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1.
Arch Pharm Res ; 38(6): 1090-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25315636

RESUMO

Aldose reductase (AR) is a key enzyme in the polyol pathway that is strongly implicated in the pathogenesis of diabetic complications. AR inhibitors have been proposed as therapeutic agents for diabetic complications through suppression of sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus, loganin and 7-O-galloyl-D-sedoheptulose, had an inhibitory effect on diabetic complications through AR inhibition. Because the iridoid glycoside loganin and the low-molecular-weight polyphenol 7-O-galloyl-D-sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of diabetic complications. In kinetic analysis using Lineweaver-Burk plots and Dixon plots, loganin and 7-O-galloyl-D-sedoheptulose were both mixed inhibitors of RLAR with inhibition constants (K i) of 27.99 and 128.68 µΜ, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = -6.7; -7.5 kcal/mol; Fred 2.0 = -59.4; -63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the enzyme. Iridoid nucleus and aromatic ring systems and glycoside and sedoheptulose moieties were found to bind tightly to the specificity pocket and the anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that loganin and 7-O-galloyl-D-sedoheptulose have great promise for the treatment of diabetic complications through inhibition of AR.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Complicações do Diabetes/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Heptoses/farmacocinética , Heptoses/uso terapêutico , Iridoides/farmacocinética , Iridoides/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Cornus/química , Inibidores Enzimáticos/química , Heptoses/química , Humanos , Indicadores e Reagentes , Iridoides/química , Cinética , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes
2.
Fitoterapia ; 89: 131-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23567861

RESUMO

The aim of the present study was to evaluate the beneficial effects of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus, using type 2 diabetic mice. GS was orally administered to db/db mice at doses of 20 and 100 mg/kg body weight per day for 6 weeks, and the effects of GS on biochemical factors in serum and adipose tissue were investigated. To define the underlying mechanism of these effects, protein expressions related to lipid metabolism, inflammation, fibrosis, and apoptosis, were measured. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, interleukin-6, triglycerides, total cholesterol, non-esterified fatty acids, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol/low-density lipoprotein cholesterol, reactive oxygen species (ROS), and thiobarbituric acid-reactive substance (TBARS) in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, the elevated lipid, ROS, and TBARS contents in adipose tissue as well as serum levels in db/db mice were significantly decreased by the oral administration of GS. From protein analysis, the decreased expressions of peroxisome proliferator activated receptor (PPAR)α, PPARγ, and B-cell lymphoma 2 were up-regulated in the adipose tissue of db/db mice. The administration of GS significantly decreased sterol regulatory element binding protein-1, nuclear factor-kappa ?>Bp65, cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemotactic protein-1, intracellular adhesion molecule-1, phosphor c-Jun N-terminal kinase, activator protein-1, transforming growth factor-ß1, Bax, cytochrome c, and caspase-3 expressions. These results suggest that GS acts as a regulator of oxidative stress, inflammation, fibrosis, and apoptosis in the adipose tissue of db/db mice.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Cornus/química , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Heptoses/farmacologia , Fitoterapia , Tecido Adiposo/metabolismo , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose , Frutas/química , Heptoses/isolamento & purificação , Heptoses/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos
3.
Biol Pharm Bull ; 36(5): 723-32, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23412668

RESUMO

Compelling evidence indicates that polyphenolic antioxidants show protective effects against diabetic complications. We investigated the effects of a polyphenolic compound, 7-O-galloyl-D-sedoheptulose (GS), from Corni Fructus on a type 2 diabetic db/db mouse model. After 6 weeks of GS treatment, the effects of GS on serum and pancreatic biochemical factors were investigated. To define the underlying mechanism of these effects, we examined several key inflammatory markers, and inflammation-related oxidative stress markers. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, and interleukin-6 in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, GS suppressed reactive oxygen species and lipid peroxidation in the pancreas, but increased the pancreatic insulin and pancreatic C-peptide contents. Moreover, GS modulated protein expressions of pro-inflammatory nuclear factor-kappa Bp 65, cyclooxygenase-2, inducible nitric oxide synthase, c-Jun N-terminal kinase (JNK), phospho-JNK, activator protein-1, transforming growth factor-ß1, and fibronectin. Based on these results, we conclude that a plausible mechanism of GS's anti-diabetic action may well be its anti-inflammatory property and anti-inflammatory-related anti-oxidative action. Thus, further investigation of GS as an effective anti-diabetic treatment for type 2 diabetes is warranted.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heptoses/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Glicemia/análise , Peptídeo C/metabolismo , Cornus , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Fibronectinas/metabolismo , Heptoses/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Transcrição AP-1/metabolismo
4.
J Pharm Pharmacol ; 64(12): 1730-40, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23146036

RESUMO

OBJECTIVES: This study was carried out to verify the preventive effects of 7-O-galloyl-d-sedoheptulose (GS), a phenolic compound isolated from Corni Fructus, underlying diabetic renal damage in type 2 diabetes. METHODS: GS was orally administered to db/db mice at doses of 20 and 100 mg/kg body weight per day for six weeks, and its effects were compared with those of the vehicle in db/db and m/m mice. KEY FINDINGS: In the serum and kidney, biochemical factors and expression of protein related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, apoptosis and inflammation were examined. GS treatment attenuated serum and renal oxidative stress through reduction of reactive oxygen species and lipid peroxidation and increase in the ratio of glutathione and its oxidised form. Importantly, GS reduced renal protein expression of Nox-4 and p22(phox) (one of the subunits of NADPH oxidase), pro-apoptotic factors (such as Bax and cytochrome c) and nuclear factor-kappa B-targeting pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2. CONCLUSIONS: These renoprotective effects of GS were achieved through attenuation of diabetes-induced oxidative stress and its sensitive protein expression associated with inflammation and apoptosis in db/db mice.


Assuntos
Apoptose/efeitos dos fármacos , Cornus/química , Nefropatias Diabéticas/prevenção & controle , Heptoses/uso terapêutico , Inflamação/prevenção & controle , Rim/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/metabolismo , Glutationa/metabolismo , Heptoses/isolamento & purificação , Heptoses/farmacologia , Inflamação/sangue , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 4 , NADPH Oxidases/sangue , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/isolamento & purificação , Fenóis/farmacologia , Fenóis/uso terapêutico , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
5.
Biol Pharm Bull ; 35(6): 950-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22687537

RESUMO

The present study was conducted to examine whether 7-O-galloyl-D-sedoheptulose (GS) has an ameliorative effect on diabetic alterations such as oxidative stress, inflammation, and apoptosis in the liver of type 2 diabetic db/db mice. GS was administered at 20 or 100 mg/kg body weight per day for 6 weeks to db/db mice, and its effect was compared with vehicle-treated db/db and m/m mice. In the serum and hepatic tissue, biochemical factors and protein expressions associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, inflammation, and apoptosis were examined. As a result, GS administration to type 2 diabetic mice lowered serum and hepatic oxidative stress through the reduction of reactive oxygen species and lipid peroxidation. These results were derived, at least in part, from attenuating the expression of NADPH oxidase subunit proteins, Nox-4 and p22(phox). In the diabetic condition, augmented nuclear factor (NF)-E2-related factor 2 and heme oxygenase-1 were reduced with a decrease in oxidative stress on GS treatment. Furthermore, in the GS-treated group, NF-kappa B-related pro-inflammatory factors and pro-apoptotic protein expressions were alleviated in the hepatic tissue. Taking these into consideration, our findings support the therapeutic evidence for GS ameliorating the development of diabetic complications via regulating oxidative stress, inflammation, and apoptosis.


Assuntos
Antioxidantes/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Heptoses/farmacologia , Hepatopatias/metabolismo , NF-kappa B/metabolismo , Animais , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Heptoses/uso terapêutico , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
6.
Biol Pharm Bull ; 35(1): 34-41, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22223334

RESUMO

The protective effect of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus as an active component, against acute renal failure (ARF) induced by glycerol was investigated. The administration of GS led to a decline in the levels of blood urea nitrogen and creatinine; on the other hand, it did not have a significant effect on creatinine clearance. Furthermore, GS also significantly decreased the urine volume and fractional excretion of sodium, but it increased the urine osmolarity, suggesting the protective role of GS against renal dysfunction. Oxidative stress under ARF was attenuated by GS through the inhibition of lipid peroxidation, scavenging of reactive oxygen species (ROS), and elevation of the antioxidative status. Renal oxidative stress is related to the overproduction of ROS by nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase; therefore, in the present study, the protein expression of p22(phox) and NAD(P)H oxidase-4 (Nox-4) was investigated. GS down-regulated the protein expression of p22(phox); on the other hand, it did not significantly affect the expression of Nox-4. This indicates that GS inhibits the production of superoxide by regulating a component of NAD(P)H oxidase, p22(phox). Furthermore, GS down-regulated the expressions of nuclear factor-κB (NF-κΒ) and inducible nitric oxide (NO) synthase (iNOS), suggesting that GS protects against NO-induced inflammatory pathological conditions under ARF through the regulation of NF-κB and iNOS expressions. The present study indicates that GS exerts a protective effect against ARF through the recovery of renal dysfunction and attenuation of renal oxidative stress by regulating related protein expression.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cornus/química , Medicamentos de Ervas Chinesas/uso terapêutico , Heptoses/uso terapêutico , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Regulação para Baixo , Medicamentos de Ervas Chinesas/farmacologia , Frutas , Glicerol , Heptoses/farmacologia , Mediadores da Inflamação/metabolismo , Rim/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Concentração Osmolar , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sódio/metabolismo , Superóxidos/metabolismo , Micção/efeitos dos fármacos
7.
J Pharm Pharmacol ; 61(5): 653-61, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19406005

RESUMO

OBJECTIVES: We investigated the lipid-lowering activity of 7-O-galloyl-D-sedoheptulose, an active component of Corni Fructus, and related mechanisms. METHODS: Rats were fed a high-fructose diet for 6 days, followed by treatment with 7-O-galloyl-D-sedoheptulose, 5, 10 or 20 mg/kg per day, or fenofibrate (positive control). KEY FINDINGS: The high-fructose diet induced an increase in body weight, hypertriglyceridaemia, hyperglycaemia and hypertension. Administration of 7-O-galloyl-D-sedoheptulose significantly reduced the levels of triglyceride in the serum and liver (being more effective than fenofibrate) but did not lead to changes in liver weight or hepatic function, whereas fenofibrate increased the liver weight markedly. The preventive effect of 7-O-galloyl-D-sedoheptulose against the accumulation of triglyceride and cholesterol was related to the up-regulation of peroxisome proliferator-activated receptor alpha expression. CONCLUSIONS: The present study supports the role of 7-O-galloyl-D-sedoheptulose as a promising agent against hypertriglyceridaemia without hepatic side-effects.


Assuntos
Cornus/química , Heptoses/isolamento & purificação , Heptoses/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Colesterol/sangue , Colesterol/metabolismo , Dieta , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Frutose/administração & dosagem , Heptoses/farmacologia , Hipolipemiantes/farmacologia , Fígado/metabolismo , Masculino , PPAR alfa/metabolismo , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Triglicerídeos/sangue , Triglicerídeos/metabolismo
8.
Cancer Lett ; 37(1): 33-9, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3664450

RESUMO

Administration of mannoheptulose partially protected mice infected with Listeria monocytogenes against the lethal effect of a subsequent endotoxin challenge. The ability of these animals to produce tumour necrosis factor was however unaffected. Mannoheptulose was observed to reverse the hypoglycaemic effect of endotoxin, possibly through inhibition of insulin secretion. The therapeutic significance of these observations is discussed.


Assuntos
Antitoxinas/uso terapêutico , Heptoses/uso terapêutico , Manoeptulose/uso terapêutico , Choque Séptico/prevenção & controle , Fator de Necrose Tumoral alfa/metabolismo , Animais , Hipoglicemia/prevenção & controle , Lipopolissacarídeos/toxicidade , Listeriose/prevenção & controle , Masculino , Camundongos
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