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The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study
Freshly mixed root canal sealers when proximate the periapical tissues, trigger varying degrees of cytotoxicity/inflammatory reactions. Simvastatin, a class of the drug statin, is a widely used cholesterol-lowering agent with additional anti-inflammatory activities. This study assessed the effects o...
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Published in: | BMC oral health 2022-01, Vol.22 (1), p.6-6, Article 6 |
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description | Freshly mixed root canal sealers when proximate the periapical tissues, trigger varying degrees of cytotoxicity/inflammatory reactions. Simvastatin, a class of the drug statin, is a widely used cholesterol-lowering agent with additional anti-inflammatory activities. This study assessed the effects of simvastatin on cytotoxicity and the release of IL-6 (Interleukin-6) production when incorporated in zinc oxide eugenol and methacrylate resin-based sealers.
Experimental groups consisted of conventional zinc oxide eugenol and methacrylate based-EndoREZ sealers (ZE & ER respectively) and 0.5 mg/mL simvastatin incorporated sealers (ZES & ERS). L929 mouse fibroblast cells were exposed to freshly mixed experimental sealers and evaluated for cytotoxicity (MTT assay) and inflammation levels (inflammatory marker IL-6 for ELISA) at various time intervals (0h, 24h and 7th day). The values were compared to the cell control (CC; L929 cells alone) and solvent control (SC; L929 cells + DMSO) groups. All the experiments were conducted in triplicates and subjected to statistical analysis using IBM SPSS Statistics software. Non parametric tests were conducted using Kruskal-Wallis and Friedman tests for inter-group and intra-group comparisons respectively. Pairwise comparison was conducted by post hoc Dunn test followed by Bonferroni correction. P values < 0.05 were considered statistically significant.
All the experimental groups (ZE, ER, ZES, ERS) exhibited varying degree of cytotoxicity and IL-6 expression compared to the control groups CC and SC. The cell viability for ZE and ER decreased on day 7 as compared to 24 h. ZES and ERS had higher viable cells (75.93% & 79.90%) compared to ZE and ER (54.39% & 57.84%) at all time periods. Increased expression of IL-6 was observed in ZE & ER (25.49 pg/mL & 23.14 pg/mL) when compared to simvastatin incorporated ZE & ER (ZES-12.70 pg/mL & ERS-14.68 pg/mL) at all time periods. Highest level of cytotoxicity and inflammation was observed in ZE compared to all the other groups on day 7.
Addition of 0.5 mg/mL of simvastatin to the sealers (ZES and ERS) decreased the cytotoxicity in the freshly mixed state and reduces their inflammatory effect. |
doi_str_mv | 10.1186/s12903-022-02039-y |
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Experimental groups consisted of conventional zinc oxide eugenol and methacrylate based-EndoREZ sealers (ZE & ER respectively) and 0.5 mg/mL simvastatin incorporated sealers (ZES & ERS). L929 mouse fibroblast cells were exposed to freshly mixed experimental sealers and evaluated for cytotoxicity (MTT assay) and inflammation levels (inflammatory marker IL-6 for ELISA) at various time intervals (0h, 24h and 7th day). The values were compared to the cell control (CC; L929 cells alone) and solvent control (SC; L929 cells + DMSO) groups. All the experiments were conducted in triplicates and subjected to statistical analysis using IBM SPSS Statistics software. Non parametric tests were conducted using Kruskal-Wallis and Friedman tests for inter-group and intra-group comparisons respectively. Pairwise comparison was conducted by post hoc Dunn test followed by Bonferroni correction. P values < 0.05 were considered statistically significant.
All the experimental groups (ZE, ER, ZES, ERS) exhibited varying degree of cytotoxicity and IL-6 expression compared to the control groups CC and SC. The cell viability for ZE and ER decreased on day 7 as compared to 24 h. ZES and ERS had higher viable cells (75.93% & 79.90%) compared to ZE and ER (54.39% & 57.84%) at all time periods. Increased expression of IL-6 was observed in ZE & ER (25.49 pg/mL & 23.14 pg/mL) when compared to simvastatin incorporated ZE & ER (ZES-12.70 pg/mL & ERS-14.68 pg/mL) at all time periods. Highest level of cytotoxicity and inflammation was observed in ZE compared to all the other groups on day 7.
Addition of 0.5 mg/mL of simvastatin to the sealers (ZES and ERS) decreased the cytotoxicity in the freshly mixed state and reduces their inflammatory effect.]]></description><identifier>ISSN: 1472-6831</identifier><identifier>EISSN: 1472-6831</identifier><identifier>DOI: 10.1186/s12903-022-02039-y</identifier><identifier>PMID: 35012572</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Animals ; Cell viability ; Cholesterol ; Clinical trials ; Cytokine ; Cytokines ; Cytotoxicity ; Dental Pulp Cavity ; Dosage and administration ; Drug therapy ; Endodontics ; Enzyme-linked immunosorbent assay ; Epoxy Resins ; Eugenol ; Fibroblasts ; Flow cytometry ; Gene expression ; Humans ; IL-6 receptor ; Inflammation ; Interleukin 6 ; Materials Testing ; Methods ; Mice ; Microscopy ; Root Canal Filling Materials - toxicity ; Root canal sealers ; Root canal therapy ; Root canals ; Sealing compounds ; Simvastatin ; Simvastatin - pharmacology ; Statistical analysis ; Zinc oxide ; Zinc Oxide-Eugenol Cement ; Zinc oxides</subject><ispartof>BMC oral health, 2022-01, Vol.22 (1), p.6-6, Article 6</ispartof><rights>2022. The Author(s).</rights><rights>COPYRIGHT 2022 BioMed Central Ltd.</rights><rights>2022. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-fa079916366ddf07a425c03e82f7befc8b37f88b7a98740cdcc88a309084e7193</citedby><cites>FETCH-LOGICAL-c563t-fa079916366ddf07a425c03e82f7befc8b37f88b7a98740cdcc88a309084e7193</cites><orcidid>0000-0002-7024-6570 ; 0000-0002-3783-4688 ; 0000-0002-7159-8180 ; 0000-0002-4537-8440 ; 0000-0002-2455-4468</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/PMC8751161/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2621091194?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25751,27922,27923,37010,37011,44588,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35012572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sharma, Apoorva</creatorcontrib><creatorcontrib>Sanjeev, Kavitha</creatorcontrib><creatorcontrib>Selvanathan, Vinola M J</creatorcontrib><creatorcontrib>Sekar, Mahalaxmi</creatorcontrib><creatorcontrib>Harikrishnan, Nikhil</creatorcontrib><title>The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study</title><title>BMC oral health</title><addtitle>BMC Oral Health</addtitle><description><![CDATA[Freshly mixed root canal sealers when proximate the periapical tissues, trigger varying degrees of cytotoxicity/inflammatory reactions. Simvastatin, a class of the drug statin, is a widely used cholesterol-lowering agent with additional anti-inflammatory activities. This study assessed the effects of simvastatin on cytotoxicity and the release of IL-6 (Interleukin-6) production when incorporated in zinc oxide eugenol and methacrylate resin-based sealers.
Experimental groups consisted of conventional zinc oxide eugenol and methacrylate based-EndoREZ sealers (ZE & ER respectively) and 0.5 mg/mL simvastatin incorporated sealers (ZES & ERS). L929 mouse fibroblast cells were exposed to freshly mixed experimental sealers and evaluated for cytotoxicity (MTT assay) and inflammation levels (inflammatory marker IL-6 for ELISA) at various time intervals (0h, 24h and 7th day). The values were compared to the cell control (CC; L929 cells alone) and solvent control (SC; L929 cells + DMSO) groups. All the experiments were conducted in triplicates and subjected to statistical analysis using IBM SPSS Statistics software. Non parametric tests were conducted using Kruskal-Wallis and Friedman tests for inter-group and intra-group comparisons respectively. Pairwise comparison was conducted by post hoc Dunn test followed by Bonferroni correction. P values < 0.05 were considered statistically significant.
All the experimental groups (ZE, ER, ZES, ERS) exhibited varying degree of cytotoxicity and IL-6 expression compared to the control groups CC and SC. The cell viability for ZE and ER decreased on day 7 as compared to 24 h. ZES and ERS had higher viable cells (75.93% & 79.90%) compared to ZE and ER (54.39% & 57.84%) at all time periods. Increased expression of IL-6 was observed in ZE & ER (25.49 pg/mL & 23.14 pg/mL) when compared to simvastatin incorporated ZE & ER (ZES-12.70 pg/mL & ERS-14.68 pg/mL) at all time periods. Highest level of cytotoxicity and inflammation was observed in ZE compared to all the other groups on day 7.
Addition of 0.5 mg/mL of simvastatin to the sealers (ZES and ERS) decreased the cytotoxicity in the freshly mixed state and reduces their inflammatory effect.]]></description><subject>Animals</subject><subject>Cell viability</subject><subject>Cholesterol</subject><subject>Clinical trials</subject><subject>Cytokine</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Dental Pulp Cavity</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Endodontics</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Epoxy Resins</subject><subject>Eugenol</subject><subject>Fibroblasts</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Humans</subject><subject>IL-6 receptor</subject><subject>Inflammation</subject><subject>Interleukin 6</subject><subject>Materials Testing</subject><subject>Methods</subject><subject>Mice</subject><subject>Microscopy</subject><subject>Root Canal Filling Materials - toxicity</subject><subject>Root canal sealers</subject><subject>Root canal therapy</subject><subject>Root canals</subject><subject>Sealing compounds</subject><subject>Simvastatin</subject><subject>Simvastatin - pharmacology</subject><subject>Statistical analysis</subject><subject>Zinc oxide</subject><subject>Zinc Oxide-Eugenol Cement</subject><subject>Zinc oxides</subject><issn>1472-6831</issn><issn>1472-6831</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptksuO0zAUhiMEYoaBF2CBIrFhk8HHTnxhgTQacalUic2wtlxfWpc0LrbTIQ_C--K2M2UGociKffL9_5Fz_qp6DegSgNP3CbBApEEYl4WIaKYn1Tm0DDeUE3j6YH9WvUhpjRAw3rbPqzPSIcAdw-fV75uVre1O9aPKPgx1cLWecsjhl9c-T7UazKHwww-2ns0bWm9jMKO-h2MIudZqUH2drOptTPWtz6uDbr8JY65zaeEHHeI2xFOX5Dc7lXI5Dx8KXYCdzzHUKY9melk9c6pP9tXd-6L6_vnTzfXXZv7ty-z6at7ojpLcOIWYEEAJpcY4xFSLO42I5dixhXWaLwhznC-YEpy1SButOVcECcRby0CQi2p29DVBreU2-o2KkwzKy0MhxKVUMXvdW8mEMg60pRhUC2DUwoJzlAnTdpgTXLw-Hr2242JjjbZDjqp_ZPr4y-BXchl2krMOgEIxeHdnEMPP0aYsNz5p2_dqsGFMElPgZd4FL-jbf9B1GGMZwp7CgASAaP9SyzIY6QcXSl-9N5VXVBAqKEd7r8v_UOUxduN1GKzzpf5IgI8CHUNK0brTHQHJfTDlMZiyBFMegimnInrz8O-cJPdJJH8AMPfgmQ</recordid><startdate>20220111</startdate><enddate>20220111</enddate><creator>Sharma, Apoorva</creator><creator>Sanjeev, Kavitha</creator><creator>Selvanathan, Vinola M J</creator><creator>Sekar, Mahalaxmi</creator><creator>Harikrishnan, Nikhil</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</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>3V.</scope><scope>7QP</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7024-6570</orcidid><orcidid>https://orcid.org/0000-0002-3783-4688</orcidid><orcidid>https://orcid.org/0000-0002-7159-8180</orcidid><orcidid>https://orcid.org/0000-0002-4537-8440</orcidid><orcidid>https://orcid.org/0000-0002-2455-4468</orcidid></search><sort><creationdate>20220111</creationdate><title>The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study</title><author>Sharma, Apoorva ; Sanjeev, Kavitha ; Selvanathan, Vinola M J ; Sekar, Mahalaxmi ; Harikrishnan, Nikhil</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c563t-fa079916366ddf07a425c03e82f7befc8b37f88b7a98740cdcc88a309084e7193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Cell viability</topic><topic>Cholesterol</topic><topic>Clinical trials</topic><topic>Cytokine</topic><topic>Cytokines</topic><topic>Cytotoxicity</topic><topic>Dental Pulp Cavity</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>Endodontics</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Epoxy Resins</topic><topic>Eugenol</topic><topic>Fibroblasts</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Humans</topic><topic>IL-6 receptor</topic><topic>Inflammation</topic><topic>Interleukin 6</topic><topic>Materials Testing</topic><topic>Methods</topic><topic>Mice</topic><topic>Microscopy</topic><topic>Root Canal Filling Materials - toxicity</topic><topic>Root canal sealers</topic><topic>Root canal therapy</topic><topic>Root canals</topic><topic>Sealing compounds</topic><topic>Simvastatin</topic><topic>Simvastatin - pharmacology</topic><topic>Statistical analysis</topic><topic>Zinc oxide</topic><topic>Zinc Oxide-Eugenol Cement</topic><topic>Zinc oxides</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sharma, Apoorva</creatorcontrib><creatorcontrib>Sanjeev, Kavitha</creatorcontrib><creatorcontrib>Selvanathan, Vinola M J</creatorcontrib><creatorcontrib>Sekar, Mahalaxmi</creatorcontrib><creatorcontrib>Harikrishnan, Nikhil</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Biological Science Journals</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>BMC oral health</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sharma, Apoorva</au><au>Sanjeev, Kavitha</au><au>Selvanathan, Vinola M J</au><au>Sekar, Mahalaxmi</au><au>Harikrishnan, Nikhil</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study</atitle><jtitle>BMC oral health</jtitle><addtitle>BMC Oral Health</addtitle><date>2022-01-11</date><risdate>2022</risdate><volume>22</volume><issue>1</issue><spage>6</spage><epage>6</epage><pages>6-6</pages><artnum>6</artnum><issn>1472-6831</issn><eissn>1472-6831</eissn><abstract><![CDATA[Freshly mixed root canal sealers when proximate the periapical tissues, trigger varying degrees of cytotoxicity/inflammatory reactions. Simvastatin, a class of the drug statin, is a widely used cholesterol-lowering agent with additional anti-inflammatory activities. This study assessed the effects of simvastatin on cytotoxicity and the release of IL-6 (Interleukin-6) production when incorporated in zinc oxide eugenol and methacrylate resin-based sealers.
Experimental groups consisted of conventional zinc oxide eugenol and methacrylate based-EndoREZ sealers (ZE & ER respectively) and 0.5 mg/mL simvastatin incorporated sealers (ZES & ERS). L929 mouse fibroblast cells were exposed to freshly mixed experimental sealers and evaluated for cytotoxicity (MTT assay) and inflammation levels (inflammatory marker IL-6 for ELISA) at various time intervals (0h, 24h and 7th day). The values were compared to the cell control (CC; L929 cells alone) and solvent control (SC; L929 cells + DMSO) groups. All the experiments were conducted in triplicates and subjected to statistical analysis using IBM SPSS Statistics software. Non parametric tests were conducted using Kruskal-Wallis and Friedman tests for inter-group and intra-group comparisons respectively. Pairwise comparison was conducted by post hoc Dunn test followed by Bonferroni correction. P values < 0.05 were considered statistically significant.
All the experimental groups (ZE, ER, ZES, ERS) exhibited varying degree of cytotoxicity and IL-6 expression compared to the control groups CC and SC. The cell viability for ZE and ER decreased on day 7 as compared to 24 h. ZES and ERS had higher viable cells (75.93% & 79.90%) compared to ZE and ER (54.39% & 57.84%) at all time periods. Increased expression of IL-6 was observed in ZE & ER (25.49 pg/mL & 23.14 pg/mL) when compared to simvastatin incorporated ZE & ER (ZES-12.70 pg/mL & ERS-14.68 pg/mL) at all time periods. Highest level of cytotoxicity and inflammation was observed in ZE compared to all the other groups on day 7.
Addition of 0.5 mg/mL of simvastatin to the sealers (ZES and ERS) decreased the cytotoxicity in the freshly mixed state and reduces their inflammatory effect.]]></abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>35012572</pmid><doi>10.1186/s12903-022-02039-y</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-7024-6570</orcidid><orcidid>https://orcid.org/0000-0002-3783-4688</orcidid><orcidid>https://orcid.org/0000-0002-7159-8180</orcidid><orcidid>https://orcid.org/0000-0002-4537-8440</orcidid><orcidid>https://orcid.org/0000-0002-2455-4468</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell viability Cholesterol Clinical trials Cytokine Cytokines Cytotoxicity Dental Pulp Cavity Dosage and administration Drug therapy Endodontics Enzyme-linked immunosorbent assay Epoxy Resins Eugenol Fibroblasts Flow cytometry Gene expression Humans IL-6 receptor Inflammation Interleukin 6 Materials Testing Methods Mice Microscopy Root Canal Filling Materials - toxicity Root canal sealers Root canal therapy Root canals Sealing compounds Simvastatin Simvastatin - pharmacology Statistical analysis Zinc oxide Zinc Oxide-Eugenol Cement Zinc oxides |
title | The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T11%3A57%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20evaluation%20of%20cytotoxicity%20and%20cytokine%20IL-6%20production%20of%20root%20canal%20sealers%20with%20and%20without%20the%20incorporation%20of%20simvastatin:%20an%20invitro%20study&rft.jtitle=BMC%20oral%20health&rft.au=Sharma,%20Apoorva&rft.date=2022-01-11&rft.volume=22&rft.issue=1&rft.spage=6&rft.epage=6&rft.pages=6-6&rft.artnum=6&rft.issn=1472-6831&rft.eissn=1472-6831&rft_id=info:doi/10.1186/s12903-022-02039-y&rft_dat=%3Cgale_doaj_%3EA693696805%3C/gale_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c563t-fa079916366ddf07a425c03e82f7befc8b37f88b7a98740cdcc88a309084e7193%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2621091194&rft_id=info:pmid/35012572&rft_galeid=A693696805&rfr_iscdi=true |