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1.
Molecules ; 23(10)2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262742

RESUMO

Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects on Caenorhabditis elegans through inactivation of the oncogenic kinase, p21-activated kinase 1 (PAK1). Herein, five prenylated flavonoids from OP, nymphaeol-A (NA), nymphaeol-B (NB), nymphaeol-C (NC), isonymphaeol-B (INB), and 3'-geranyl-naringenin (GN), were evaluated for their anti-inflammatory, anti-diabetic, and anti-Alzheimer's effects using in vitro techniques. They showed significant anti-inflammatory effects through inhibition of albumin denaturation (half maximal inhibitory concentration (IC50) values of 0.26⁻1.02 µM), nitrite accumulation (IC50 values of 2.4⁻7.0 µM), and cyclooxygenase-2 (COX-2) activity (IC50 values of 11.74⁻24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with IC50 values of 3.77⁻5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with IC50 values of 7.23 and 7.77 µM, respectively. Molecular docking results indicated that OP compounds have good binding affinity to the α-glucosidase and acetylcholinesterase proteins, making non-bonded interactions with their active residues and surrounding allosteric residues. In addition, none of the compounds violated Lipinski's rule of five and showed notable toxicity parameters. Density functional theory (DFT)-based global reactivity descriptors demonstrated their high reactive nature along with the kinetic stability. In conclusion, this combined study suggests that OP components might be beneficial in the treatment of inflammation, type 2 diabetes mellitus, and Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer , Anti-Inflamatórios/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Própole/química , alfa-Glucosidases/química , Animais , Proteínas Ligadas por GPI/química , Humanos , Japão , Camundongos , Células RAW 264.7
2.
Molecules ; 22(1)2017 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-28098826

RESUMO

PAK1 (p21-activated kinase 1) is an emerging target for the treatment of hair loss (alopecia) and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of PAK1 inhibitors isolated from Alpinia zerumbet (alpinia) in cell culture. The bioactive compounds isolated from alpinia were found to markedly promote hair cell growth. Kaempferol-3-O-ß-d-glucuronide (KOG) and labdadiene, two of the isolated compounds, increased the proliferation of human follicle dermal papilla cells by approximately 117%-180% and 132%-226%, respectively, at 10-100 µM. MTD (2,5-bis(1E,3E,5E)-6-methoxyhexa-1,3,5-trien-1-yl)-2,5-dihydrofuran) and TMOQ ((E)-2,2,3,3-tetramethyl-8-methylene-7-(oct-6-en-1-yl)octahydro-1H-quinolizine) showed growth-promoting activity around 164% and 139% at 10 µM, respectively. The hair cell proliferation induced by these compounds was significantly higher than that of minoxidil, a commercially available treatment for hair loss. Furthermore, the isolated compounds from alpinia exhibited anticancer activity against A549 lung cancer cells with IC50 in the range of 67-99 µM. Regarding the mechanism underlying their action, we hypothesized that the anti-alopecia and anticancer activities of these compounds could be attributed to the inhibition of the oncogenic/aging kinase PAK1.


Assuntos
Alpinia/química , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Glucuronídeos/farmacologia , Quempferóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/genética , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Células Epiteliais/citologia , Células Epiteliais/enzimologia , Flores/química , Furanos/química , Furanos/isolamento & purificação , Furanos/farmacologia , Expressão Gênica , Glucuronídeos/química , Glucuronídeos/isolamento & purificação , Folículo Piloso/citologia , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/enzimologia , Humanos , Quempferóis/química , Quempferóis/isolamento & purificação , Minoxidil/farmacologia , Folhas de Planta/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Quinolizinas/química , Quinolizinas/isolamento & purificação , Quinolizinas/farmacologia , Rizoma/química , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/metabolismo
3.
J Agric Food Chem ; 64(27): 5484-9, 2016 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-27337169

RESUMO

Propolis from different areas has been reported to inhibit oncogenic/aging kinase PAK1, which is responsible for a variety of conditions, including cancer, longevity, and melanogenesis. Here, a crude extract of Okinawa propolis (OP) was tested against PAK1 activity, Caenorhabditis elegans (C. elegans) longevity, melanogenesis, and growth of cancer cells. We found that OP blocks PAK1 and exhibits anticancer activity in the A549 cell (human lung cancer cell) line with IC50 values of 6 µg/mL and 12 µg/mL, respectively. Most interestingly, OP (1 µg/mL) significantly reduces reproduction and prolongs the lifespan of C. elegans by activating the HSP-16.2 gene, as shown in the PAK1-deficient strain. Furthermore, OP inhibits melanogenesis in a melanoma cell line (B16F10) by downregulating intracellular tyrosinase activity with an IC50 of 30 µg/mL. Our results suggest that OP demonstrated a life span extending effect, C. elegans, anticancer, and antimelanogenic effects via PAK1 inactivation; therefore, this can be a potent natural medicinal supplement against PAK1-dependent diseases.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Melaninas/metabolismo , Neoplasias/fisiopatologia , Própole/química , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Humanos , Japão , Neoplasias/enzimologia , Quinases Ativadas por p21/metabolismo
4.
Phytother Res ; 30(1): 120-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26537230

RESUMO

PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic kinase, and a number of herbal PAK1-blockers such as propolis and curcumin have been shown to be anti-oncogenic and anti-melanogenic as well as anti-alopecia (promoting hair growth). Previously, we found several distinct PAK1-inhibitors in Okinawa plants including Alpinia zerumbet (alpinia). Thus, here, we tested the effects of these herbal compounds and their derivatives on the growth of cancer or normal hair cells, and melanogenesis in cell culture of A549 lung cancer, hair follicle dermal papilla cell, and B16F10 melanoma. Among these herbal PAK1-inhibitors, cucurbitacin I from bitter melon (Goya) turned out to be the most potent to inhibit the growth of human lung cancer cells with the IC50 around 140 nM and to promote the growth of hair cells with the effective dose around 10 nM. Hispidin, a metabolite of 5,6-dehydrokawain from alpinia, inhibited the growth of cancer cells with the IC50 of 25 µM as does artepillin C, the major anti-cancer ingredient in Brazilian green propolis. Mimosine tetrapeptides (MFWY, MFYY, and MFFY) and hispidin derivatives (H1-3) also exhibited a strong anti-cancer activity with the IC50 ranging from 16 to 30 µM. Mimosine tetrapeptides and hispidin derivatives strongly suppressed the melanogenesis in melanoma cells.


Assuntos
Alpinia/química , Folículo Piloso/efeitos dos fármacos , Fenilpropionatos/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Brasil , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Folículo Piloso/citologia , Humanos , Quinases Lim/antagonistas & inibidores , Melaninas/biossíntese , Melanoma Experimental/patologia , Camundongos , Momordica charantia/química , Pironas/farmacologia , Triterpenos/farmacologia
5.
Drug Discov Ther ; 8(6): 238-44, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25639302

RESUMO

The p21-activated kinase 1 (PAK1) is emerging as a promising therapeutic target, and the search for blockers of this oncogenic/aging kinase would be potentially useful for the treatment of various diseases/disorders in the future. Here, we report for the first time the anti-PAK1 activity of compounds derived from three distinct Okinawa plants. 5,6-Dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) from alpinia inhibited directly PAK1 more strongly than mimosine and mimosinol from leucaena. Cucurbitacin I isolated from bitter gourd/melon also exhibited a moderate anti-PAK1 activity. Hispidin, a metabolite of DK, strongly inhibited PAK1 with the IC50 = 5.7 µM. The IC50 of three hispidin derivatives (H1-3) for PAK1 inhibition ranges from 1.2 to 2.0 µM, while mimosine tetrapeptides [mimosine-Phe-Phe-Tyr (MFFY) and mimosine-Phe-Trp-Tyr (MFWY)] inhibit PAK1 at nanomolar level (IC50 of 0.13 and 0.60 µM, respectively). Thus, we hope these derivatives of hispidin and mimosine could be used as potential leading compounds for developing far more potent anti-PAK1 drugs which would be useful for clinical application in the future.


Assuntos
Envelhecimento/efeitos dos fármacos , Neoplasias/enzimologia , Plantas Medicinais/química , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Humanos , Japão , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação
6.
Biosci Biotechnol Biochem ; 77(2): 217-23, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23391900

RESUMO

The beneficial effects of the phytochemical compounds in fruits and vegetables have been extrapolated mainly from in vitro studies or short-term dietary supplementation studies. Recent approaches using animal models of Caenorhabditis elegans are becoming quite popular, and in this regard the effects of Alpinia zerumbet leaf extract (ALP) on C. elegans lifespan were investigated under both normal and stress conditions. ALP significantly increased, mean lifespan by 22.6%, better than the positive control, resveratrol. Furthermore, both under thermal and oxidative stressed conditions, ALP increased the survival rate significantly better than quercetin. Further studies indicated that the significant longevity-extending effects of ALP on C. elegans can be attributed to its in vitro free-radical scavenging effects and its upregulation of stress-resistance proteins, including superoxide dismutase 3 (SOD-3) and heat-shock protein (HSP-16.2). These results suggest that phytochemical compounds in A. zerumbet have beneficial effects on the lifespan of C. elegans, and that they can be used as a source of dietary supplements for aging and age-related diseases.


Assuntos
Alpinia/química , Caenorhabditis elegans/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Longevidade/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/isolamento & purificação , Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Temperatura Alta , Estresse Oxidativo , Extratos Vegetais/isolamento & purificação , Quercetina/farmacologia , Resveratrol , Solventes , Estilbenos/farmacologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
7.
J Agric Food Chem ; 59(24): 12858-63, 2011 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-22047208

RESUMO

Neuraminidase is a rational target for influenza inhibition, and the search for neuraminidase inhibitors has been intensified. Mimosine, a nonprotein amino acid, was for the first time identified as a neuraminidase inhibitor with an IC(50) of 9.8 ± 0.2 µM. It was found that mimosine had slow, time-dependent competitive inhibition against the neuraminidase. Furthermore, a small library of mimosine tetrapeptides (M-A(1)-A(2)-A(3)) was synthesized by solid-phase synthesis and was assayed to evaluate their neuraminidase and tyrosinase inhibitory properties. Most of the tetrapeptides showed better activities than mimosine. Mimosine-FFY was the best compound, and it exhibited 50% neuraminidase inhibition at a low micromolar range of 1.8 ± 0.2 µM, whereas for tyrosinase inhibition, it had an IC(50) of 18.3 ± 0.5 µM. The kinetic studies showed that all of the synthesized peptides inhibited neuraminidase noncompetitively with K(i) values ranging from 1.9 -to 7.2 µM. These results suggest that mimosine could be used as a source of bioactive compounds and may have possibilities in the design of drugs as neuraminidase and tyrosinase inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Mimosina/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Neuraminidase/antagonistas & inibidores , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Antivirais , Fabaceae/química , Cinética , Mimosina/análise , Mimosina/farmacologia , Folhas de Planta/química , Estações do Ano , Técnicas de Síntese em Fase Sólida
8.
Cancer Lett ; 186(1): 67-74, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12183077

RESUMO

We reported previously that diverse combination of the vitamin D(3) analogue KH1060 together with 12-O-tetradecanoylphorbol-13-acetate (TPA) synergistically induces the differentiation of ML-1 cells into mature macrophages. To investigate the mechanism involved in their interaction, we examined the role of protein kinase C (PKC) in the differentiation of ML-1 cells to mature macrophages. We found that the specific PKC inhibitor GF109203 suppressed the morphological change and the alpha-naphthyl acetate esterase activity induced in ML-1 cells by treatment with KH1060 plus TPA. This treatment increased the translocation of PKC alpha, PKC epsilon, and PKC theta from cytosol to membranes. ML-1 cells treated with KH1060 alone increased translocation of PKC theta, whereas cells treated with TPA alone increased translocation of PKC alpha and PKC epsilon. These data showed that in human myeloblastic leukemia cells, diverse isoforms of PKC, including PKC alpha, epsilon, and theta, participate in the regulation of cell differentiation.


Assuntos
Calcitriol/análogos & derivados , Calcitriol/farmacologia , Isoenzimas/fisiologia , Leucemia Mieloide Aguda/patologia , Proteína Quinase C/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/enzimologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteína Quinase C-alfa , Proteína Quinase C-épsilon , Proteína Quinase C-theta , Células Tumorais Cultivadas
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