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1.
Biol Pharm Bull ; 30(8): 1395-9, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17666792

ABSTRACT

Alpha-ketoglutarate is a key intermediate in the Krebs cycle, and a rate-limiting cofactor of prolyl-4-hydroxylase. It also has a potent effect on increasing the proline pool during collagen production, but the details underlying the boosting effect on collagen production by alpha-ketoglutarate remain as yet unreported. To investigate the effects of alpha-ketoglutarate on procollagen production and wrinkle formation, we conducted experiments in cultured human dermal fibroblasts and UVB-irradiated hairless mice. Based on ELISA measurements, alpha-ketoglutarate (10 microM) stimulated procollagen production in fibroblasts by 25.6+/-4.6% compared to vehicle (dH(2)O)-treated control cells. Also, we demonstrated that alpha-ketoglutarate increased activities of prolidase, which is known to play an important role in collagen metabolism, in fibroblasts and N-benzyloxycarbonyl-L-proline (Cbz-Pro), prolidase inhibitor, inhibited procollagen synthesis by alpha-ketoglutarate in fibroblasts. To determine the effect of topically applied alpha-ketoglutarate on wrinkle formation, alpha-ketoglutarate (1%) and vehicle (70% propylene glycol, 30% ethanol) were applied on the dorsal skin of UVB-induced hairless mice for twelve weeks. We found that alpha-ketoglutarate decreased wrinkle formation upon long-term topical application. These results suggest that alpha-ketoglutarate diminishes UVB-induced wrinkle formation by increasing collagen production, through a pathway that involves prolidase activation. Therefore, application of alpha-ketoglutarate may represent an effective anti-wrinkle agent for the cosmetic field.


Subject(s)
Fibroblasts/metabolism , Ketoglutaric Acids/pharmacology , Procollagen/biosynthesis , Skin Aging/drug effects , Skin Aging/radiation effects , Skin/drug effects , Skin/radiation effects , Administration, Topical , Animals , Blotting, Western , Cells, Cultured , Collagen Type I/biosynthesis , Dipeptidases/antagonists & inhibitors , Dipeptidases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Fibroblasts/drug effects , Humans , Image Processing, Computer-Assisted , Ketoglutaric Acids/administration & dosage , Mice , Mice, Hairless , Proline/analogs & derivatives , Proline/pharmacology , Skin/metabolism , Stimulation, Chemical , Tetrazolium Salts , Thiazoles , Ultraviolet Rays
2.
J Invest Dermatol ; 124(6): 1149-61, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15955089

ABSTRACT

To investigate the effects of topically applied 17beta-estradiol on the expression of extracellular matrix proteins in aged human skin, 17beta-estradiol (0.01%) and its vehicle (70% propylene glycol, 30% ethanol) were applied to aged (68-82 y, eight females and five males) human buttock skin under occlusion for 2 wk (three times per week). Topical 17beta-estradiol was found to increase the expression of type 1 procollagen mRNA and protein significantly in human aged skin in vivo. In addition, metalloproteinase (MMP-1 protein levels were reduced by topical 17beta-estradiol. The expressions of TGF-beta1, TGF-beta type II receptor, and Sma and Mad related (Smad)3 were increased by topical 17 beta-estradiol in aged human skin, and TGF-beta1 neutralizing antibody inhibited 17beta-estradiol-induced procollagen synthesis in cultured fibroblasts. We also found that the expressions of tropoelastin and fibrillin-1 mRNA and protein, and elastic fibers in aged skin were also increased by topical 17beta-estradiol. Topical 17beta-estradiol also increased keratinocyte proliferation and the epidermal thickness in aged human skin. We also observed the same effects of topical 17beta-estradiol in young skin. In conclusion, our results suggest that topical 17beta-estradiol treatment may improve the cutaneous function of aged human skin by improving the connective tissue and increasing epidermal thickness.


Subject(s)
Estradiol/administration & dosage , Extracellular Matrix Proteins/biosynthesis , Signal Transduction/physiology , Skin Aging/physiology , Transforming Growth Factor beta/metabolism , Administration, Topical , Adult , Aged , Aged, 80 and over , Antibodies/pharmacology , Cell Proliferation/drug effects , Collagen Type I/antagonists & inhibitors , Collagen Type I/genetics , Collagen Type I/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Estradiol/pharmacology , Female , Fibrillin-1 , Fibrillins , Humans , In Vitro Techniques , Keratinocytes/cytology , Male , Matrix Metalloproteinase 1/metabolism , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Middle Aged , Protein Serine-Threonine Kinases , RNA, Messenger/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Smad3 Protein , Smad7 Protein , Trans-Activators/genetics , Trans-Activators/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta1 , Tropoelastin/genetics , Tropoelastin/metabolism
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