title: Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells.
abstract: Previously, betulinic acid was identified as one of the main compounds responsible for the anti-melanogenic effect in Vitis amurensis root. In this study, we investigated the precise mechanism underlying the anti-melanogenic activity of betulinic acid in B16F10 cells. Betulinic acid significantly attenuated 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production by inhibiting tyrosinase, tyrosinase related protein (TRP)-1, and TRP-2 expression through the modulation of their corresponding transcription factors, microphthalamia associated transcription factor (MITF) and cAMP response element binding protein (CREB), in B16F10 cells. In addition, phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt, involved in the melanogenic processes, were ameliorated by betulinic acid treatment. Role of MEK/ERK and PI3K/Akt signaling pathway in the melanogenesis was confirmed by using specific inhibitors, PD98059 (for MEK/ERK) and LY294002 (for PI3K/Akt), respectively. As a result, betulinic acid inhibited melanin production by tyrosinase, TRP-1, and TRP-2 inhibition through the regulation of CREB and MITF, which was accompanied with MEK/ERK and PI3K/Akt inactivation in IBMX-stimulated B16F10 cells. Consequently, these results demonstrate a novel molecular function of betulinic acid derived from V. amurensis root in melanogenesis, which in turn enhances our understanding on the application of cosmetic therapy for reducing skin hyperpigmentation.
authors.affiliation: Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busan 614-714, Republic of Korea.
authors.forename: Kyong-Suk
authors.initials: KS
authors.lastname: Jin
authors.affiliation: Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busan 614-714, Republic of Korea.
authors.forename: You Na
authors.initials: YN
authors.lastname: Oh
authors.affiliation: Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busan 614-714, Republic of Korea; Department of Food Science and Nutrition, College of Natural Science, Dong-Eui University, Busan 614-714, Republic of Korea.
authors.forename: Sook Kyung
authors.initials: SK
authors.lastname: Hyun
authors.affiliation: Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busan 614-714, Republic of Korea; Department of Life Science and Biotechnology, College of Natural Science, Dong-Eui University, Busan 614-714, Republic of Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Blue-Bio Industry Regional Innovation Center, Dong-Eui University, Busan 614-714, Republic of Korea; Department of Life Science and Biotechnology, College of Natural Science, Dong-Eui University, Busan 614-714, Republic of Korea. Electronic address: bwkim@deu.ac.kr.
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Kim
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000633:toxicity*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D017495:Hyperpigmentation / Q000188:drug therapy; D007370:Interferon Type I / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D011257:Pregnancy Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology*; D027843:Vitis / Q000737:chemistry*; D000094062:Betulinic Acid
chemical_list: D015056:1-Methyl-3-isobutylxanthine; D050882:CREB-Binding Protein; D002867:Chromones; D005419:Flavonoids; D007370:Interferon Type I; D019746:Intramolecular Oxidoreductases; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D010088:Oxidoreductases; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases; D011257:Pregnancy Proteins; D051057:Proto-Oncogene Proteins c-akt; D014315:Triterpenes; D000094062:Betulinic Acid; C497235:Mitf protein, mouse; C020947:interferon tau; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C064056:tyrosinase-related protein-1; C494364:Crebbp protein, mouse; C042501:dopachrome isomerase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Anti-melanogenesis; Betulinic acid; MEK/ERK; PI3K/Akt; Vitis amurensis root