title: Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts.
abstract: During senescence, cells express molecules called senescence-associated secretory phenotype (SASP), including growth factors, proinflammatory cytokines, chemokines, and proteases. The SASP induces a chronic low-grade inflammation adjacent to cells and tissues, leading to degenerative diseases. The anti-inflammatory activity of flavonoids was investigated on SASP expression in senescent fibroblasts. Effects of flavonoids on SASP expression such as IL-1α, IL-1β, IL-6, IL-8, GM-CSF, CXCL1, MCP-2 and MMP-3 and signaling molecules were examined in bleomycin-induced senescent BJ cells. In vivo activity of apigenin on SASP suppression was identified in the kidney of aged rats. Among the five naturally-occurring flavonoids initially tested, apigenin and kaempferol strongly inhibited the expression of SASP. These flavonoids inhibited NF-κB p65 activity via the IRAK1/IκBα signaling pathway and expression of IκBζ. Blocking IκBζ expression especially reduced the expression of SASP. A structure-activity relationship study using some synthetic flavones demonstrated that hydroxyl substitutions at C-2',3',4',5 and 7 were important in inhibiting SASP production. Finally, these results were verified by results showing that the oral administration of apigenin significantly reduced elevated levels of SASP and IκBζ mRNA in the kidneys of aged rats. This study is the first to show that certain flavonoids are inhibitors of SASP production, partially related to NF-κB p65 and IκBζ signaling pathway, and may effectively protect or alleviate chronic low-grade inflammation in degenerative diseases such as cardiovascular diseases and late-stage cancer.
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Haeil
authors.initials: H
authors.lastname: Park
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: hpkim@kangwon.ac.kr.
authors.forename: Hyun Pyo
authors.initials: HP
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D002460:Cell Line; D016922:Cellular Senescence; D054412:Chemokine CCL8 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C515453:CCL8 protein, human; D054412:Chemokine CCL8; D054360:Chemokine CXCL1; D005419:Flavonoids; D020672:I-kappa B Proteins; D007378:Interleukins; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D001761:Bleomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019278:Matrix Metalloproteinase 3
keywords: Chronic low-grade inflammation; Flavonoid; IκBζ; SASP; Senescence