi trypomastigotes with LC 50/24 h of 54.18 ± 6.62 and 41.20 ± 4.28 μg/mL, respectively. High selectivity indices (7.9 to >12) for T. cruzi cells over murine peritoneal macrophages and Vero cells were found for the extract and MoFTI. The results show that MoFTI is a trypanocidal principle of the flower extract.
doi_str_mv 10.1080/14786419.2017.1389932
format article
fullrecord <record><control><sourceid>proquest_infor</sourceid><recordid>TN_cdi_proquest_journals_2186646759</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2186646759</sourcerecordid><originalsourceid>FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013</originalsourceid><addsrcrecordid>eNp9kE1v1DAQhi0EoqXwE0CWOO9iO3Yc36iq8iEVcSlna-LYXVdOvIy93YY7_5usdtsjpxmNnvcd6SHkPWdrzjr2iUvdtZKbtWBcr3nTGdOIF-T8cF-1UuiXzzs3Z-RNKfeMCa6Uek3OhGFSN4Kdk7-XtOK8LXGicdrEPtaMNGAe6Y-McboDmpOPwSPQkPLeI_WPFcFVGgt1c801P0ZHa6a3Sw1MueQRqMPdn0j3sW7oJt5taPHJuxofYp1pflhKRhhHSBEm6nxK5S15FSAV_-40L8ivL9e3V99WNz-_fr-6vFk5KXldGTkII8H0IKTxXDEIQjLhXCc6CFoq8MGxITSgtDAt03rolfRcc9GInvHmgnw89m4x_975Uu193uG0vLSCd20rW63MQqkj5TCXgj7YLcYRcLac2YN8-yTfHuTbk_wl9-HUvutHPzynnmwvwOcjEKeQcYR9xjTYCnPKGBAmF4tt_v_jH5lblf0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2186646759</pqid></control><display><type>article</type><title>A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells</title><source>Taylor and Francis Science and Technology Collection</source><creator>Pontual, Emmanuel V. ; Pires-Neto, Divar F. ; Fraige, Karina ; Higino, Taciana M. M. ; Carvalho, Belany E. A. ; Alves, Neyla M. P. ; Lima, Thâmarah A. ; Zingali, Russolina B. ; Coelho, Luana C. B. B. ; Bolzani, Vanderlan S. ; Figueiredo, Regina C. B. Q. ; Napoleão, Thiago H. ; Paiva, Patrícia M. G.</creator><creatorcontrib>Pontual, Emmanuel V. ; Pires-Neto, Divar F. ; Fraige, Karina ; Higino, Taciana M. M. ; Carvalho, Belany E. A. ; Alves, Neyla M. P. ; Lima, Thâmarah A. ; Zingali, Russolina B. ; Coelho, Luana C. B. B. ; Bolzani, Vanderlan S. ; Figueiredo, Regina C. B. Q. ; Napoleão, Thiago H. ; Paiva, Patrícia M. G.</creatorcontrib><description>In this study, Moringa oleifera flower extract and a trypsin inhibitor (MoFTI) isolated from it were evaluated for anti-protozoal activity against Trypanosoma cruzi and cytotoxicity to mammalian cells. The presence of flavonoids was remarkable in the HPLC fingerprints of the extract at 254 and 360 nm. Amino acid sequences of peptides derived from in-gel digestion of MoFTI were determined. Both the extract and MoFTI caused lysis of T. cruzi trypomastigotes with LC 50/24 h of 54.18 ± 6.62 and 41.20 ± 4.28 μg/mL, respectively. High selectivity indices (7.9 to &gt;12) for T. cruzi cells over murine peritoneal macrophages and Vero cells were found for the extract and MoFTI. The results show that MoFTI is a trypanocidal principle of the flower extract.</description><identifier>ISSN: 1478-6419</identifier><identifier>EISSN: 1478-6427</identifier><identifier>DOI: 10.1080/14786419.2017.1389932</identifier><identifier>PMID: 29047320</identifier><language>eng</language><publisher>England: Taylor &amp; Francis</publisher><subject>Animals ; Cell Line ; Cercopithecus aethiops ; chagas disease ; Cytotoxicity ; Flavonoids ; Flavonoids - analysis ; Flowers - chemistry ; High-performance liquid chromatography ; Liquid chromatography ; Lysis ; Macrophages ; Macrophages, Peritoneal - drug effects ; Mammalian cells ; Mammals ; Mice ; Moringa oleifera ; Moringa oleifera - chemistry ; Peptides ; Peritoneum ; Plant Extracts - chemistry ; Plant Extracts - pharmacology ; protease inhibitor ; Protozoa ; Selectivity ; Toxicity ; Trypanocidal Agents - pharmacology ; Trypanosoma cruzi ; Trypanosoma cruzi - drug effects ; trypomastigote ; Trypomastigotes ; Trypsin ; Trypsin inhibitors ; Trypsin Inhibitors - isolation &amp; purification ; Trypsin Inhibitors - pharmacology ; Vero cells ; Vero Cells - drug effects</subject><ispartof>Natural product research, 2018-12, Vol.32 (24), p.2940-2944</ispartof><rights>2017 Informa UK Limited, trading as Taylor &amp; Francis Group 2017</rights><rights>2017 Informa UK Limited, trading as Taylor &amp; Francis Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013</citedby><cites>FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29047320$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pontual, Emmanuel V.</creatorcontrib><creatorcontrib>Pires-Neto, Divar F.</creatorcontrib><creatorcontrib>Fraige, Karina</creatorcontrib><creatorcontrib>Higino, Taciana M. M.</creatorcontrib><creatorcontrib>Carvalho, Belany E. A.</creatorcontrib><creatorcontrib>Alves, Neyla M. P.</creatorcontrib><creatorcontrib>Lima, Thâmarah A.</creatorcontrib><creatorcontrib>Zingali, Russolina B.</creatorcontrib><creatorcontrib>Coelho, Luana C. B. B.</creatorcontrib><creatorcontrib>Bolzani, Vanderlan S.</creatorcontrib><creatorcontrib>Figueiredo, Regina C. B. Q.</creatorcontrib><creatorcontrib>Napoleão, Thiago H.</creatorcontrib><creatorcontrib>Paiva, Patrícia M. G.</creatorcontrib><title>A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells</title><title>Natural product research</title><addtitle>Nat Prod Res</addtitle><description>In this study, Moringa oleifera flower extract and a trypsin inhibitor (MoFTI) isolated from it were evaluated for anti-protozoal activity against Trypanosoma cruzi and cytotoxicity to mammalian cells. The presence of flavonoids was remarkable in the HPLC fingerprints of the extract at 254 and 360 nm. Amino acid sequences of peptides derived from in-gel digestion of MoFTI were determined. Both the extract and MoFTI caused lysis of T. cruzi trypomastigotes with LC 50/24 h of 54.18 ± 6.62 and 41.20 ± 4.28 μg/mL, respectively. High selectivity indices (7.9 to &gt;12) for T. cruzi cells over murine peritoneal macrophages and Vero cells were found for the extract and MoFTI. The results show that MoFTI is a trypanocidal principle of the flower extract.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Cercopithecus aethiops</subject><subject>chagas disease</subject><subject>Cytotoxicity</subject><subject>Flavonoids</subject><subject>Flavonoids - analysis</subject><subject>Flowers - chemistry</subject><subject>High-performance liquid chromatography</subject><subject>Liquid chromatography</subject><subject>Lysis</subject><subject>Macrophages</subject><subject>Macrophages, Peritoneal - drug effects</subject><subject>Mammalian cells</subject><subject>Mammals</subject><subject>Mice</subject><subject>Moringa oleifera</subject><subject>Moringa oleifera - chemistry</subject><subject>Peptides</subject><subject>Peritoneum</subject><subject>Plant Extracts - chemistry</subject><subject>Plant Extracts - pharmacology</subject><subject>protease inhibitor</subject><subject>Protozoa</subject><subject>Selectivity</subject><subject>Toxicity</subject><subject>Trypanocidal Agents - pharmacology</subject><subject>Trypanosoma cruzi</subject><subject>Trypanosoma cruzi - drug effects</subject><subject>trypomastigote</subject><subject>Trypomastigotes</subject><subject>Trypsin</subject><subject>Trypsin inhibitors</subject><subject>Trypsin Inhibitors - isolation &amp; purification</subject><subject>Trypsin Inhibitors - pharmacology</subject><subject>Vero cells</subject><subject>Vero Cells - drug effects</subject><issn>1478-6419</issn><issn>1478-6427</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kE1v1DAQhi0EoqXwE0CWOO9iO3Yc36iq8iEVcSlna-LYXVdOvIy93YY7_5usdtsjpxmNnvcd6SHkPWdrzjr2iUvdtZKbtWBcr3nTGdOIF-T8cF-1UuiXzzs3Z-RNKfeMCa6Uek3OhGFSN4Kdk7-XtOK8LXGicdrEPtaMNGAe6Y-McboDmpOPwSPQkPLeI_WPFcFVGgt1c801P0ZHa6a3Sw1MueQRqMPdn0j3sW7oJt5taPHJuxofYp1pflhKRhhHSBEm6nxK5S15FSAV_-40L8ivL9e3V99WNz-_fr-6vFk5KXldGTkII8H0IKTxXDEIQjLhXCc6CFoq8MGxITSgtDAt03rolfRcc9GInvHmgnw89m4x_975Uu193uG0vLSCd20rW63MQqkj5TCXgj7YLcYRcLac2YN8-yTfHuTbk_wl9-HUvutHPzynnmwvwOcjEKeQcYR9xjTYCnPKGBAmF4tt_v_jH5lblf0</recordid><startdate>20181217</startdate><enddate>20181217</enddate><creator>Pontual, Emmanuel V.</creator><creator>Pires-Neto, Divar F.</creator><creator>Fraige, Karina</creator><creator>Higino, Taciana M. M.</creator><creator>Carvalho, Belany E. A.</creator><creator>Alves, Neyla M. P.</creator><creator>Lima, Thâmarah A.</creator><creator>Zingali, Russolina B.</creator><creator>Coelho, Luana C. B. B.</creator><creator>Bolzani, Vanderlan S.</creator><creator>Figueiredo, Regina C. B. Q.</creator><creator>Napoleão, Thiago H.</creator><creator>Paiva, Patrícia M. G.</creator><general>Taylor &amp; Francis</general><general>Taylor &amp; Francis Ltd</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>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope></search><sort><creationdate>20181217</creationdate><title>A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells</title><author>Pontual, Emmanuel V. ; Pires-Neto, Divar F. ; Fraige, Karina ; Higino, Taciana M. M. ; Carvalho, Belany E. A. ; Alves, Neyla M. P. ; Lima, Thâmarah A. ; Zingali, Russolina B. ; Coelho, Luana C. B. B. ; Bolzani, Vanderlan S. ; Figueiredo, Regina C. B. Q. ; Napoleão, Thiago H. ; Paiva, Patrícia M. G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Cercopithecus aethiops</topic><topic>chagas disease</topic><topic>Cytotoxicity</topic><topic>Flavonoids</topic><topic>Flavonoids - analysis</topic><topic>Flowers - chemistry</topic><topic>High-performance liquid chromatography</topic><topic>Liquid chromatography</topic><topic>Lysis</topic><topic>Macrophages</topic><topic>Macrophages, Peritoneal - drug effects</topic><topic>Mammalian cells</topic><topic>Mammals</topic><topic>Mice</topic><topic>Moringa oleifera</topic><topic>Moringa oleifera - chemistry</topic><topic>Peptides</topic><topic>Peritoneum</topic><topic>Plant Extracts - chemistry</topic><topic>Plant Extracts - pharmacology</topic><topic>protease inhibitor</topic><topic>Protozoa</topic><topic>Selectivity</topic><topic>Toxicity</topic><topic>Trypanocidal Agents - pharmacology</topic><topic>Trypanosoma cruzi</topic><topic>Trypanosoma cruzi - drug effects</topic><topic>trypomastigote</topic><topic>Trypomastigotes</topic><topic>Trypsin</topic><topic>Trypsin inhibitors</topic><topic>Trypsin Inhibitors - isolation &amp; purification</topic><topic>Trypsin Inhibitors - pharmacology</topic><topic>Vero cells</topic><topic>Vero Cells - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pontual, Emmanuel V.</creatorcontrib><creatorcontrib>Pires-Neto, Divar F.</creatorcontrib><creatorcontrib>Fraige, Karina</creatorcontrib><creatorcontrib>Higino, Taciana M. M.</creatorcontrib><creatorcontrib>Carvalho, Belany E. A.</creatorcontrib><creatorcontrib>Alves, Neyla M. P.</creatorcontrib><creatorcontrib>Lima, Thâmarah A.</creatorcontrib><creatorcontrib>Zingali, Russolina B.</creatorcontrib><creatorcontrib>Coelho, Luana C. B. B.</creatorcontrib><creatorcontrib>Bolzani, Vanderlan S.</creatorcontrib><creatorcontrib>Figueiredo, Regina C. B. Q.</creatorcontrib><creatorcontrib>Napoleão, Thiago H.</creatorcontrib><creatorcontrib>Paiva, Patrícia M. G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Natural product research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pontual, Emmanuel V.</au><au>Pires-Neto, Divar F.</au><au>Fraige, Karina</au><au>Higino, Taciana M. M.</au><au>Carvalho, Belany E. A.</au><au>Alves, Neyla M. P.</au><au>Lima, Thâmarah A.</au><au>Zingali, Russolina B.</au><au>Coelho, Luana C. B. B.</au><au>Bolzani, Vanderlan S.</au><au>Figueiredo, Regina C. B. Q.</au><au>Napoleão, Thiago H.</au><au>Paiva, Patrícia M. G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells</atitle><jtitle>Natural product research</jtitle><addtitle>Nat Prod Res</addtitle><date>2018-12-17</date><risdate>2018</risdate><volume>32</volume><issue>24</issue><spage>2940</spage><epage>2944</epage><pages>2940-2944</pages><issn>1478-6419</issn><eissn>1478-6427</eissn><abstract>In this study, Moringa oleifera flower extract and a trypsin inhibitor (MoFTI) isolated from it were evaluated for anti-protozoal activity against Trypanosoma cruzi and cytotoxicity to mammalian cells. The presence of flavonoids was remarkable in the HPLC fingerprints of the extract at 254 and 360 nm. Amino acid sequences of peptides derived from in-gel digestion of MoFTI were determined. Both the extract and MoFTI caused lysis of T. cruzi trypomastigotes with LC 50/24 h of 54.18 ± 6.62 and 41.20 ± 4.28 μg/mL, respectively. High selectivity indices (7.9 to &gt;12) for T. cruzi cells over murine peritoneal macrophages and Vero cells were found for the extract and MoFTI. The results show that MoFTI is a trypanocidal principle of the flower extract.</abstract><cop>England</cop><pub>Taylor &amp; Francis</pub><pmid>29047320</pmid><doi>10.1080/14786419.2017.1389932</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1478-6419
ispartof Natural product research, 2018-12, Vol.32 (24), p.2940-2944
issn 1478-6419
1478-6427
language eng
recordid cdi_proquest_journals_2186646759
source Taylor and Francis Science and Technology Collection
subjects Animals
Cell Line
Cercopithecus aethiops
chagas disease
Cytotoxicity
Flavonoids
Flavonoids - analysis
Flowers - chemistry
High-performance liquid chromatography
Liquid chromatography
Lysis
Macrophages
Macrophages, Peritoneal - drug effects
Mammalian cells
Mammals
Mice
Moringa oleifera
Moringa oleifera - chemistry
Peptides
Peritoneum
Plant Extracts - chemistry
Plant Extracts - pharmacology
protease inhibitor
Protozoa
Selectivity
Toxicity
Trypanocidal Agents - pharmacology
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
trypomastigote
Trypomastigotes
Trypsin
Trypsin inhibitors
Trypsin Inhibitors - isolation & purification
Trypsin Inhibitors - pharmacology
Vero cells
Vero Cells - drug effects
title A trypsin inhibitor from Moringa oleifera flower extract is cytotoxic to Trypanosoma cruzi with high selectivity over mammalian cells
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-13T21%3A31%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_infor&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20trypsin%20inhibitor%20from%20Moringa%20oleifera%20flower%20extract%20is%20cytotoxic%20to%20Trypanosoma%20cruzi%20with%20high%20selectivity%20over%20mammalian%20cells&rft.jtitle=Natural%20product%20research&rft.au=Pontual,%20Emmanuel%20V.&rft.date=2018-12-17&rft.volume=32&rft.issue=24&rft.spage=2940&rft.epage=2944&rft.pages=2940-2944&rft.issn=1478-6419&rft.eissn=1478-6427&rft_id=info:doi/10.1080/14786419.2017.1389932&rft_dat=%3Cproquest_infor%3E2186646759%3C/proquest_infor%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c441t-94d294a9ba249e150af2402cc828af745aefc0df3a57296077db54e171232b013%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2186646759&rft_id=info:pmid/29047320&rfr_iscdi=true