Antioxidant and Anti-Inflammatory Effects of Anacardium occidentale L. and Anacardium microcarpum D. Extracts on the Liver of IL-10 Knockout Mice
Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammator...
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| creator | Peluzio, Maria do Carmo Gouveia Gonçalves da Costa, Cláudio Novaes, Rômulo Dias Gonçalves, Reggiani Vilela Sarandy, Mariáurea M. Baptista, Anderson Barbosa Leite, João Paulo Viana |
| description | Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods. Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results. Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion. Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma. |
| doi_str_mv | 10.1155/2020/3054521 |
| format | Article |
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Extracts on the Liver of IL-10 Knockout Mice</title><source>PubMed Central Open Access</source><source>Wiley-Blackwell Open Access Titles</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Peluzio, Maria do Carmo Gouveia ; Gonçalves da Costa, Cláudio ; Novaes, Rômulo Dias ; Gonçalves, Reggiani Vilela ; Sarandy, Mariáurea M. ; Baptista, Anderson Barbosa ; Leite, João Paulo Viana</creator><contributor>Wall Medrano, Abraham ; Abraham Wall Medrano</contributor><creatorcontrib>Peluzio, Maria do Carmo Gouveia ; Gonçalves da Costa, Cláudio ; Novaes, Rômulo Dias ; Gonçalves, Reggiani Vilela ; Sarandy, Mariáurea M. ; Baptista, Anderson Barbosa ; Leite, João Paulo Viana ; Wall Medrano, Abraham ; Abraham Wall Medrano</creatorcontrib><description>Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods. Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results. Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion. Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma.</description><identifier>ISSN: 1741-427X</identifier><identifier>EISSN: 1741-4288</identifier><identifier>DOI: 10.1155/2020/3054521</identifier><identifier>PMID: 33376496</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Aluminum ; Anacardium ; Anacardium microcarpum ; Anacardium occidentale ; Analgesics ; Anti-inflammatory agents ; Antioxidants ; Carbonyl compounds ; Catechin ; Cytokines ; Edema ; Enzymes ; Ethanol ; Flavonoids ; Free radicals ; Functional morphology ; Gallic acid ; Gene expression ; High-performance liquid chromatography ; Homeostasis ; Inflammation ; Interleukin 10 ; Leaves ; Leukocytes ; Lipid peroxidation ; Liver ; Neutrophils ; Paracetamol ; Parenchyma ; Phenolic acids ; Polyphenols ; Proteins ; Reagents</subject><ispartof>Evidence-based complementary and alternative medicine, 2020, Vol.2020 (2020), p.1-13</ispartof><rights>Copyright © 2020 Anderson Barbosa Baptista et al.</rights><rights>Copyright © 2020 Anderson Barbosa Baptista et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2020 Anderson Barbosa Baptista et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-f6b37598135ed6e3e00284956687f8a061bfeeca17b7072bb7232dfe493d115f3</citedby><cites>FETCH-LOGICAL-c471t-f6b37598135ed6e3e00284956687f8a061bfeeca17b7072bb7232dfe493d115f3</cites><orcidid>0000-0003-2297-5039 ; 0000-0002-3186-5328 ; 0000-0002-5831-3590 ; 0000-0003-2788-4013 ; 0000-0003-4665-7043 ; 0000-0002-3747-4424 ; 0000-0003-1313-7877</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/PMC7744185/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744185/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4024,27923,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33376496$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wall Medrano, Abraham</contributor><contributor>Abraham Wall Medrano</contributor><creatorcontrib>Peluzio, Maria do Carmo Gouveia</creatorcontrib><creatorcontrib>Gonçalves da Costa, Cláudio</creatorcontrib><creatorcontrib>Novaes, Rômulo Dias</creatorcontrib><creatorcontrib>Gonçalves, Reggiani Vilela</creatorcontrib><creatorcontrib>Sarandy, Mariáurea M.</creatorcontrib><creatorcontrib>Baptista, Anderson Barbosa</creatorcontrib><creatorcontrib>Leite, João Paulo Viana</creatorcontrib><title>Antioxidant and Anti-Inflammatory Effects of Anacardium occidentale L. and Anacardium microcarpum D. Extracts on the Liver of IL-10 Knockout Mice</title><title>Evidence-based complementary and alternative medicine</title><addtitle>Evid Based Complement Alternat Med</addtitle><description>Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods. Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results. Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion. Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma.</description><subject>Aluminum</subject><subject>Anacardium</subject><subject>Anacardium microcarpum</subject><subject>Anacardium occidentale</subject><subject>Analgesics</subject><subject>Anti-inflammatory agents</subject><subject>Antioxidants</subject><subject>Carbonyl compounds</subject><subject>Catechin</subject><subject>Cytokines</subject><subject>Edema</subject><subject>Enzymes</subject><subject>Ethanol</subject><subject>Flavonoids</subject><subject>Free radicals</subject><subject>Functional morphology</subject><subject>Gallic acid</subject><subject>Gene expression</subject><subject>High-performance liquid chromatography</subject><subject>Homeostasis</subject><subject>Inflammation</subject><subject>Interleukin 10</subject><subject>Leaves</subject><subject>Leukocytes</subject><subject>Lipid peroxidation</subject><subject>Liver</subject><subject>Neutrophils</subject><subject>Paracetamol</subject><subject>Parenchyma</subject><subject>Phenolic acids</subject><subject>Polyphenols</subject><subject>Proteins</subject><subject>Reagents</subject><issn>1741-427X</issn><issn>1741-4288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkU1vEzEQhi0EoqVw44wscYRN_bmze0GqSloigriAxM3yem3ikrVTr7e0P4N_XKcJAW6cPKN55vXMvAi9pGRGqZSnjDByyokUktFH6JiCoJVgTfP4EMO3I_RsHK8IYS0APEVHnHOoRVsfo19nIft463sdMtahx9u8WgS31sOgc0x3eO6cNXnE0ZWiNjr1fhpwNMb3NmS9tng527ceqoM3KZZkU-L3Mzy_zUk_aAScV6XB39i0FVwsK0rwxxDNjzhl_Mkb-xw9cXo92hf79wR9vZh_Of9QLT9fLs7PlpURQHPl6o6DbBvKpe1ry23ZrhGtrOsGXKNJTTtnrdEUOiDAug4YZ72zouV9uZvjJ-jdTnczdYPtTdkl6bXaJD_odKei9urfSvAr9T3eKAAhaCOLwOu9QIrXkx2zuopTCmVmxQSIRgJjUKi3O6ocZByTdYcfKFFbA9XWQLU3sOCv_p7qAP92rABvdsDKh17_9P8pZwtjnf5DF1Ryxu8B1CSthA</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>Peluzio, Maria do Carmo Gouveia</creator><creator>Gonçalves da Costa, Cláudio</creator><creator>Novaes, Rômulo Dias</creator><creator>Gonçalves, Reggiani Vilela</creator><creator>Sarandy, Mariáurea M.</creator><creator>Baptista, Anderson Barbosa</creator><creator>Leite, João Paulo Viana</creator><general>Hindawi Publishing Corporation</general><general>Hindawi</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>5PM</scope><orcidid>https://orcid.org/0000-0003-2297-5039</orcidid><orcidid>https://orcid.org/0000-0002-3186-5328</orcidid><orcidid>https://orcid.org/0000-0002-5831-3590</orcidid><orcidid>https://orcid.org/0000-0003-2788-4013</orcidid><orcidid>https://orcid.org/0000-0003-4665-7043</orcidid><orcidid>https://orcid.org/0000-0002-3747-4424</orcidid><orcidid>https://orcid.org/0000-0003-1313-7877</orcidid></search><sort><creationdate>2020</creationdate><title>Antioxidant and Anti-Inflammatory Effects of Anacardium occidentale L. and Anacardium microcarpum D. Extracts on the Liver of IL-10 Knockout Mice</title><author>Peluzio, Maria do Carmo Gouveia ; Gonçalves da Costa, Cláudio ; Novaes, Rômulo Dias ; Gonçalves, Reggiani Vilela ; Sarandy, Mariáurea M. ; Baptista, Anderson Barbosa ; Leite, João Paulo Viana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-f6b37598135ed6e3e00284956687f8a061bfeeca17b7072bb7232dfe493d115f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aluminum</topic><topic>Anacardium</topic><topic>Anacardium microcarpum</topic><topic>Anacardium occidentale</topic><topic>Analgesics</topic><topic>Anti-inflammatory agents</topic><topic>Antioxidants</topic><topic>Carbonyl compounds</topic><topic>Catechin</topic><topic>Cytokines</topic><topic>Edema</topic><topic>Enzymes</topic><topic>Ethanol</topic><topic>Flavonoids</topic><topic>Free radicals</topic><topic>Functional morphology</topic><topic>Gallic acid</topic><topic>Gene expression</topic><topic>High-performance liquid chromatography</topic><topic>Homeostasis</topic><topic>Inflammation</topic><topic>Interleukin 10</topic><topic>Leaves</topic><topic>Leukocytes</topic><topic>Lipid peroxidation</topic><topic>Liver</topic><topic>Neutrophils</topic><topic>Paracetamol</topic><topic>Parenchyma</topic><topic>Phenolic acids</topic><topic>Polyphenols</topic><topic>Proteins</topic><topic>Reagents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peluzio, Maria do Carmo Gouveia</creatorcontrib><creatorcontrib>Gonçalves da Costa, Cláudio</creatorcontrib><creatorcontrib>Novaes, Rômulo Dias</creatorcontrib><creatorcontrib>Gonçalves, Reggiani Vilela</creatorcontrib><creatorcontrib>Sarandy, Mariáurea M.</creatorcontrib><creatorcontrib>Baptista, Anderson Barbosa</creatorcontrib><creatorcontrib>Leite, João Paulo Viana</creatorcontrib><collection>الدوريات العلمية والإحصائية - 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Extracts on the Liver of IL-10 Knockout Mice</atitle><jtitle>Evidence-based complementary and alternative medicine</jtitle><addtitle>Evid Based Complement Alternat Med</addtitle><date>2020</date><risdate>2020</risdate><volume>2020</volume><issue>2020</issue><spage>1</spage><epage>13</epage><pages>1-13</pages><issn>1741-427X</issn><eissn>1741-4288</eissn><abstract>Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods. Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results. Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion. Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>33376496</pmid><doi>10.1155/2020/3054521</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-2297-5039</orcidid><orcidid>https://orcid.org/0000-0002-3186-5328</orcidid><orcidid>https://orcid.org/0000-0002-5831-3590</orcidid><orcidid>https://orcid.org/0000-0003-2788-4013</orcidid><orcidid>https://orcid.org/0000-0003-4665-7043</orcidid><orcidid>https://orcid.org/0000-0002-3747-4424</orcidid><orcidid>https://orcid.org/0000-0003-1313-7877</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Evidence-based complementary and alternative medicine, 2020, Vol.2020 (2020), p.1-13 |
| issn | 1741-427X 1741-4288 |
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| source | PubMed Central Open Access; Wiley-Blackwell Open Access Titles; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Aluminum Anacardium Anacardium microcarpum Anacardium occidentale Analgesics Anti-inflammatory agents Antioxidants Carbonyl compounds Catechin Cytokines Edema Enzymes Ethanol Flavonoids Free radicals Functional morphology Gallic acid Gene expression High-performance liquid chromatography Homeostasis Inflammation Interleukin 10 Leaves Leukocytes Lipid peroxidation Liver Neutrophils Paracetamol Parenchyma Phenolic acids Polyphenols Proteins Reagents |
| title | Antioxidant and Anti-Inflammatory Effects of Anacardium occidentale L. and Anacardium microcarpum D. Extracts on the Liver of IL-10 Knockout Mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T06%3A32%3A17IST&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=Antioxidant%20and%20Anti-Inflammatory%20Effects%20of%20Anacardium%20occidentale%20L.%20and%20Anacardium%20microcarpum%20D.%20Extracts%20on%20the%20Liver%20of%20IL-10%20Knockout%20Mice&rft.jtitle=Evidence-based%20complementary%20and%20alternative%20medicine&rft.au=Peluzio,%20Maria%20do%20Carmo%20Gouveia&rft.date=2020&rft.volume=2020&rft.issue=2020&rft.spage=1&rft.epage=13&rft.pages=1-13&rft.issn=1741-427X&rft.eissn=1741-4288&rft_id=info:doi/10.1155/2020/3054521&rft_dat=%3Cproquest_pubme%3E2474857227%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=2474857227&rft_id=info:pmid/33376496&rfr_iscdi=true |