A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK
Low-level laser therapy (LLLT) with various types of lasers promotes fibroblast proliferation and migration during the process of wound healing. Although LLLT with a carbon dioxide (CO2) laser was also reported to promote wound healing, the underlying mechanisms at the cellular level have not been p...
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description | Low-level laser therapy (LLLT) with various types of lasers promotes fibroblast proliferation and migration during the process of wound healing. Although LLLT with a carbon dioxide (CO2) laser was also reported to promote wound healing, the underlying mechanisms at the cellular level have not been previously described. Herein, we investigated the effect of LLLT with a CO2 laser on fibroblast proliferation and migration.
Cultured human dermal fibroblasts were prepared. MTS and cell migration assays were performed with fibroblasts after LLLT with a CO2 laser at various doses (0.1, 0.5, 1.0, 2.0, or 5.0 J/cm2) to observe the effects of LLLT with a CO2 laser on the proliferation and migration of fibroblasts. The non-irradiated group served as the control. Moreover, western blot analysis was performed using fibroblasts after LLLT with a CO2 laser to analyze changes in the activities of Akt, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), which are signaling molecules associated with cell proliferation and migration. Finally, the MTS assay, a cell migration assay, and western blot analysis were performed using fibroblasts treated with inhibitors of Akt, ERK, or JNK before LLLT with a CO2 laser.
In MTS and cell migration assays, fibroblast proliferation and migration were promoted after LLLT with a CO2 laser at 1.0 J/cm2. Western blot analysis revealed that Akt, ERK, and JNK activities were promoted in fibroblasts after LLLT with a CO2 laser at 1.0 J/cm2. Moreover, inhibition of Akt, ERK, or JNK significantly blocked fibroblast proliferation and migration.
These findings suggested that LLLT with a CO2 laser would accelerate wound healing by promoting the proliferation and migration of fibroblasts. Activation of Akt, ERK, and JNK was essential for CO2 laser-induced proliferation and migration of fibroblasts. |
doi_str_mv | 10.1371/journal.pone.0168937 |
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Cultured human dermal fibroblasts were prepared. MTS and cell migration assays were performed with fibroblasts after LLLT with a CO2 laser at various doses (0.1, 0.5, 1.0, 2.0, or 5.0 J/cm2) to observe the effects of LLLT with a CO2 laser on the proliferation and migration of fibroblasts. The non-irradiated group served as the control. Moreover, western blot analysis was performed using fibroblasts after LLLT with a CO2 laser to analyze changes in the activities of Akt, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), which are signaling molecules associated with cell proliferation and migration. Finally, the MTS assay, a cell migration assay, and western blot analysis were performed using fibroblasts treated with inhibitors of Akt, ERK, or JNK before LLLT with a CO2 laser.
In MTS and cell migration assays, fibroblast proliferation and migration were promoted after LLLT with a CO2 laser at 1.0 J/cm2. Western blot analysis revealed that Akt, ERK, and JNK activities were promoted in fibroblasts after LLLT with a CO2 laser at 1.0 J/cm2. Moreover, inhibition of Akt, ERK, or JNK significantly blocked fibroblast proliferation and migration.
These findings suggested that LLLT with a CO2 laser would accelerate wound healing by promoting the proliferation and migration of fibroblasts. Activation of Akt, ERK, and JNK was essential for CO2 laser-induced proliferation and migration of fibroblasts.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0168937</identifier><identifier>PMID: 28045948</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; AKT protein ; Assaying ; Biology and Life Sciences ; Carbon Dioxide ; Carbon dioxide lasers ; Cell migration ; Cell Movement ; Cell Proliferation ; Engineering and Technology ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - radiation effects ; Growth ; Healing ; Health aspects ; Humans ; JNK protein ; Kinases ; Lasers ; Lasers, Gas ; Levels ; Low-Level Light Therapy ; MAP Kinase Kinase 4 - metabolism ; Medicine and Health Sciences ; Methods ; Physical Sciences ; Plastic surgery ; Proto-Oncogene Proteins c-akt - metabolism ; Research and analysis methods ; Rodents ; Signal Transduction ; Signaling ; Skin ; Skin - metabolism ; Wound healing</subject><ispartof>PloS one, 2017-01, Vol.12 (1), p.e0168937-e0168937</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Shingyochi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Shingyochi et al 2017 Shingyochi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c864t-4ab5cb6a9f16df2ff189001972d16711003d4b5922c52af5e29368e90836e2b73</citedby><cites>FETCH-LOGICAL-c864t-4ab5cb6a9f16df2ff189001972d16711003d4b5922c52af5e29368e90836e2b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207507/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207507/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28045948$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shingyochi, Yoshiaki</creatorcontrib><creatorcontrib>Kanazawa, Shigeyuki</creatorcontrib><creatorcontrib>Tajima, Satoshi</creatorcontrib><creatorcontrib>Tanaka, Rica</creatorcontrib><creatorcontrib>Mizuno, Hiroshi</creatorcontrib><creatorcontrib>Tobita, Morikuni</creatorcontrib><title>A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Low-level laser therapy (LLLT) with various types of lasers promotes fibroblast proliferation and migration during the process of wound healing. Although LLLT with a carbon dioxide (CO2) laser was also reported to promote wound healing, the underlying mechanisms at the cellular level have not been previously described. Herein, we investigated the effect of LLLT with a CO2 laser on fibroblast proliferation and migration.
Cultured human dermal fibroblasts were prepared. MTS and cell migration assays were performed with fibroblasts after LLLT with a CO2 laser at various doses (0.1, 0.5, 1.0, 2.0, or 5.0 J/cm2) to observe the effects of LLLT with a CO2 laser on the proliferation and migration of fibroblasts. The non-irradiated group served as the control. Moreover, western blot analysis was performed using fibroblasts after LLLT with a CO2 laser to analyze changes in the activities of Akt, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), which are signaling molecules associated with cell proliferation and migration. Finally, the MTS assay, a cell migration assay, and western blot analysis were performed using fibroblasts treated with inhibitors of Akt, ERK, or JNK before LLLT with a CO2 laser.
In MTS and cell migration assays, fibroblast proliferation and migration were promoted after LLLT with a CO2 laser at 1.0 J/cm2. Western blot analysis revealed that Akt, ERK, and JNK activities were promoted in fibroblasts after LLLT with a CO2 laser at 1.0 J/cm2. Moreover, inhibition of Akt, ERK, or JNK significantly blocked fibroblast proliferation and migration.
These findings suggested that LLLT with a CO2 laser would accelerate wound healing by promoting the proliferation and migration of fibroblasts. Activation of Akt, ERK, and JNK was essential for CO2 laser-induced proliferation and migration of fibroblasts.</description><subject>Activation</subject><subject>AKT protein</subject><subject>Assaying</subject><subject>Biology and Life Sciences</subject><subject>Carbon Dioxide</subject><subject>Carbon dioxide lasers</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Engineering and Technology</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - radiation effects</subject><subject>Growth</subject><subject>Healing</subject><subject>Health aspects</subject><subject>Humans</subject><subject>JNK protein</subject><subject>Kinases</subject><subject>Lasers</subject><subject>Lasers, Gas</subject><subject>Levels</subject><subject>Low-Level Light Therapy</subject><subject>MAP Kinase Kinase 4 - metabolism</subject><subject>Medicine and Health Sciences</subject><subject>Methods</subject><subject>Physical Sciences</subject><subject>Plastic surgery</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Research and analysis methods</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Skin</subject><subject>Skin - metabolism</subject><subject>Wound healing</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkIgrcUfsRPfIFVlg7LC0Pi4tZzETt2lcbGdUv49TptNDdrFlIvEx8958_ocnyh6DsEY4hS-W5rWNqIer00jxwDSjOH0QXQMGUYjigB-ePB9FD1xbgkAwRmlj6MjlIGEsCQ7jraTeG7-jOZyI-t4KmxumviDNltdyngunLTxN2tWxksXn-vcmrwWznexWitphdeBF00Zf9FVv_ILa9pqEU8Krzf7kFHx5NqfxmdXF6c7-vPXi6fRIyVqJ5_175Po5_nZj-mn0fzy42w6mY-KjCZ-lIicFDkVTEFaKqQUzBgAkKWohDSFEABcJjlhCBUECUUkYphmkoEMU4nyFJ9EL_e669o43hfNcZgRAihISRaI2Z4ojVjytdUrYf9yIzTfBYytuLBeF7XkKSwBBAwmVOUJY8FWKkrMMolKgYhQQet9_7c2X8mykI23oh6IDncaveCV2XCCghfQ2X3TC1jzu5XO85V2haxr0UjT7nyHvhHI2H1QglFGd6qv_kPvLkRPVSKcVTfKBItFJ8onSUoRTpOk0xrfQYWnlCtdhMuodIgPEt4OEgLj5dZXonWOz75f3Z-9_DVkXx-wCylqv3Cmbrsr54ZgsgcLa5yzUt32AwLezdJNNXg3S7yfpZD24rCXt0k3w4P_AS5LFuU</recordid><startdate>20170103</startdate><enddate>20170103</enddate><creator>Shingyochi, Yoshiaki</creator><creator>Kanazawa, Shigeyuki</creator><creator>Tajima, Satoshi</creator><creator>Tanaka, Rica</creator><creator>Mizuno, Hiroshi</creator><creator>Tobita, Morikuni</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170103</creationdate><title>A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK</title><author>Shingyochi, Yoshiaki ; Kanazawa, Shigeyuki ; Tajima, Satoshi ; Tanaka, Rica ; Mizuno, Hiroshi ; Tobita, Morikuni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c864t-4ab5cb6a9f16df2ff189001972d16711003d4b5922c52af5e29368e90836e2b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>AKT protein</topic><topic>Assaying</topic><topic>Biology and Life Sciences</topic><topic>Carbon Dioxide</topic><topic>Carbon dioxide lasers</topic><topic>Cell migration</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Engineering and Technology</topic><topic>Extracellular signal-regulated kinase</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - radiation effects</topic><topic>Growth</topic><topic>Healing</topic><topic>Health aspects</topic><topic>Humans</topic><topic>JNK protein</topic><topic>Kinases</topic><topic>Lasers</topic><topic>Lasers, Gas</topic><topic>Levels</topic><topic>Low-Level Light Therapy</topic><topic>MAP Kinase Kinase 4 - metabolism</topic><topic>Medicine and Health Sciences</topic><topic>Methods</topic><topic>Physical Sciences</topic><topic>Plastic surgery</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Research and analysis methods</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Skin</topic><topic>Skin - metabolism</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shingyochi, Yoshiaki</creatorcontrib><creatorcontrib>Kanazawa, Shigeyuki</creatorcontrib><creatorcontrib>Tajima, Satoshi</creatorcontrib><creatorcontrib>Tanaka, Rica</creatorcontrib><creatorcontrib>Mizuno, Hiroshi</creatorcontrib><creatorcontrib>Tobita, Morikuni</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shingyochi, Yoshiaki</au><au>Kanazawa, Shigeyuki</au><au>Tajima, Satoshi</au><au>Tanaka, Rica</au><au>Mizuno, Hiroshi</au><au>Tobita, Morikuni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-01-03</date><risdate>2017</risdate><volume>12</volume><issue>1</issue><spage>e0168937</spage><epage>e0168937</epage><pages>e0168937-e0168937</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Low-level laser therapy (LLLT) with various types of lasers promotes fibroblast proliferation and migration during the process of wound healing. Although LLLT with a carbon dioxide (CO2) laser was also reported to promote wound healing, the underlying mechanisms at the cellular level have not been previously described. Herein, we investigated the effect of LLLT with a CO2 laser on fibroblast proliferation and migration.
Cultured human dermal fibroblasts were prepared. MTS and cell migration assays were performed with fibroblasts after LLLT with a CO2 laser at various doses (0.1, 0.5, 1.0, 2.0, or 5.0 J/cm2) to observe the effects of LLLT with a CO2 laser on the proliferation and migration of fibroblasts. The non-irradiated group served as the control. Moreover, western blot analysis was performed using fibroblasts after LLLT with a CO2 laser to analyze changes in the activities of Akt, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), which are signaling molecules associated with cell proliferation and migration. Finally, the MTS assay, a cell migration assay, and western blot analysis were performed using fibroblasts treated with inhibitors of Akt, ERK, or JNK before LLLT with a CO2 laser.
In MTS and cell migration assays, fibroblast proliferation and migration were promoted after LLLT with a CO2 laser at 1.0 J/cm2. Western blot analysis revealed that Akt, ERK, and JNK activities were promoted in fibroblasts after LLLT with a CO2 laser at 1.0 J/cm2. Moreover, inhibition of Akt, ERK, or JNK significantly blocked fibroblast proliferation and migration.
These findings suggested that LLLT with a CO2 laser would accelerate wound healing by promoting the proliferation and migration of fibroblasts. Activation of Akt, ERK, and JNK was essential for CO2 laser-induced proliferation and migration of fibroblasts.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28045948</pmid><doi>10.1371/journal.pone.0168937</doi><tpages>e0168937</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Activation AKT protein Assaying Biology and Life Sciences Carbon Dioxide Carbon dioxide lasers Cell migration Cell Movement Cell Proliferation Engineering and Technology Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Fibroblasts Fibroblasts - cytology Fibroblasts - radiation effects Growth Healing Health aspects Humans JNK protein Kinases Lasers Lasers, Gas Levels Low-Level Light Therapy MAP Kinase Kinase 4 - metabolism Medicine and Health Sciences Methods Physical Sciences Plastic surgery Proto-Oncogene Proteins c-akt - metabolism Research and analysis methods Rodents Signal Transduction Signaling Skin Skin - metabolism Wound healing |
title | A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T10%3A55%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Low-Level%20Carbon%20Dioxide%20Laser%20Promotes%20Fibroblast%20Proliferation%20and%20Migration%20through%20Activation%20of%20Akt,%20ERK,%20and%20JNK&rft.jtitle=PloS%20one&rft.au=Shingyochi,%20Yoshiaki&rft.date=2017-01-03&rft.volume=12&rft.issue=1&rft.spage=e0168937&rft.epage=e0168937&rft.pages=e0168937-e0168937&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0168937&rft_dat=%3Cgale_plos_%3EA476237447%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1855060758&rft_id=info:pmid/28045948&rft_galeid=A476237447&rft_doaj_id=oai_doaj_org_article_71d0109146fb4996a97ad398e2da25af&rfr_iscdi=true |