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1.
Biol Pharm Bull ; 41(8): 1307-1310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30068884

RESUMO

In our research program to find novel agents for alopecia from natural plant resources, we screened Euphorbiaceae plant extracts using an anti-5α-reductase assay. Among the samples tested, the extract of Phyllanthus urinaria showed the most potent activity with 24.3 and 64.6% inhibition at 50 and 200 µg/mL against the enzyme, respectively. The extract also suppressed the androgen activity of dihydrotestosterone in LNCaP cell line. These results show that the extract of P. urinaria may be a multi-potent agent for androgen-derived alopecia. We tested for activity on a hair regrowth model using mice. The extract of P. urinaria showed hair regrowth activity at 5 mg/mouse/d administration. Furthermore, the active principle for anti-5α-reductase activity was determined as stigmasterol glucoside from activity-guided fractionation and the IC50 was 27.2 µM. These results suggest that extract of P. urinaria may be a promising candidate anti-alopecia agent.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Euphorbiaceae , Cabelo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alopecia/tratamento farmacológico , Androgênios/metabolismo , Animais , Linhagem Celular , Colestenona 5 alfa-Redutase , Di-Hidrotestosterona/metabolismo , Cabelo/crescimento & desenvolvimento , Masculino , Camundongos Endogâmicos C57BL
2.
Chem Pharm Bull (Tokyo) ; 66(7): 741-747, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29695658

RESUMO

Hydroxychavicol (HC), which is obtained from the leaves of Piper betle LINN. (Piperaceae), inhibits xanthine oxidase (XO) with an IC50 value of 16.7 µM, making it more potent than the clinically used allopurinol (IC50=30.7 µM). Herein, a structure-activity relationship analysis of the polar part analogs of HC was conducted and an inhibitor was discovered with a potency 13 times that of HC. Kinetic studies have revealed that HC and its active analog inhibit XO in an uncompetitive manner. The binding structure prediction of these inhibitor molecules to the XO complex with xanthine suggested that both compounds (HC and its analog) could simultaneously form hydrogen bonds with xanthine and XO.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Eugenol/análogos & derivados , Simulação de Acoplamento Molecular , Xantina Oxidase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/isolamento & purificação , Eugenol/química , Eugenol/isolamento & purificação , Eugenol/farmacologia , Humanos , Estrutura Molecular , Piperaceae/química , Folhas de Planta/química , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
3.
Toxicol Appl Pharmacol ; 306: 105-12, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27417526

RESUMO

Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Xantonas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Integrinas/genética , Masculino , Metaloproteinases da Matriz/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Xantonas/farmacologia , Quinase Induzida por NF-kappaB
4.
Biol Pharm Bull ; 39(5): 823-31, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27150151

RESUMO

Asiasarum root (roots and rhizome of Asiasarum sieboldii or A. heterotropoides var. mandshuricum) has been frequently used in traditional Chinese medicinal formulas for the management of oral malodor syndrome caused by periodontal disease. However, there are no scientific reports concerning these effects and the mechanism of action. The objective of this study was to examine the inhibitory effects of Asiasarum root and its constituents on oral malodor syndrome and periodontal disease. A 50% ethanolic extract of Asiasarum root (AR-ext) showed L-methionine γ-lyase (METase) inhibitory activity at a concentration of 200 µg/mL, and inhibited interleukin (IL)-1ß-stimulated matrix metalloproteinase (MMP)-1 secretion from human gingival fibroblasts (HGFs) at a concentration of 10 and 50 µg/mL without cytotoxic effects. Activity-guided fractionation of the AR-ext suggested that METase inhibitory activity was attributable to a mixture of linoleic and oleic acid, because these unsaturated fatty acids showed weak METase inhibitory activities. Similar fractionation using MMP-1 secretion inhibitory activity led to the isolation of two unsaturated fatty acid amides, (2E,4E,8Z,10E)-N-(2-methylpropyl)dodeca-2,4,8,10-tetraenamide (1) and (2E,4E,8Z,10Z)-N-(2-methylpropyl)dodeca-2,4,8,10-tetraenamide (2), as active constituents with inhibitory activity on MMP-1 secretion from HGFs. To elucidate the inhibition mechanism on MMP-1 secretion, the effect of 2 on mitogen-activated protein kinase (MAPK) phosphorylation was examined. Western blotting analysis revealed that 2 (10 µM) reduced the phosphorylation of p38 and c-Jun-N-terminal kinase. These results suggested that 2 suppresses intracellular MMP-1 expression and MMP-1 secretion from IL-1ß-stimulated HGFs by down-regulation of MAPK phosphorylation.


Assuntos
Aristolochiaceae , Liases de Carbono-Enxofre/antagonistas & inibidores , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Metaloproteinase 1 da Matriz/metabolismo , Extratos Vegetais/farmacologia , Liases de Carbono-Enxofre/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Halitose , Humanos , Interleucina-1beta/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Raízes de Plantas , Porphyromonas gingivalis/efeitos dos fármacos
5.
Phytother Res ; 27(2): 212-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22517595

RESUMO

Topical administration of Rosmarinus officinalis leaf extract (RO-ext, 2 mg/day/mouse) improved hair regrowth in C57BL/6NCrSlc mice that experienced hair regrowth interruption induced by testosterone treatment. In addition, RO-ext promoted hair growth in C3H/He mice that had their dorsal areas shaved. To investigate the antiandrogenic activity mechanism of RO-ext, we focused on inhibition of testosterone 5α-reductase, which is well recognized as one of the most effective strategies for the treatment of androgenic alopecia. RO-ext showed inhibitory activity of 82.4% and 94.6% at 200 and 500 µg/mL, respectively. As an active constituent of 5α-reductase inhibition, 12-methoxycarnosic acid was identified with activity-guided fractionation. In addition, the extract of R. officinalis and 12-methoxycarnosic acid inhibited androgen-dependent proliferation of LNCaP cells as 64.5% and 66.7% at 5 µg/mL and 5 µM, respectively. These results suggest that they inhibit the binding of dihydrotestosterone to androgen receptors. Consequently, RO-ext is a promising crude drug for hair growth.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Cabelo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rosmarinus/química , Alopecia/induzido quimicamente , Alopecia/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Animais , Linhagem Celular Tumoral , Cabelo/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Fitoterapia , Folhas de Planta/química , Ratos , Ratos Wistar , Testosterona/farmacologia
6.
Chem Pharm Bull (Tokyo) ; 61(5): 551-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23649198

RESUMO

The acetone-soluble parts of Garcinia subelliptica leaves were analyzed and six new biflavonoids were isolated, i.e., garciniaflavones A-F (1-6), as well as the five known biflavonoids amentoflavone (7), podocarpusflavone A (8), (+)-morelloflavone (9), (+)-morelloflavone-7"-O-ß-glucopyranoside (10), and (+)-4'''-O-methylmorelloflavone (11) and the three triterpenoids oleanan-3-one, ß-amyrin, and cycloartenol. The structures of the isolates were established based on spectroscopic analyses, including a detailed NMR spectroscopic investigation. The new biflavonoids are rare mono-isoprenylated derivatives that have a flavone-(3'-8")-flavone core (1-4: amentoflavone type) and a flavanone-(3-8")-flavone core (5, 6: morelloflavone type). The absolute configurations of the morelloflavone-type biflavonoids (5, 6) were confirmed by circular dichroism to be 2R,3S. The biflavonoids with an isoprenyloxy group (1) and a 2-hydroxy-3-methyl-3-butenyl group (2), and the morelloflavone-type biflavonoids with a C(5) unit are the first examples in nature. We found that 7, one of the major biflavonoids, strongly inhibited hypoxia-inducible factor-1 in human embryonic kidney 293 cells under hypoxic conditions.


Assuntos
Biflavonoides/isolamento & purificação , Garcinia/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Biflavonoides/química , Estrutura Molecular , Extratos Vegetais/química , Prenilação , Estereoisomerismo
7.
Biol Pharm Bull ; 35(1): 78-83, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22223341

RESUMO

The objective of this study was to examine the effects of Morinda citrifolia (noni) extract and its constituents on α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis in cultured murine B16 melanoma cells (B16 cells). A 50% ethanolic extract of noni seeds (MCS-ext) showed significant inhibition of melanogenesis with no effect on cell proliferation. MCS-ext was more active than noni leaf and fruit flesh extracts. Activity guided fractionation of MCS-ext led to the isolation of two lignans, 3,3'-bisdemethylpinoresinol (1) and americanin A (2), as active constituents. To elucidate the mechanism of melanogenesis inhibition by the lignans, α-MSH-stimulated B16 cells were treated with 1 (5 µM) and 2 (200 µM). Time-dependent increases of intracellular melanin content and tyrosinase activity, during 24 to 72 h, were inhibited significantly by treatment with the lignans. The activity of 1 was greater than that of 2. Western blot analysis suggested that the lignans inhibited melanogenesis by down regulation of the levels of phosphorylation of p38 mitogen-activated protein kinase, resulting in suppression of tyrosinase expression.


Assuntos
Dioxinas/farmacologia , Lignanas/farmacologia , Melaninas/biossíntese , Melanoma Experimental/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Morinda/química , Extratos Vegetais/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Western Blotting , Dioxinas/isolamento & purificação , Lignanas/isolamento & purificação , Camundongos , Fosforilação , Estruturas Vegetais , alfa-MSH/metabolismo
8.
Biol Pharm Bull ; 35(2): 210-5, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22293351

RESUMO

The objective of this study was to examine whether a 50% ethanolic extract (MCS-ext) of the seeds of Morinda citrifolia (noni) and its constituents have matrix metalloproteinase-1 (MMP-1) inhibitory activity in UVA-irradiated normal human dermal fibroblasts (NHDFs). The MCS-ext (10 µg/mL) inhibited MMP-1 secretion from UVA-irradiated NHDFs, without cytotoxic effects, at 48 h after UV exposure. The ethyl acetate-soluble fraction of MCS-ext was the most potent inhibitor of MMP-1 secretion. Among the constituents of the fraction, a lignan, 3,3'-bisdemethylpinoresinol (1), inhibited the MMP-1 secretion at a concentration of 0.3 µM without cytotoxic effects. Furthermore, 1 (0.3 µM) reduced the level of intracellular MMP-1 expression. Other constituents, namely americanin A (2), quercetin (3) and ursolic acid (4), were inactive. To elucidate inhibition mechanisms of MMP-1 expression and secretion, the effect of 1 on mitogen-activated protein kinases (MAPKs) phosphorylation was examined. Western blot analysis revealed that 1 (0.3 µM) reduced the phosphorylations of p38 and c-Jun-N-terminal kinase (JNK). These results suggested that 1 suppresses intracellular MMP-1 expression, and consequent secretion from UVA-irradiated NHDFs, by down-regulation of MAPKs phosphorylation.


Assuntos
Fibroblastos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Morinda , Extratos Vegetais/farmacologia , Inibidores de Proteases/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dioxinas/farmacologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Humanos , Recém-Nascido , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lignanas/farmacologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Quercetina/farmacologia , Sementes , Triterpenos/farmacologia , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ácido Ursólico
9.
Phytother Res ; 26(1): 48-53, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21538628

RESUMO

This research program on the novel functions of Panax ginseng C. A. Meyer focused on the effects of ginseng rhizome on hair re-growth in androgenetic alopecia. Extracts of red ginseng rhizome showed greater dose-dependent inhibitory effects against testosterone 5α-reductase (5αR) when compared with extracts of the main root. Ginsenoside Ro, the predominant ginsenoside in the rhizome, and ginsenoside Rg(3), a unique ginsenoside in red ginseng, showed inhibitory activity against 5αR with IC(50) values of 259.4 and 86.1 µm, respectively. The rhizome of P. japonicus, which contains larger amounts of ginsenoside Ro, also inhibited 5αR. Topical administration of extracts of red ginseng rhizomes (2 mg/mouse) and ginsenoside Ro (0.2 mg/mouse) to shaved skin inhibited hair re-growth suppression after shaving in the testosterone-treated C57BL/6 mice. These results suggest that red ginseng rhizomes containing both oleanane- and dammarane-type ginsenosides are a promising raw material for cosmetic use. This is the first report that ginsenoside Ro enhances in vivo hair re-growth based on their inhibitory activity against 5αR in the androgenetic alopecia model.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Alopecia/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Cabelo/efeitos dos fármacos , Panax/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Alopecia/induzido quimicamente , Alopecia/enzimologia , Animais , Relação Dose-Resposta a Droga , Ginsenosídeos/farmacologia , Cabelo/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Raízes de Plantas , Rizoma , Testosterona/farmacologia
10.
Clin Ther ; 44(12): 1552-1565, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36376130

RESUMO

PURPOSE: The safety and efficacy of intravenous edaravone, a neuroprotectant used for the treatment of amyotrophic lateral sclerosis (ALS), have been shown in clinical trials. An oral suspension of edaravone has been developed, but the food effect on its pharmacokinetic profile has not been evaluated. This study aimed to assess the food effect on the pharmacokinetic profile of edaravone after oral administration and to investigate dosing regimens and administration instructions with different meal intake and timing. METHODS: Data from 3 Phase I clinical studies were used to evaluate the effect of food on the pharmacokinetic profiles of a single dose of edaravone oral suspension. In all 3 studies, participants received a single dose of edaravone with various meal conditions. Healthy Japanese adult male participants (Studies 1, 2, and 3) or female participants (Study 3) aged 20 to 45 years at the time of informed consent were included. FINDINGS: In Study 1, 6 participants were enrolled and 5 completed the study. Nine and 16 participants were treated in Studies 2 and 3, respectively, and all completed the study. The Cmax and AUC0-∞ of edaravone were lower when administered 30 minutes after a high-fat meal compared with those in a fasted condition (Study 1). Lower plasma edaravone concentrations (approximately within the first hour) and subsequent lower Cmax and AUC0-∞ were observed after administration of edaravone 4 hours after a high-fat meal (Study 2) or 2 hours after a low-fat meal (Study 3). The Cmax and AUC0-∞ of oral edaravone were generally similar and not affected when administered 8 hours after a high-fat meal, 4 hours after a low-fat meal, or 2 hours after a light meal relative to the fasted condition. Administration of edaravone 1 hour before a high-fat meal resulted in no effect on Cmax or AUC0-∞ relative to the fasted condition. Administration of edaravone in the fed or fasted conditions resulted in a similar urine pharmacokinetic profile. IMPLICATIONS: Oral administration of edaravone with a meal decreased the plasma concentration of edaravone. Oral administration of edaravone 8 hours after a high-fat meal, 4 hours after a low-fat meal, 2 hours after a light meal, and 1 hour before a high-fat meal showed no effect of food on the PK profile of unchanged edaravone compared with that observed under a fasted condition. CLINICALTRIALS: gov identifiers: NCT04481750, NCT04481789, and NCT05342597.


Assuntos
Jejum , Interações Alimento-Droga , Adulto , Feminino , Humanos , Masculino , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Edaravone , Voluntários Saudáveis
11.
Biol Pharm Bull ; 34(7): 1143-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21720029

RESUMO

Kaempferia parviflora (KP), a Zingiberaceae plant, is used as a folk medicine in Thailand for the treatment of various symptoms, including general pains, colic gastrointestinal disorders, and male impotence. In this study, the inhibitory activities of KP against xanthine oxidase (XOD) were investigated. The extract of KP rhizomes showed more potent inhibitory activity (38% at 500 µg/ml) than those of the other Zingiberaceae plants tested. Ten methoxyflavones were isolated from the KP extract as the major chemical components and their chemical structures were elucidated by X-ray crystallography. The structurally confirmed methoxyflavones were subjected to the XOD inhibitory test. Among them, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone showed inhibitory activities (IC(50) of 0.9 and >4 mM, respectively) and their modes of inhibition are clarified as competitive/non-competitive mixed type. To the best of our knowledge, this is the first report to present the inhibitory activities of KP, 3,5,7,4',5'-pentamethoxyflavone and 3',4',5,7-tetramethoxyflavone against XOD.


Assuntos
Inibidores Enzimáticos/farmacologia , Flavonas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Zingiberaceae/química , Inibidores Enzimáticos/química , Flavonas/química , Modelos Moleculares , Estrutura Molecular , Análise Espectral , Difração de Raios X
12.
Clin Pharmacol Drug Dev ; 10(10): 1174-1187, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33704925

RESUMO

Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug-drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo-controlled, randomized, single-blind study of single-ascending-dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple-dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single-dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100-mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of  ≈100 mg, with an absolute bioavailability of ≈60%.


Assuntos
Povo Asiático , Edaravone/administração & dosagem , Edaravone/farmacocinética , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/farmacocinética , População Branca , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Suspensões , Adulto Jovem
13.
Biol Pharm Bull ; 33(4): 659-64, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20410602

RESUMO

The enhancement of blood fluidity may lead to improvements in skin problems resulting from unsmooth circulation or blood stagnation. Since a 50% ethanolic extract (CH-ext) obtained from unripe Citrus hassaku fruits may be a useful ingredient in skin-whitening cosmetics, the present study was designed to examine the effect of CH-ext on blood fluidity. CH-ext concentration-dependently inhibited in vitro collagen-induced rabbit platelet aggregation and in vitro polybrene-induced rat erythrocyte aggregation. The CH-ext showed in vitro fibrinolysis activity in fibrin plate assay. Activity-guided fractionation of the CH-ext using antiplatelet activity, inhibitory activity of erythrocyte aggregation, and fibrinolysis activity revealed that these activities of CH-ext were attributable to naringenin-7-glycoside (prunin). Successive oral administration of CH-ext to rats inhibited the lipopolysaccharide (LPS)-induced decrease of blood platelets and fibrinogen, and LPS-induced increase of fibrin degradation products (FDP) in LPS-induced disseminated intravascular coagulation (DIC) model rats. Effects of CH-ext on blood fluidity were analyzed by a micro channel array flow analyzer (MC-FAN). Preventive oral administration of CH-ext to rats showed dose-dependent reduction of the passage time of whole blood flow of the DIC model rats in comparison with that of the vehicle control rats. These results imply that CH-ext may have effects which improve effects on blood fluidity.


Assuntos
Citrus/química , Agregação Eritrocítica/efeitos dos fármacos , Flavanonas/farmacologia , Glicosídeos/farmacologia , Fármacos Hematológicos/farmacologia , Extratos Vegetais/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Colágeno , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Fibrina/metabolismo , Fibrinogênio/metabolismo , Frutas , Testes Hematológicos , Hemorreologia/efeitos dos fármacos , Lipopolissacarídeos , Masculino , Coelhos , Ratos , Ratos Wistar
14.
Neuropharmacology ; 138: 232-244, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29913186

RESUMO

Since Cav3.2 T-type Ca2+ channels (T-channels) expressed in the primary afferents and CNS contribute to intractable pain, we explored T-channel-blocking components in distinct herbal extracts using a whole-cell patch-clamp technique in HEK293 cells stably expressing Cav3.2 or Cav3.1, and purified and identified sophoraflavanone G (SG) as an active compound from SOPHORAE RADIX (SR). Interestingly, hop-derived SG analogues, (2S)-6-prenylnaringenin (6-PNG) and (2S)-8-PNG, but not naringenin, also blocked T-channels; IC50 (µM) of SG, (2S)-6-PNG and (2S)-8-PNG was 0.68-0.75 for Cav3.2 and 0.99-1.41 for Cav3.1. (2S)-6-PNG and (2S)-8-PNG, but not SG, exhibited reversible inhibition. The racemic (2R/S)-6-PNG as well as (2S)-6-PNG potently blocked Cav3.2, but exhibited minor effect on high-voltage-activated Ca2+ channels and voltage-gated Na+ channels in differentiated NG108-15 cells. In mice, the mechanical allodynia following intraplantar (i.pl.) administration of an H2S donor was abolished by oral or i.p. SR extract and by i.pl. SG, (2S)-6-PNG or (2S)-8-PNG, but not naringenin. Intraperitoneal (2R/S)-6-PNG strongly suppressed visceral pain and spinal ERK phosphorylation following intracolonic administration of an H2S donor in mice. (2R/S)-6-PNG, administered i.pl. or i.p., suppressed the neuropathic allodynia induced by partial sciatic nerve ligation or oxaliplatin, an anti-cancer agent, in mice. (2R/S)-6-PNG had little or no effect on open-field behavior, motor performance or cardiovascular function in mice, and on the contractility of isolated rat aorta. (2R/S)-6-PNG, but not SG, was detectable in the brain after their i.p. administration in mice. Our data suggest that 6-PNG, a hop component, blocks T-channels, and alleviates neuropathic and visceral pain with little side effects.


Assuntos
Analgésicos não Narcóticos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Flavonoides/farmacologia , Neuralgia/tratamento farmacológico , Dor Visceral/tratamento farmacológico , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/isolamento & purificação , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Flavonoides/química , Flavonoides/isolamento & purificação , Células HEK293 , Humanos , Humulus , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuralgia/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Distribuição Aleatória , Ratos Wistar , Dor Visceral/metabolismo
15.
J Chromatogr A ; 1163(1-2): 43-8, 2007 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-17597137

RESUMO

We developed a rapid sample preparation method for the toxicological analysis of methamphetamine and amphetamine (the major metabolite of methamphetamine) in human hair by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), to facilitate fast screening and quantitation. Two milligrams of hair were mechanically micropulverized for 5 min in a 2-ml plastic tube together with 100 microl of an aqueous solvent containing 10% acetonitrile, 100 mM trifluoroacetic acid and the corresponding deuterium analogues as internal standards. The pulverizing highly disintegrated the hair components, simultaneously allowing the extraction of any drugs present in the hair. After filtering the suspension with a membrane-filter unit, the clear filtrate was directly analyzed by HPLC-MS/MS. No evaporation processes were required for sample preparation. Method optimization and validation study were carried out using real-case specimens and fortified samples in which the drugs had been artificially absorbed, respectively. Concentration ranges for quantitation were 0.040-125 and 0.040-25 ng/mg for methamphetamine and amphetamine, respectively. Real-case specimens were analyzed by the method presented here and by conventional ones to verify the applicability of our method to real-world analysis. Our method took less than 30 min for a set of chromatograms to be obtained from a washed hair sample.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cabelo/química , Metanfetamina/química , Espectrometria de Massas em Tandem/métodos , Anfetamina/análise , Anfetamina/química , Humanos , Masculino , Metanfetamina/análise , Reprodutibilidade dos Testes , Detecção do Abuso de Substâncias/métodos
16.
J Nat Med ; 71(1): 114-122, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27568312

RESUMO

In our research program to identify cholinesterase and ß-secretase inhibitors, we investigated Ginseng (root of Panax ginseng), a crude drug described as a multifunctional drug in the ancient Chinese herbal book Shennong Ben Cao Jing. Results from hexane and methanol extracts showed moderate inhibitory activities. This suggests that ginseng roots may be effective for the prevention of and therapy for dementia. We then focused on hexane extracts of raw ginseng root and dried ginseng root since the determination of hexane extract constituents has not been studied extensively. Activity-guided fractionation and purification led to the isolation of 4 polyacetylene compounds; homopanaxynol, homopanaxydol, (9Z)-heptadeca-1, 9-diene-4,6-diyn-3-one, and (8E)-octadeca-1,8-diene-4,6-diyn-3,10-diol. The chemical structures of these compounds, including stereochemistry, were determined. This is the first study to identify the structure of homopanaxynol and homopanaxydol. Moreover, the modes of action of some compounds were characterized as competitive inhibitors. This study showed, for the first time, that polyacetylene compounds possess acetylcholinesterase inhibitory activities.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Panax/química , Extratos Vegetais/química , Raízes de Plantas/química , Poli-Inos/química , Poli-Inos/análise
17.
Artigo em Inglês | MEDLINE | ID: mdl-28546807

RESUMO

BACKGROUND: Mass spectrometry-guided venom peptide profiling is a powerful tool to explore novel substances from venomous animals in a highly sensitive manner. In this study, this peptide profiling approach is successfully applied to explore the venom peptides of a Japanese solitary carpenter bee, Xylocopa appendiculata (Hymenoptera: Apoidea: Apidae: Anthophila: Xylocopinae: Xylocopini). Although interesting biological effects of the crude venom of carpenter bees have been reported, the structure and biological function of the venom peptides have not been elucidated yet. METHODS: The venom peptide profiling of the crude venom of X. appendiculata was performed by matrix-assisted laser desorption/ionization-time of flight mass spectroscopy. The venom was purified by a reverse-phase HPLC. The purified peptides were subjected to the Edman degradation, MS/MS analysis, and/or molecular cloning methods for peptide sequencing. Biological and functional characterization was performed by circular dichroism analysis, liposome leakage assay, and antimicrobial, histamine releasing and hemolytic activity tests. RESULTS: Three novel peptides with m/z 16508, 1939.3, and 1900.3 were isolated from the venom of X. appendiculata. The peptide with m/z 16508 was characterized as a secretory phospholipase A2 (PLA2) homolog in which the characteristic cysteine residues as well as the active site residues found in bee PLA2s are highly conserved. Two novel peptides with m/z 1939.3 and m/z 1900.3 were named as Xac-1 and Xac-2, respectively. These peptides are found to be amphiphilic and displayed antimicrobial and hemolytic activities. The potency was almost the same as that of mastoparan isolated from the wasp venom. CONCLUSION: We found three novel biologically active peptides in the venom of X. appendiculata and analyzed their molecular functions, and compared their sequential homology to discuss their molecular diversity. Highly sensitive mass analysis plays an important role in this study.

18.
Forensic Sci Int ; 158(2-3): 94-103, 2006 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-16024197

RESUMO

Numerical features obtained from the guard hairs of dogs and cats (total 300 hairs per dog or cat) were statistically compared, in an attempt to discriminate between them. Using hairs from each of five mongrel dogs and cats, eight measurements (length (Len), maximum width (MaxWid), cross sectional maximum diameter, cross sectional minimum diameter, cuticular thickness of the cross section and three scale counts per 100 microm length (observed at three positions: distal third (disSC), middle (midSC) and the proximal third (proSC) portions) and five indexes (hair width index (HWI), medulla index (MI), hair index, cuticle index and the difference in scale counts between the distal and proximal parts (defSC)) were examined. The range for each numerical feature overlapped each other extensively, and none of the features permitted a discrimination between dog and cat hairs, based on the values obtained. However, 12 numerical features, except for the midSC, showed a statistically significant difference between dog and cat hairs, as evidenced by a t-test. For the purpose of comprehensively comparing numerical features and statistically discriminating between dog and cat hairs, a discriminant analysis between the two were carried out using a multiple regression analysis. Four types of discriminant functions produced by combining over five numerical features were examined. Dog and cat hairs could clearly be discriminated using any of the discriminant functions. Species discrimination using the discriminant function permitted the species of a dog or cat to be determined, based on the overall morphologies of various numerical features. When experimentally collected test samples were investigated using the discriminant function using Combination-2, consisting of eight numerical features (Len, MaxWid, MI, HWI, disSC, midSC, proSC and defSC), all 10 cat hairs were correctly determined to be cat hair and 22 of 23 dog hairs were correctly identified. This discriminant function produced good results for species discrimination between dog and cat hairs.


Assuntos
Análise Discriminante , Cabelo/patologia , Animais , Gatos , Cães , Medicina Legal , Especificidade da Espécie
19.
Nat Prod Commun ; 11(4): 507-10, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27396206

RESUMO

The growing number of Alzheimer's disease (AD) patients prompted us to seek effective natural resources for the prevention of AD. We focused on the inhibition of ß-secretase, which is known to catalyze the production of senile plaque. Sixteen spices used in Asian countries were selected for the screening. Among the extracts tested, hexane extracts obtained from turmeric, cardamom, long pepper, cinnamon, Sichuan pepper, betel, white turmeric and aromatic ginger showed potent inhibitory activities. Their active principles were identified as sesquiterpenoids, monoterpenoids, fatty acid derivatives and phenylpropanoids using GC-MS analyses. The chemical structures and IC50 values of the compounds are disclosed. The results suggest that long-term consumption'of aromatic compounds from spices could be effective in the prevention of AD.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Fitoterapia , Extratos Vegetais/farmacologia , Especiarias , Doença de Alzheimer/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Extratos Vegetais/uso terapêutico
20.
Nat Prod Commun ; 11(11): 1671-1674, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30475504

RESUMO

The need for a preventive agent against dementia led us to screen natural plant resources. Among the herbs and spices tested, sesame seed prepared from Sesamum indicum seeds showed potent ß-secretase inhibitory activity. The active principles were determined to be sesamin and sesamolin, typical lignans in S. indicum. The IC(50) values of sesamin and sesamolin were 257 and 140 µM, respectively. These compounds were investigated in a preliminary absorption experiment. After oral administration, these compounds were detected in an intact form in the brain and serum. These results suggest that consumption of sesame seeds may prevent dementia by sesamin and sesamolin, the constituents in sesame seeds.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores da Colinesterase/farmacologia , Extratos Vegetais/farmacologia , Sementes/química , Sesamum/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Extratos Vegetais/química
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