RESUMEN
Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer's disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses ß-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.
Asunto(s)
Envejecimiento/efectos de los fármacos , Crassulaceae/química , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Humanos , Longevidad/efectos de los fármacos , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Gastrodiae Rhizoma (Tianma), the dried tuber of Gastrodia elata Bl. (Orchidaceae), is listed as a top-grade herbal medicine in Shen-nong Ben-ts'ao Jing and has been used for treating headaches, dizziness, vertigo and convulsion. It has a neuroprotective effect and extends the lifespan in mouse models of Huntington's disease and Niemann-Pick type C disease. However, its effect on senescence remains unknown. PURPOSE: This study aimed to investigate the anti-aging effects and the underlying mechanism of Gastrodiae Rhizoma. METHODS: D-galactose (D-gal)- and BeSO4-induced cellular senescence and senescence-associated ß-galactosidase (SA-ß-gal) activity were evaluated in SH-SY5Y and PC12 cells. D-gal-induced aging mice were used as an in vivo model. Animal behaviors including nesting and burrowing and Morris water maze were conducted. Neurogenesis in the hippocampus was assessed by immunohistochemistry and confocal microscopy, and the aging-related proteins were assessed by Western blot analysis. The potential neuritogenesis activity of the partially purified fraction of Gastrodiae Rhizoma (TM-2) and its major ingredients were investigated in PC12 cells. RESULTS: TM-2 could improve D-gal-induced learning and memory impairement by inhibiting oxidative stress, increasing hippocampal neurogenesis and regulating the SH2B1-Akt pathway. Moreover, N6-(4-hydroxybenzyl)adenine riboside (T1-11) and parishins A and B, three constituents of TM-2, had anti-aging activity, as did T1-11 and parishin A induced neuritogenesis. CONCLUSION: Our data suggested that TM-2 slowed down D-gal-induced cellular and mouse brain aging. These results indicate that Gastrodiae Rhizoma has a beneficial effect on senescence. It may be used for neuroprotection and promoting neurogenesis.
Asunto(s)
Envejecimiento/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Gastrodia/química , Hipocampo/efectos de los fármacos , Rizoma/química , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Galactosa , Hipocampo/citología , Hipocampo/fisiología , Masculino , Ratones , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Células PC12 , RatasRESUMEN
Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.
Asunto(s)
Acridinas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Acetilcolinesterasa/metabolismo , Acridinas/síntesis química , Acridinas/química , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Ratones , Estructura Molecular , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-ß. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Anticipación Psicológica/efectos de los fármacos , Dieta de Carga de Carbohidratos/efectos adversos , Ingestión de Alimentos/psicología , Hipotálamo/metabolismo , Leptina/metabolismo , Transducción de Señal/efectos de los fármacos , Sacarosa/efectos adversos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Animales , Inflamación , Ratones Transgénicos , Factor de Transcripción STAT3/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common type of dementia and also one of the leading causes of death worldwide. However, the underlying mechanisms remain unclear, and currently there is no drug treatment that can prevent or cure AD. Here, we have applied the advantages of using induced pluripotent stem cell (iPSC)-derived neurons (iNs) from AD patients, which are able to offer human-specific drug responsiveness, in order to evaluate therapeutic candidates for AD. Using approach involving an inducible neurogenin-2 transgene, we have established a robust and reproducible protocol for differentiating human iPSCs into glutamatergic neurons. The AD-iN cultures that result have mature phenotypic and physiological properties, together with AD-like biochemical features that include extracellular ß-amyloid (Aß) accumulation and Tau protein phosphorylation. By screening using a gene set enrichment analysis (GSEA) approach, Graptopetalum paraguayense (GP) has been identified as a potential therapeutic agent for AD from among a range of Chinese herbal medicines. We found that administration of a GP extract caused a significantly reduction in the AD-associated phenotypes of the iNs, including decreased levels of extracellular Aß40 and Aß42, as well as reduced Tau protein phosphorylation at positions Ser214 and Ser396. Additionally, the effect of GP was more prominent in AD-iNs compared to non-diseased controls. These findings provide valuable information that suggests moving extracts of GP toward drug development, either for treating AD or as a health supplement to prevent AD. Furthermore, our human iN-based platform promises to be a useful strategy when it is used for AD drug discovery.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/genética , Crassulaceae/química , Fragmentos de Péptidos/genética , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/efectos de los fármacos , Descubrimiento de Drogas , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Neuronas/patologíaRESUMEN
BACKGROUND: Boschniakia rossica is a well-known traditional Chinese medicine for tonifying kidney and improving impotence. Boschnaloside is the major iridoid glycoside in this herb but therapeutic benefits for diabetes remained to be evaluated. HYPOTHESIS/PURPOSE: The current investigation aims to study the antidiabetic effect and the underlying pharmacological mechanisms. STUDY DESIGN AND METHODS: Receptor binding, cAMP production, Ins secretion, glucagon-like peptide 1 (GLP-1) secretion, and dipeptidyl peptidase-4 activity assays were performed. Therapeutic benefits of orally administrated boschnaloside (150 and 300â¯mg/kg/day) were evaluated using severely 12-week old female diabetic db/db mice (Hemoglobin A1c >10%). RESULTS: Oral treatment of boschnaloside for 4 weeks improved diabetic symptoms including fasting blood sugar, hemoglobin A1c, glucose intolerance, and Homeostatic Model Assessment of Ins Resistance, accompanied by circulating GLP-1active and adiponectin levels. In addition, bochnaloside treatment improved islet/ß cell function associated with an alteration of the pancreatic and duodenal homeobox 1 level. It was shown that boschnaloside interacted with the extracellular domain of GLP-1 receptor and enhanced glucose stimulated Ins secretion. Boschnaloside also augmented the insulinotropic effect of GLP-1. Finally, the presence of boschnaloside caused a reduction of dipeptidyl peptidase-4 activity while enhanced GLP-1 secretion from STC-1 cells. CONCLUSION: It appears that bochnaloside at oral dosage greater than 150â¯mg/kg/day exerts antidiabetic effects in vivo through modulating the action of GLP-1.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Iridoides/farmacología , Administración Oral , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Femenino , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Trastornos del Metabolismo de la Glucosa/tratamiento farmacológico , Trastornos del Metabolismo de la Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/administración & dosificación , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Iridoides/administración & dosificación , Ratones , Orobanchaceae/química , Plantas Medicinales/química , RatasRESUMEN
Ischemic stroke is one of the most common causes of death worldwide and is a major cause of acquired disability in adults. However, there is still a need for an effective drug for its treatment. Buyang Huanwu decoction (BHD), a traditional Chinese medicine (TCM) prescription, has long been used clinically to aid neurological recovery after stroke. To establish potential clinical indicators of BHD efficacy in stroke treatment and prognosis, we conducted a combined proteomic and metabolomic analysis of cerebrospinal fluid (CSF) samples in a mouse stroke model. CSF samples were obtained from male mice with acute ischemic stroke induced by middle cerebral ischemic/reperfusion (CI/R) injury, some of which were then treated with BHD. Label-free quantitative proteomics was conducted using nano-LC-MS/MS on an LTQ Orbitrap mass and metabolomic analysis was performed using nanoprobe NMR and UHPLC-QTOF-MS. The results showed that several proteins and metabolites were present at significantly different concentrations in the CSF samples from mice with CI/R alone and those treated with BHD. These belonged to pathways related to energy demand, inflammatory signaling, cytoskeletal regulation, Wnt signaling, and neuroprotection against neurodegenerative diseases. In conclusion, our in silico data suggest that BHD treatment is not only protective but can also ameliorate defects in pathways affected by neurological disorders. These data shed light on the mechanism whereby BHD may be effective in the treatment and prevention of stroke-related neurodegenerative disease.
Asunto(s)
Isquemia Encefálica/líquido cefalorraquídeo , Isquemia Encefálica/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Accidente Cerebrovascular/líquido cefalorraquídeo , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Proteínas del Líquido Cefalorraquídeo/metabolismo , Modelos Animales de Enfermedad , Masculino , Medicina Tradicional China , Redes y Vías Metabólicas , Metabolómica , Ratones , Ratones Endogámicos ICR , Proteómica , Daño por Reperfusión/líquido cefalorraquídeo , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Hericium erinaceus was used in traditional Chinese medicine for physiologically beneficial medicines. Recently, it has become a candidate in causing positive brain health-related activities. We previously reported that Hericium erinaceus mycelium ameliorates Alzheimer's disease (AD)-related pathologies. To reveal the role of the cyanthin diterpenoid and sesterterpene constituents on this effects, erinacine A and S were isolated and their effects on attenuating AD-related pathology in APPswe/PS1dE9 transgenic mice were investigated. A 30 day short-term administration of erinacine A and S were performed to explore the effect of each erinacine on AD-related pathology including amyloid ß production and degradation, plaque formation, plaque growth, glial activation and neurogenesis deterioration. Our results indicated the benefit effects of both erinacine A and S in cerebrum of APPswe/PS1dE9 mice, including: (1) attenuating cerebral plaque loading by inhibiting plaque growth; (2) diminishing the activation of glial cells; (3) raising the level of insulin degrading enzyme; and (4) promoting hippocampal neurogenesis. Moreover, erinacine A reduced the level of insoluble amyloid ß and C-terminal fragment of amyloid precursor protein which was not mediated by erinacine S. We further performed a long term administration of erinacine A and found that erinacine A recovered the impairment in the tasks including burrowing, nesting, and Morris water maze. Our data pointed out that although both erinacine A and S reduce AD pathology via reducing amyloid deposition and promoting neurogenesis, erinacine A can also inhibit amyloid ß production and is worth to be further developed for AD therapeutic use.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Neurogénesis/efectos de los fármacos , Placa Amiloide/tratamiento farmacológico , Agregación Patológica de Proteínas/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Animales , Basidiomycota/química , Diterpenos/administración & dosificación , Diterpenos/química , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Humanos , Insulisina/genética , Ratones , Ratones Transgénicos , Micelio/química , Neuroglía/efectos de los fármacos , Oligopéptidos/genética , Placa Amiloide/genética , Placa Amiloide/patología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Sesterterpenos/administración & dosificación , Sesterterpenos/químicaRESUMEN
Astragalus membranaceus is commonly used in traditional Chinese medicine for strengthening the host defense system. Astragalus membranaceus-polysaccharides is an effective component with various important bioactivities, such as immunomodulation, antioxidant, anti-diabetes, anti-inflammation and neuroprotection. In the present study, we determine the effects of Astragalus membranaceus-polysaccharides on metabolically stressed transgenic mice in order to develop this macromolecules for treatment of sporadic Alzheimer's disease, a neurodegenerative disease with metabolic risk factors. Transgenic mice, at 10 weeks old prior to the appearance of senile plaques, were treated in combination of administrating high-fat diet and injecting low-dose streptozotocin to create the metabolically stressed mice model. Astragalus membranaceus-polysaccharides was administrated starting at 14 weeks for 7 weeks. We found that Astragalus membranaceus-polysaccharides reduced metabolic stress-induced increase of body weight, insulin and insulin and leptin level, insulin resistance, and hepatic triglyceride. Astragalus membranaceus-polysaccharides also ameliorated metabolic stress-exacerbated oral glucose intolerance, although the fasting blood glucose was only temporally reduced. In brain, metabolic stress-elicited astrogliosis and microglia activation in the vicinity of plaques was also diminished by Astragalus membranaceus-polysaccharides administration. The plaque deposition, however, was not significantly affected by Astragalus membranaceus-polysaccharides administration. These findings suggest that Astragalus membranaceus-polysaccharides may be used to ameliorate metabolic stress-induced diabesity and the subsequent neuroinflammation, which improved the behavior performance in metabolically stressed transgenic mice.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Astragalus propinquus/química , Disfunción Cognitiva/tratamiento farmacológico , Hígado Graso/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Polisacáridos/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Hígado Graso/metabolismo , Femenino , Masculino , Ratones , Obesidad/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated. MATERIALS AND METHOD: The animal model of AD with metabolic stress was created by administrating high-fat diet and a low-dose injection of streptozotocin prior to the appearance of senile plaques in APP/PS1 transgenic mice. The diabesity-associated metabolic changes and AD-related pathological alterations were examined. RESULTS: We found that XZD reduced body weight, insulin and leptin level, HOMA-IR, hepatic triglyceride, serum Aß42 in the metabolic stressed AD animal. XZD also ameliorated oral glucose tolerant, Aß deposition, astrocyte and microglia activation in the vicinity of plaques, and nesting behavior in the metabolic stressed AD animal. CONCLUSION: The results of this study suggest that XZD is able to reduce the peripheral metabolic stress-mediated vascular hypoperfusion, neuroinflammation and AD-related pathology in APP/PS1 mice.
Asunto(s)
Amiloide/metabolismo , Disfunción Cognitiva/prevención & control , Medicamentos Herbarios Chinos/farmacología , Hígado Graso/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Glucemia/efectos de los fármacos , Homeostasis , Insulina/sangre , Resistencia a la Insulina , Leptina/sangre , Masculino , Ratones , Ratones Transgénicos , Estrés Fisiológico , Triglicéridos/metabolismoRESUMEN
Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA) is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR) injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877), 1.71% (15/877), and 2.62% (23/877) of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood-brain barrier (BBB) (Alb, Fga, and Trf), suppressed excitotoxicity (Grm5, Gnai, and Gdi), and enhanced energy metabolism (Bdh), thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3) and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Proteómica/métodos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Animales , Western Blotting , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos ICR , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Microglial inflammation may significantly contribute to the pathology of Alzheimer's disease. To examine the potential of Cudrania cochinchinensis to ameliorate amyloid ß protein (Aß)-induced microglia activation, BV-2 microglial cell line, and the ramified microglia in the primary glial mixed cultured were employed. RESULTS: Lipopolysaccharide (LPS), Interferon-γ (IFN-γ), fibrillary Aß (fAß), or oligomeric Aß (oAß) were used to activate microglia. LPS and IFN-γ, but not Aßs, activated BV-2 cells to produce nitric oxide through an increase in inducible nitric oxide synthase (iNOS) expression without significant effects on cell viability of microglia. fAß, but not oAß, enhanced the IFN-γ-stimulated nitric oxide production and iNOS expression.The ethanol/water extracts of Cudrania cochinchinensis (CC-EW) and the purified isolated components (i.e. CCA to CCF) effectively reduced the nitric oxide production and iNOS expression stimulated by IFN-γ combined with fAß. On the other hand, oAß effectively activated the ramified microglia in mixed glial culture by observing the morphological alteration of the microglia from ramified to amoeboid. CC-EW and CCB effectively prohibit the Aß-mediated morphological change of microglia. Furthermore, CC-EW and CCB effectively decreased Aß deposition and remained Aß in the conditioned medium suggesting the effect of CC-EW and CCB on promoting Aß clearance. Results are expressed as mean ± S.D. and were analyzed by ANOVA with post-hoc multiple comparisons with a Bonferroni test. CONCLUSIONS: The components of Cudrania cochinchinensis including CC-EW and CCB are potential for novel therapeutic intervention for Alzheimer's disease.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Microglía/efectos de los fármacos , Moraceae/química , Extractos Vegetales/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Células Cultivadas , Interferón gamma/metabolismo , Microglía/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan as anti-inflammatory, promoting blood circulation and antidiabetes agent. Recent study also suggested its neuroprotective activity against Alzheimer's disease. Therefore, the effects of F. macrophylla on Aß production and degradation were studied. The effect of F. macrophylla on Aß metabolism was detected using the cultured mouse neuroblastoma cells N2a transfected with human Swedish mutant APP (swAPP-N2a cells). The effects on Aß degradation were evaluated on a cell-free system. An ELISA assay was applied to detect the level of Aß1-40 and Aß1-42. Western blots assay was employed to measure the levels of soluble amyloid precursor protein and insulin degrading enzyme (IDE). Three fractions of F. macrophylla modified Aß accumulation by both inhibiting ß-secretase and activating IDE. Three flavonoids modified Aß accumulation by activating IDE. The activated IDE pool by the flavonoids was distinctly regulated by bacitracin (an IDE inhibitor). Furthermore, flavonoid 94-18-13 also modulates Aß accumulation by enhancing IDE expression. In conclusion, the components of F. macrophylla possess the potential for developing new therapeutic drugs for Alzheimer's disease.
RESUMEN
Using an Abeta-induced neurotoxicity blocking assay to direct fractionation, three new flavonoids, fleminginin (1), flemingichromone (2), and flemingichalcone (3), and twenty known compounds were isolated from the active fractions of the aerial parts of Flemingia macrophylla. The structures of 1 - 3 were elucidated on the basis of spectroscopic data. When tested for neuroprotective activity, compound 2, osajin ( 4), 5,7,4'-trihydroxy-6,8-diprenylisoflavone (5), 5,7,4'-trihydroxy-6,3'-diprenylisoflavone (6), and aureole (7) protected neuronal cells from Abeta-induced damage with EC50 values of 31.43 +/- 3.16, 5.01 +/- 1.28, 11.25 +/-1.51, 4.47 +/- 0.65, 12.09 +/- 2.55 microM, respectively.
Asunto(s)
Fabaceae , Fármacos Neuroprotectores/farmacología , Fitoterapia , Extractos Vegetales/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Animales , Células Cultivadas/efectos de los fármacos , Corteza Cerebral/citología , Flavonoides/administración & dosificación , Flavonoides/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Componentes Aéreos de las Plantas , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of nine polyphenolic compounds on glutamate-mediated toxicity were investigated. The underlying mechanisms by which a polyphenolic compound confers its effect were also elucidated. Treatment of cortical neurons with 50 microm glutamate for 24 h decreased cell viability by 45.8 +/- 7.9%, and 50 microm of tournefolic acid B methyl ester attenuated glutamate-induced cell death by 46.8 +/- 17.8%. Glutamate increased the activity of caspase 35.2-fold, and to a similar extent for caspase 2, 6, 8 and 9. Tournefolic acid B methyl ester abrogated glutamate-induced activation of caspase 2, 3, 6 and 9 by about 70%, and to a lesser extent for caspase 8. Treatment with glutamate for 1 h elevated reactive oxygen species (ROS) by 208.3 +/- 21.3%. Tournefolic acid B methyl ester eliminated the glutamate-induced accumulation of ROS. Glutamate increased the phosphorylation of p54-c-jun N-terminal kinase (JNK) concomitantly with activation of the endogenous antioxidant defense system. Tournefolic acid B methyl ester at 50 microm diminished the activity of p54-JNK in control and glutamate-treated cells, coinciding with the abolishment of the glutamate-triggered antioxidant defense system. Therefore, tournefolic acid B methyl ester blocked the activation of the caspase cascade, eliminated ROS accumulation and abrogated the activation of JNK, thereby conferring a neuroprotective effect on glutamate-mediated neurotoxicity.