Hesperidin Inhibits UVB-Induced VEGF Production and Angiogenesis via the Inhibition of PI3K/Akt Pathway in HR-1 Hairless Mice
Hesperidin is a citrus flavanone glycoside with potent anti-inflammatory effects that interferes with UVB-stimulated angiogenesis in skin, but its molecular mechanisms of action remain unclear. Here, we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We foun...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2021/10/01, Vol.44(10), pp.1492-1498 |
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| creator | Kim, Ki Mo Im, A-Rang Lee, Joo Young Kim, Taesoo Ji, Kon-Young Park, Dae-Hun Chae, Sungwook |
| description | Hesperidin is a citrus flavanone glycoside with potent anti-inflammatory effects that interferes with UVB-stimulated angiogenesis in skin, but its molecular mechanisms of action remain unclear. Here, we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We found hesperidin treatment inhibited skin neovascularization skin induced by repetitive UVB light exposure. Exposure to UVB radiation induces the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-13 (MMP-13), and MMP-9, but we found all of these were inhibited by treatment with hesperidin. Using immunohistochemistry and Western blotting, we also found hesperidin inhibited the increase in hypoxia inducible factor-1 (HIF-1)α expression induced by UVB exposure. After discovering that UVB induces VEGF expression via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, we found hesperidin reduces UVB-induced VEGF expression by inhibiting UVB-induced PI3K activity. This, in turn, reduces the UVB-induced Akt/p70S6K phosphorylation in human primary keratinocytes and fibroblast cells. Because it affects the mediators of angiogenesis, our data suggest hesperidin has an anti-angiogenic effect on the pathologic skin neovascularization induced by UVB light. Thus, hesperidin may prove useful in the treatment of skin injuries caused by UVB light exposure. |
| doi_str_mv | 10.1248/bpb.b21-00367 |
| format | Article |
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Here, we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We found hesperidin treatment inhibited skin neovascularization skin induced by repetitive UVB light exposure. Exposure to UVB radiation induces the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-13 (MMP-13), and MMP-9, but we found all of these were inhibited by treatment with hesperidin. Using immunohistochemistry and Western blotting, we also found hesperidin inhibited the increase in hypoxia inducible factor-1 (HIF-1)α expression induced by UVB exposure. After discovering that UVB induces VEGF expression via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, we found hesperidin reduces UVB-induced VEGF expression by inhibiting UVB-induced PI3K activity. This, in turn, reduces the UVB-induced Akt/p70S6K phosphorylation in human primary keratinocytes and fibroblast cells. Because it affects the mediators of angiogenesis, our data suggest hesperidin has an anti-angiogenic effect on the pathologic skin neovascularization induced by UVB light. Thus, hesperidin may prove useful in the treatment of skin injuries caused by UVB light exposure.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b21-00367</identifier><identifier>PMID: 34602557</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Angiogenesis ; Animals ; Collagenase 3 ; Disease Models, Animal ; Fibroblasts ; Gelatinase B ; Hairless ; Hesperidin ; Hesperidin - pharmacology ; Hesperidin - therapeutic use ; Humans ; hypoxia inducible factor-1α ; Hypoxia-inducible factor 1 ; Immunohistochemistry ; Inflammation ; Keratinocytes ; Male ; Matrix metalloproteinase ; matrix metalloproteinase-9 (MMP-9) ; Metalloproteinase ; Mice ; Mice, Hairless ; Molecular modelling ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - etiology ; Neovascularization, Pathologic - pathology ; Phosphatidylinositol 3-Kinases - metabolism ; phosphoinositide 3-kinase ; Phosphorylation ; Phosphorylation - drug effects ; Primary Cell Culture ; Proto-Oncogene Proteins c-akt - metabolism ; Ribosomal Protein S6 Kinases, 70-kDa - metabolism ; Signal Transduction - drug effects ; Skin ; Skin - blood supply ; Skin - drug effects ; Skin - pathology ; Skin - radiation effects ; Ultraviolet radiation ; Ultraviolet Rays - adverse effects ; UVB light ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor A - metabolism ; Vascularization ; Western blotting</subject><ispartof>Biological and Pharmaceutical Bulletin, 2021/10/01, Vol.44(10), pp.1492-1498</ispartof><rights>2021 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-9d3b29eb855a802a8747ee87400f8f9b12bb0ef55d77f2347ec385a7bffe90b43</citedby><cites>FETCH-LOGICAL-c659t-9d3b29eb855a802a8747ee87400f8f9b12bb0ef55d77f2347ec385a7bffe90b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34602557$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Ki Mo</creatorcontrib><creatorcontrib>Im, A-Rang</creatorcontrib><creatorcontrib>Lee, Joo Young</creatorcontrib><creatorcontrib>Kim, Taesoo</creatorcontrib><creatorcontrib>Ji, Kon-Young</creatorcontrib><creatorcontrib>Park, Dae-Hun</creatorcontrib><creatorcontrib>Chae, Sungwook</creatorcontrib><creatorcontrib>bDepartment of Nursing</creatorcontrib><creatorcontrib>aHerbal Medicine Research Division</creatorcontrib><creatorcontrib>Korea Institute of Oriental Medicine</creatorcontrib><creatorcontrib>Dongshin University</creatorcontrib><title>Hesperidin Inhibits UVB-Induced VEGF Production and Angiogenesis via the Inhibition of PI3K/Akt Pathway in HR-1 Hairless Mice</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>Hesperidin is a citrus flavanone glycoside with potent anti-inflammatory effects that interferes with UVB-stimulated angiogenesis in skin, but its molecular mechanisms of action remain unclear. Here, we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We found hesperidin treatment inhibited skin neovascularization skin induced by repetitive UVB light exposure. Exposure to UVB radiation induces the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-13 (MMP-13), and MMP-9, but we found all of these were inhibited by treatment with hesperidin. Using immunohistochemistry and Western blotting, we also found hesperidin inhibited the increase in hypoxia inducible factor-1 (HIF-1)α expression induced by UVB exposure. After discovering that UVB induces VEGF expression via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, we found hesperidin reduces UVB-induced VEGF expression by inhibiting UVB-induced PI3K activity. This, in turn, reduces the UVB-induced Akt/p70S6K phosphorylation in human primary keratinocytes and fibroblast cells. Because it affects the mediators of angiogenesis, our data suggest hesperidin has an anti-angiogenic effect on the pathologic skin neovascularization induced by UVB light. Thus, hesperidin may prove useful in the treatment of skin injuries caused by UVB light exposure.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Collagenase 3</subject><subject>Disease Models, Animal</subject><subject>Fibroblasts</subject><subject>Gelatinase B</subject><subject>Hairless</subject><subject>Hesperidin</subject><subject>Hesperidin - pharmacology</subject><subject>Hesperidin - therapeutic use</subject><subject>Humans</subject><subject>hypoxia inducible factor-1α</subject><subject>Hypoxia-inducible factor 1</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Keratinocytes</subject><subject>Male</subject><subject>Matrix metalloproteinase</subject><subject>matrix metalloproteinase-9 (MMP-9)</subject><subject>Metalloproteinase</subject><subject>Mice</subject><subject>Mice, Hairless</subject><subject>Molecular modelling</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Neovascularization, Pathologic - etiology</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>phosphoinositide 3-kinase</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Primary Cell Culture</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Skin</subject><subject>Skin - blood supply</subject><subject>Skin - drug effects</subject><subject>Skin - pathology</subject><subject>Skin - radiation effects</subject><subject>Ultraviolet radiation</subject><subject>Ultraviolet Rays - adverse effects</subject><subject>UVB light</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascularization</subject><subject>Western blotting</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1vEzEQxVcIREPhyBVZ4sJlW3_G9jGUNokoIkK015W9O5s4bOxg74J64H_Hm7RB4jKWNT-_eeNXFG8JviCUq0u7txeWkhJjNpXPiglhXJaCEvG8mGBNVDklQp0Vr1LaYowlpuxlccb4FFMh5KT4s4C0h-ga59HSb5x1fUJ39x_LpW-GGhp0fz2_QasY8q13wSPjGzTzaxfW4CG5hH45g_oNPL0emdCi1ZJ9vpz96NHK9Jvf5gFl_cW3kqCFcbGDlNAXV8Pr4kVrugRvHs_z4u7m-vvVorz9Ol9ezW7Leip0X-qGWarBKiGMwtQoySVArhi3qtWWUGsxtEI0UrY0fwDUTAkjbduCxpaz8-LDUXcfw88BUl_tXKqh64yHMKSKCqmxFpqyjL7_D92GIfrsbqSUIJJzlanySNUxpBShrfbR7Ux8qAiuxlyqnEuVc6kOuWT-3aPqYHfQnOinIDIwPwK562rTBd85D_9m10laF7pQUXwQ5TwPwkRXhGs6FsWUZlM-LvDpqLRNvVnDaZSJvas7OBjjfPSZ68nhqV1vTKzAs79g_LW2</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Kim, Ki Mo</creator><creator>Im, A-Rang</creator><creator>Lee, Joo Young</creator><creator>Kim, Taesoo</creator><creator>Ji, Kon-Young</creator><creator>Park, Dae-Hun</creator><creator>Chae, Sungwook</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20211001</creationdate><title>Hesperidin Inhibits UVB-Induced VEGF Production and Angiogenesis via the Inhibition of PI3K/Akt Pathway in HR-1 Hairless Mice</title><author>Kim, Ki Mo ; Im, A-Rang ; Lee, Joo Young ; Kim, Taesoo ; Ji, Kon-Young ; Park, Dae-Hun ; Chae, Sungwook</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c659t-9d3b29eb855a802a8747ee87400f8f9b12bb0ef55d77f2347ec385a7bffe90b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Collagenase 3</topic><topic>Disease Models, Animal</topic><topic>Fibroblasts</topic><topic>Gelatinase B</topic><topic>Hairless</topic><topic>Hesperidin</topic><topic>Hesperidin - pharmacology</topic><topic>Hesperidin - therapeutic use</topic><topic>Humans</topic><topic>hypoxia inducible factor-1α</topic><topic>Hypoxia-inducible factor 1</topic><topic>Immunohistochemistry</topic><topic>Inflammation</topic><topic>Keratinocytes</topic><topic>Male</topic><topic>Matrix metalloproteinase</topic><topic>matrix metalloproteinase-9 (MMP-9)</topic><topic>Metalloproteinase</topic><topic>Mice</topic><topic>Mice, Hairless</topic><topic>Molecular modelling</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Neovascularization, Pathologic - etiology</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>phosphoinositide 3-kinase</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Primary Cell Culture</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Skin</topic><topic>Skin - blood supply</topic><topic>Skin - drug effects</topic><topic>Skin - pathology</topic><topic>Skin - radiation effects</topic><topic>Ultraviolet radiation</topic><topic>Ultraviolet Rays - adverse effects</topic><topic>UVB light</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascularization</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Ki Mo</creatorcontrib><creatorcontrib>Im, A-Rang</creatorcontrib><creatorcontrib>Lee, Joo Young</creatorcontrib><creatorcontrib>Kim, Taesoo</creatorcontrib><creatorcontrib>Ji, Kon-Young</creatorcontrib><creatorcontrib>Park, Dae-Hun</creatorcontrib><creatorcontrib>Chae, Sungwook</creatorcontrib><creatorcontrib>bDepartment of Nursing</creatorcontrib><creatorcontrib>aHerbal Medicine Research Division</creatorcontrib><creatorcontrib>Korea Institute of Oriental Medicine</creatorcontrib><creatorcontrib>Dongshin University</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Ki Mo</au><au>Im, A-Rang</au><au>Lee, Joo Young</au><au>Kim, Taesoo</au><au>Ji, Kon-Young</au><au>Park, Dae-Hun</au><au>Chae, Sungwook</au><aucorp>bDepartment of Nursing</aucorp><aucorp>aHerbal Medicine Research Division</aucorp><aucorp>Korea Institute of Oriental Medicine</aucorp><aucorp>Dongshin University</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hesperidin Inhibits UVB-Induced VEGF Production and Angiogenesis via the Inhibition of PI3K/Akt Pathway in HR-1 Hairless Mice</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>44</volume><issue>10</issue><spage>1492</spage><epage>1498</epage><pages>1492-1498</pages><artnum>b21-00367</artnum><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>Hesperidin is a citrus flavanone glycoside with potent anti-inflammatory effects that interferes with UVB-stimulated angiogenesis in skin, but its molecular mechanisms of action remain unclear. Here, we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We found hesperidin treatment inhibited skin neovascularization skin induced by repetitive UVB light exposure. Exposure to UVB radiation induces the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-13 (MMP-13), and MMP-9, but we found all of these were inhibited by treatment with hesperidin. Using immunohistochemistry and Western blotting, we also found hesperidin inhibited the increase in hypoxia inducible factor-1 (HIF-1)α expression induced by UVB exposure. After discovering that UVB induces VEGF expression via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, we found hesperidin reduces UVB-induced VEGF expression by inhibiting UVB-induced PI3K activity. This, in turn, reduces the UVB-induced Akt/p70S6K phosphorylation in human primary keratinocytes and fibroblast cells. Because it affects the mediators of angiogenesis, our data suggest hesperidin has an anti-angiogenic effect on the pathologic skin neovascularization induced by UVB light. Thus, hesperidin may prove useful in the treatment of skin injuries caused by UVB light exposure.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>34602557</pmid><doi>10.1248/bpb.b21-00367</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Angiogenesis Animals Collagenase 3 Disease Models, Animal Fibroblasts Gelatinase B Hairless Hesperidin Hesperidin - pharmacology Hesperidin - therapeutic use Humans hypoxia inducible factor-1α Hypoxia-inducible factor 1 Immunohistochemistry Inflammation Keratinocytes Male Matrix metalloproteinase matrix metalloproteinase-9 (MMP-9) Metalloproteinase Mice Mice, Hairless Molecular modelling Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - etiology Neovascularization, Pathologic - pathology Phosphatidylinositol 3-Kinases - metabolism phosphoinositide 3-kinase Phosphorylation Phosphorylation - drug effects Primary Cell Culture Proto-Oncogene Proteins c-akt - metabolism Ribosomal Protein S6 Kinases, 70-kDa - metabolism Signal Transduction - drug effects Skin Skin - blood supply Skin - drug effects Skin - pathology Skin - radiation effects Ultraviolet radiation Ultraviolet Rays - adverse effects UVB light Vascular endothelial growth factor Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - metabolism Vascularization Western blotting |
| title | Hesperidin Inhibits UVB-Induced VEGF Production and Angiogenesis via the Inhibition of PI3K/Akt Pathway in HR-1 Hairless Mice |
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