Assuntos
Drosophila , Doença de Machado-Joseph , Animais , Etanol , Estresse Oxidativo , Micélio , Extratos Vegetais/farmacologiaRESUMO
Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.
Assuntos
Doença de Machado-Joseph , Animais , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/patologia , Camundongos , Camundongos Transgênicos , Peptídeos , Ubiquinona/análogos & derivadosRESUMO
Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid ß protein (Aß) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aß-induced neurotoxicity. However, whether RIN can prevent soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Aß1-42-related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Aß1-42-induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Aß1-42-induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca2+ overload contributed to the soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Aß1-42-induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B-NMDAR expression in the DG region, which inhibited Aß1-42-induced Ca2+ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD.
Assuntos
Transtornos da Memória/tratamento farmacológico , Oxindóis/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Aprendizagem Espacial/efeitos dos fármacos , Peptídeos beta-Amiloides/farmacologia , Animais , Giro Denteado/fisiologia , Regulação para Baixo/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxindóis/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/biossínteseRESUMO
A new periplogenin cardenolide, periplogulcoside (1), together with three known cardenolides, was isolated from the seeds of Antiaris toxicaria. The structure of the new compound was characterized as periplogenin-3-O-ß-D-glucopyranosyl-(1 â 4)-ß-D-glucopyranoside (1) by spectroscopic methods including 1D and 2D NMR, HR-TOF-MS, and CD spectrometry, and the known compounds were identified by comparison of their NMR and HR-TOF-MS data with those reported in the literature. Compound 1 showed significant cytotoxicity against Hela and HepG-2 cell lines.
Assuntos
Antiaris/química , Antineoplásicos Fitogênicos/isolamento & purificação , Cardenolídeos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cardenolídeos/química , Cardenolídeos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células HeLa , Células Hep G2 , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Extratos Vegetais/química , Sementes/químicaRESUMO
Because induction of phase II detoxification enzyme is important for chemoprevention, we study the effects of Indigofera suffruticosa Mill, a medicinal herb, on the expression of π class of glutathione S-transferase (GSTP) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in rat Clone 9 liver cells. Both water and ethanolic extracts of I. suffruticosa significantly increased the expression and enzyme activities of GSTP and NQO1. I. suffruticosa extracts up-regulated GSTP promoter activity and the binding affinity of nuclear factor erythroid 2-related factor 2 (Nrf2) with the GSTP enhancer I oligonucleotide. Moreover, I. suffruticosa extracts increased nuclear Nrf2 accumulation as well as ARE transcriptional activity. The level of phospho-ERK was augmented by I. suffruticosa extracts, and the ERK inhibitor PD98059 abolished the I. suffruticosa extract-induced ERK activation and GSTP and NQO-1 expression. Moreover, I. suffruticosa extracts, especially the ethanolic extract increased the glutathione level in mouse liver and red blood cells as well as Clone 9 liver cells. The efficacy of I. suffruticosa extracts in induction of phase II detoxification enzymes and glutathione content implies that I. suffruticosa could be considered as a potential chemopreventive agent.
Assuntos
Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Indução Enzimática/efeitos dos fármacos , Glutationa S-Transferase pi/biossíntese , Hepatócitos/efeitos dos fármacos , Indigofera/química , NAD(P)H Desidrogenase (Quinona)/biossíntese , Animais , Antioxidantes/isolamento & purificação , Células Clonais , Medicamentos de Ervas Chinesas/isolamento & purificação , Elementos Facilitadores Genéticos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Etnofarmacologia , Glutationa/sangue , Glutationa/metabolismo , Glutationa S-Transferase pi/química , Glutationa S-Transferase pi/genética , Glutationa S-Transferase pi/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oligonucleotídeos/metabolismo , Caules de Planta/química , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos , Elementos de Resposta/efeitos dos fármacosRESUMO
BACKGROUND: Coriandrum sativum is used not only as a spice to aid flavour and taste values in food, but also as a folk medicine in many countries. Since little is known about the anti-inflammatory ability of the aerial parts (stem and leaf) of C. sativum, the present study investigated the effect of aerial parts of C. sativum on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We further explored the molecular mechanism underlying these pharmacological properties of C. sativum. RESULTS: Ethanolic extracts from both stem and leaf of C. sativum (CSEE) significantly decreased LPS-induced nitric oxide and prostaglandin E(2) production as well as inducible nitric oxide synthase, cyclooxygenase-2, and pro-interleukin-1beta expression. Moreover, LPS-induced IkappaB-alpha phosphorylation and nuclear p65 protein expression as well as nuclear factor-kappaB (NF-kappaB) nuclear protein-DNA binding affinity and reporter gene activity were dramatically inhibited by aerial parts of CSEE. Exogenous addition of CSEE stem and leaf significantly reduced LPS-induced expression of phosphorylated mitogen-activated protein kinases (MAPKs). CONCLUSION: Our data demonstrated that aerial parts of CSEE have a strong anti-inflammatory property which inhibits pro-inflammatory mediator expression by suppressing NF-kappaB activation and MAPK signal transduction pathway in LPS-induced macrophages.
Assuntos
Anti-Inflamatórios/uso terapêutico , Coriandrum , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Coriandrum/química , Genes Reporter , Proteínas I-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B , Fitoterapia , Extratos Vegetais/farmacologia , Folhas de Planta , Caules de Planta , Sinaptotagmina I/metabolismoRESUMO
Propolis, which has been used widely in folk medicine, has been shown to exhibit various biological activities but its immunoregulatory and anti-inflammatory activities in intact animals have not been well studied. We investigated these activities of propolis using an ovalbumin-induced asthma animal model. Mice were immunized and sensitized by exposure to ovalbumin (OVA) antigen and administered with low- (65 mg/kg body weight) and high-dose (325 mg/kg body weight) propolis water extracts by tube feeding. The serum OVA-specific IgE titer and cytokine profiles in cultured splenocytes and bronchoalveolar lavage fluids (BALF) were analyzed. The number of eosinophils in BALF was counted. Here we demonstrate that propolis extracts can suppress the serum levels of OVA-specific IgE and IgG(1), and airway hyperresponsiveness (AHR) in OVA-sensitized mice. There are no significant differences in the concentration of eotaxin or the number of eosinophils in BALF among the four groups. However, the higher dose of propolis extracts decreases the level of IL-5 in BALF. The splenocytes from mice administered with propolis extracts (low- and high-dose groups) exhibit a strong inhibition of IL-10 secretion and up-regulation of IFN-gamma secretion in splenocytes stimulated with concanavalin A (ConA). In addition, cytokine (IFN-gamma, IL-6, and IL-10) secretion in OVA-stimulated splenocytes from the propolis groups was significantly lower than that in the control group. These results suggest that propolis extracts may be a potential novel therapeutic agent for asthma.