Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells

Xu, Jin-Wen; Ikeda, Katsumi; Kobayakawa, Akira; Ikami, Takao; Kayano, Yasuyo; Mitani, Takahiko; Yamori, Yukio

doi:10.1016/j.lfs.2004.11.015

Cited by 44 publications

(38 citation statements)

References 43 publications

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“…[8][9][10][11][12][13] Although many HPLC methods have been developed for the determination of one or two constituents, [14][15][16][17] up to date, there have been few reports on the simultaneous determination of multiple constituents in ASH. Moreover one or two constituents could not be responsible for overall pharmacological activities of ASH.…”

Section: -7)mentioning

confidence: 99%

“…[1][2][3][4][5][6][7] ASH has been shown to contain many effective constituents, including protocatechuic acid, syringin, chlorogenic acid, caffeic acid, liriodendrin, isofraxidin (ingredient 1-6) and etc. [8][9][10][11][12][13] Although many HPLC methods have been developed for the determination of one or two constituents, [14][15][16][17] up to date, there have been few reports on the simultaneous determination of multiple constituents in ASH. Moreover one or two constituents could not be responsible for overall pharmacological activities of ASH.…”

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confidence: 99%

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Simultaneous Determination of Protocatechuic Acid, Syringin, Chlorogenic Acid, Caffeic Acid, Liriodendrin and Isofraxidin in Acanthopanax senticosus HARMS by HPLC-DAD

Jia

et al. 2006

Biological & Pharmaceutical Bulletin

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Traditional Chinese medicine (TCM) which uses natural therapeutic agents under the guidance of the theory of traditional Chinese medical science has been applied by TCM practitioners for several thousands years and has been increasingly popular. Acanthopanax senticosus (RUPR. et MAXIM.) HARMS (ASH) is a well-known TCM in China, which has been officially listed in Chinese Pharmacopoeia for a long time. It possesses various pharmacological effects, such as antibacterial, antifatigue, anti-oxidant and anti-tumor activities. 1-7)ASH has been shown to contain many effective constituents, including protocatechuic acid, syringin, chlorogenic acid, caffeic acid, liriodendrin, isofraxidin (ingredient 1-6) and etc. [8][9][10][11][12][13] Although many HPLC methods have been developed for the determination of one or two constituents, [14][15][16][17] up to date, there have been few reports on the simultaneous determination of multiple constituents in ASH. Moreover one or two constituents could not be responsible for overall pharmacological activities of ASH. In the present study, a rapid and simple HPLC method was established for the quality control of ASH and successfully applied for the assessment of ten commercial samples. MATERIALS AND METHODS Reagents and MaterialsASHs were purchased from TCM shops of different places of China. The standards of protocatechuic acid, syringin, chlorogenic acid, caffeic acid and isofraxidin were all ordered from the Chinese National Institute of Control of Pharmaceutical and Biological Products (Beijing, China). The standard of liriodendrin was isolated by the author from ASH and its structure was fully characterized by chemical and spectroscopic methods (UV, IR, NMR, MS). Purity analysis proved its purity above 98%. Phosphoric acid, methanol and acetonitrile were HPLC grade. Chromatographic SystemThe HPLC system consisted of a Shimadzu LC-10ATVP chromatograph, a SPD-M10AVP detector and column oven. The LC separation was performed on an Agilent SB-C 18 column (250ϫ4.6 mm i.d.; 5 mm) protected by a guard C 18 column (5 mm). The mobile phase was a stepwise gradient of water (0.05% v/v phosphoric acid)-acetonitrile (0.01 min, 94 : 6; 50 min, 65 : 35). The column temperature was maintained at 35°C. The analysis were carried out at a flow-rate of 0.9 ml · min Ϫ1 with DAD detection from 200-370 nm. Preparation of Standard SolutionsTo prepare a standard solution containing ingredient 1-6, accurately weighed amounts of each compound were dissolved in methanol to give serial concentrations of 0. 35-3.52, 5.76-57.65, 11.19-167.8, 1.61-16.12, 4.76-47.62 and 0.38-3.75 mg · ml Ϫ1 , respectively. Calibration graphs were plotted after linear regression of the peak area with concentrations. Chromatogram are presented in Fig. 1A.Preparation of Sample Solutions ASHs were powdered to a homogeneous size in a mill, sieved through a No. 40 mesh, and dried at 40°C in the oven for 6 h. The powder sample (1.0 g) was extracted with 40 ml ethanol for 30 min in an ultrasonic bath, and then filtered. The resulting ...

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Section: -7)mentioning

confidence: 99%

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confidence: 99%

Simultaneous Determination of Protocatechuic Acid, Syringin, Chlorogenic Acid, Caffeic Acid, Liriodendrin and Isofraxidin in Acanthopanax senticosus HARMS by HPLC-DAD

Jia

et al. 2006

Biological & Pharmaceutical Bulletin

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“…CA directly down-regulates RAC, leading to inactivation of PAK1 [17]. CAPE (Caffeic Acid Phenethyl Ester) is a natural ester of CA with phenethyl alcohol, and among the major PAK1-blockers in propolis.…”

Section: Caffeic Acid (Ca) and Its Ester Capementioning

confidence: 99%

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Miyata¹,

Pham-Thi²,

Ahn³

2017

J Dermatol Res Ther

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A natural sleeping pill and "elixir" (longevity-promoter) called "Melatonin" is one of the first natural anti-melanogenic compounds, and originally derived from bovine pineal glands. However, currently the majority of melatonin product in the market is chemically synthesized. Since then a wide variety of anti-melanogenic compounds such as curcumin, CAPE (Caffeic Acid Phenethyl Ester), and Artepillin C (ARC) were identified in nature as well as chemically synthesized compounds such as Gleevec. These anti-melanogenic compounds share a series of interesting biological properties such as anti-cancer, anti-inflammatory, anti-ageing (longevity-promoting), immune-boosting, anti-malaria, and anti-diabetic activities. However, the precise molecular mechanism underlying their anti-melanogenic action has remained to be clarified until recently. Finally we found the first clue to understanding of the "melanogenic" signalling pathway involving the major oncogenic/ageing kinase called PAK1 (RAC/CDC42-activated kinase 1) By siRNA-based silencing of PAK1 gene in murine melanoma cell line (B16F10): (i) The major growth hormone in serum called PDGF (Platelet-Derived Growth Factor) is essential for the inducible melanogenesis, but not for the exponential growth per se, and (ii) This cytokine activates its receptor called PDGFR, a Tyr-kinase on the cell surface, and induces another cell surface receptor Tyr-kinase called EGFR (Epidermal Growth Factor Receptor), to form a heterodimer with PDGFR, activating the down-stream melanogenic/oncogenic signalling pathway involving PAK1 and eventually MITF (Microphthalmia-Associated Transcription Factor) essential for expression of Tyrosinase and its Related Protein (TRP) genes. Melatonin and many other anti-melanogenic compounds block PAK1 directly or indirectly, and eventually down-regulate tyrosinase or TRP which is essential for melanin biosynthesis from an amino acid called tyrosine.

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“…Since the more HSP16 is activated, the longer this worm lives (63), it is most likely that like salidroside and curcumin (56,57), all these PAK1 blockers would extend significantly the life span of this worm. Furthermore, as described earlier, CA is a precursor of CAPE, and blocks PAK1 by downregulating its activator RAC (14). During 2010-2011 a German group at Humboldt University in Berlin found that CA and its covalently-linked dimer called Rosmarinic acid (RA) signifi cantly extend the life span of this worm through ''FOXO'', and activate heat shock genes such as HSP12, inducing the heat-tolerance (64).…”

Section: A ''Fl Uorescent'' In Vivo Screening For Nf Therapeuticsmentioning

confidence: 86%

“…So an interesting question has arisen: is there any common mechanism underlying the anti-cancer property among these three distinct propolis samples? In 2005, the fi rst clue to the molecular mechanism of CAPE to suppress the growth of cancers was revealed: caffeic acid (CA) down-regulates a G protein called RAC which is the direct activator of the oncogenic kinase PAK1 (14). Since CAPE is a hydrophobic derivative of CA, it is most likely that CAPE also down-regulates RAC, and eventually inactivates PAK1.…”

Section: Introductionmentioning

confidence: 99%

Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1

Miyata

2011

DD&T

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Neurofibromatosis (NF) is a family of genetic diseases which are caused by dysfunction of either NF1 gene or NF2 gene. One in 3,000 people suffer from this tumor-carrying NF. NF1 gene product is a RAS GTPase activating protein (GAP) of 2,818 amino acids, which normally attenuates the GTPdependent signal transducing activity of the G protein RAS. Dysfunction of this GAP leads to the abnormal activation of RAS, and eventually an oncogenic kinase called PAK1 as well. NF2 gene product is ''Merlin'' which directly inactivates PAK1. Thus, dysfunction of Merlin causes the abnormal activation of PAK1. In other words, dysfunction of NF1 gene (causing type 1 NF) is basically the same as dysfunction of NF2 gene (causing type 2 NF). In fact the growth of both NF1 and NF2 tumors requires PAK1, and all PAK1 blockers, synthetic chemicals or natural products, suppress the growth of these NF tumor cells both in vitro (cell culture) and in vivo (mice).However, until recently, no FDA-approved effective NF therapeutics is available on the market. Here a series of anti-PAK1 products shall be introduced, which would be potentially useful for the life-long treatment of NF patients in the future. These include the most potent HDAC (histone deacetylase) inhibitor FK228 (IC 50 : around 1 nM), that eventually blocks PAK1, the direct PAK1 inhibitor PF3758309 (IC 50 : around 10 nM), a CAPE (caffeic acid phenethyl ester)-based propolis extract called ''Bio 30'' from NZ (New Zealand), and an ARC (artepillin C)-based green propolis extract (GPE) from Brazil. Although the first two drugs are potent, none of them is available on the market as yet. The last two natural (bee-made) products are available on the market, and have been used for the therapy of NF and tuberous sclerosis (TSC) as well as many PAK1-dependent solid cancers such as breast and pancreatic cancers as well as glioma, which altogether represent more than 70% of all human cancers. Since PAK1 is not essential for the normal cell growth, propolis extracts cause no side effects.

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Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells

Cited by 44 publications

References 43 publications

Simultaneous Determination of Protocatechuic Acid, Syringin, Chlorogenic Acid, Caffeic Acid, Liriodendrin and Isofraxidin in Acanthopanax senticosus HARMS by HPLC-DAD

Simultaneous Determination of Protocatechuic Acid, Syringin, Chlorogenic Acid, Caffeic Acid, Liriodendrin and Isofraxidin in Acanthopanax senticosus HARMS by HPLC-DAD

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1

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