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Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 µM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP+-treated PC12 cells, CB6 inhibited cell apoptosis and increased cell viability by inducing autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg-1· d-1, for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD.
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Alcaloides , Fármacos Neuroprotectores , Enfermedad de Parkinson , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Alcaloides/farmacología , Animales , Autofagia , Fosfatidilinositol 3-Quinasas Clase III/farmacología , Neuronas Dopaminérgicas , Indoles , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/patología , Ratas , Compuestos de EspiroRESUMEN
The pharmacological activity of active ingredients from Chinese medicine depends greatly on the microecological environment of probiotics in the human body. After effective ingredients from traditional Chinese medicines are metabolized or biotransformed by probiotics, their metabolites can increase pharmacological activity, and can be absorbed more easily to improve the bioavailability. Therefore, the combination of Chinese medicines with probiotics is the innovation point in R&D of functional food and Chinese medicines, and also a new thinking for the modernization of Chinese medicine.This review summarizes and analyses the research progress on metabolism effects of gut microbiota on Chinese medicines components, the regulating effect of effective ingredients from Chinese medicine on intestinal probiotics, the application status of probiotics in traditional Chinese medicines, and the main problems and prospects in the research and development of Chinese medicines products with probiotic, aiming to provide theoretical guidance and practical value for the fermentation engineering of Chinese herbal medicine.
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Medicamentos Herbarios Chinos/metabolismo , Probióticos , Humanos , Medicina Tradicional ChinaRESUMEN
Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). These body fluids include urine; however, the relationship between, specifically, urinary metabolic phenotypes and PD is not fully understood. In this study, urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Our study revealed significant correlation between clinical phenotype and urinary metabolite profile. Metabolic profiles of idiopathic PD patients differed significantly and consistently from normal controls, with related metabolic pathway variations observed in steroidogenesis, fatty acid beta-oxidation, histidine metabolism, phenylalanine metabolism, tryptophan metabolism, nucleotide metabolism, and tyrosine metabolism. In the fruit fly Drosophila melanogaster, the alteration of the kynurenine pathway in tryptophan metabolism corresponded with pathogenic changes in the alpha-synuclein overexpressed Drosophila model of PD. The results suggest that LC-MS-based urinary metabolomic profiling can reveal the metabolite signatures and related variations in metabolic pathways that characterize PD. Consistent PD-related changes across species may provide the basis for understanding metabolic regulation of PD at the molecular level.
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Biomarcadores/orina , Metabolómica/métodos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/orina , Fenotipo , Animales , Cromatografía Liquida , Drosophila melanogaster , Ácidos Grasos/metabolismo , Histidina/metabolismo , Humanos , Quinurenina/metabolismo , Espectrometría de Masas , Nucleótidos/metabolismo , Fenilalanina/metabolismo , Esteroides/biosíntesis , Triptófano/metabolismo , Tirosina/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
We present a systematic review of existing research that aims to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (OM), mainly comprised of cholinesterase inhibitors, for vascular dementia (VaD). We included 47 studies conducted in mainland China, each testing different HM. Of 43 HM monotherapy studies, 37 reported HM to be significantly better than OM or placebo; six reported similar efficacy between HM and OM. All four HM adjuvant studies reported significant efficacy. No major adverse events for HM were reported. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies suggested that HM can be a safe and effective treatment for VaD, either alone or in conjunction with OM. However, methodological flaws in the design of the studies limited the extent to which the results could be interpreted. Thirty most commonly used herbal constituents, including Rhizoma Chuanxiong (Chuanxiong in Chinese), Radix Polygoni Multiflori (Heshouwu in Chinese) and Radix Astragali (Huangqi in Chinese). were ranked. Further multi-center trials with large sample sizes, high methodological quality and standardized HM ingredients are necessary for clinical recommendations to be made.
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Abnormal protein aggregation in the brain is linked to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of α-synuclein (α-syn), we systematically compared the antioligomeric and antifibrillar activities of eight compounds that were extracted from Chinese herbal medicines through three platforms that can monitor the formation of α-syn fibrils and oligomers in cell-free or cellular systems. Our results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis Georgi ("huang qin" in Chinese), is a potent inhibitor of α-syn oligomerisation both in cell-free and cellular systems, and is also an effective inhibitor of α-syn fibrillation in cell-free systems. We further tested the protective effect of baicalein against α-syn-oligomer-induced toxicity in neuronal cells. Our data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-ß peptide (Aß) aggregation and toxicity. We found that baicalein can also inhibit Aß fibrillation and oligomerisation, disaggregate pre-formed Aß amyloid fibrils and prevent Aß fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. Given the role of these processes in neurodegenerative diseases such as AD and PD, our results suggest that baicalein has potential as a therapeutic agent for the treatment of these devastating disorders.
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Medicamentos Herbarios Chinos/química , Inhibidores Enzimáticos , Flavanonas/química , Flavanonas/farmacología , alfa-Sinucleína/antagonistas & inhibidores , Amiloide/biosíntesis , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Medicamentos Herbarios Chinos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Estructura Molecular , alfa-Sinucleína/químicaRESUMEN
OBJECTIVE: To observe the antitussive and antiasthmatic effects of Radix Fici Hirtae (RFH). METHODS: Antitussive effects were observed by ammonia water steaming test in mice and by citric acid test in guinea pigs. Antiasthmatic actions in guinea pigs were observed by histamine and acetylcholine ultrasonic atomization test, involved isolated guinea pig tracheal smoth muscle experiment and anaphylactic shock of guinea pigs. RESULTS: RFH decreased the frequency of cough induced by ammonia in mice and by citric acid in guinea pig, prolonged the latent period of cough and inhibited the experimental asthma by histamine and acetylcholine solution in conscious guinea pigs, antagonisted the contraction of tracheal smooth muscle by histamine phosphate in guinea pigs and could compete anaphylactic shock in guinea pigs. CONCLUSION: RFH has obvious antitussive and antiasthmatic effects.
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Antitusígenos/uso terapéutico , Tos/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Expectorantes/uso terapéutico , Moraceae , Acetilcolina/administración & dosificación , Anafilaxia/inducido químicamente , Anafilaxia/tratamiento farmacológico , Animales , Antitusígenos/administración & dosificación , Antitusígenos/farmacología , Asma/inducido químicamente , Asma/tratamiento farmacológico , Astragalus propinquus/química , Ácido Cítrico/administración & dosificación , Tos/inducido químicamente , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Expectorantes/administración & dosificación , Expectorantes/farmacología , Femenino , Cobayas , Histamina , Masculino , Ratones , Moraceae/química , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Fitoterapia , Raíces de Plantas/química , Distribución Aleatoria , Tráquea/efectos de los fármacosRESUMEN
6-OHDA plus ascorbic acid (AA) has long been used to induce Parkinson's disease in rodents, while only 6-OHDA is commonly used to induce cell damage in cellular PD models. AA was believed to act as an anti-oxidant to prevent the degradation of 6-OHDA; however, some studies suggested that AA dramatically enhanced the selectivity and toxicity of 6-OHDA. To understand the mechanisms by which 6-OHDA/AA induces cell death, we established a 6-OHDA/AA cell toxicity model in human dopaminergic neuroblastoma SH-SY5Y cells. We confirmed that the toxicity of 6-OHDA was dramatically increased in the presence of AA, and the toxicity can be prevented by a flavonoid, baicalein. Mechanistically, our research reveals that 6-OHDA/AA induces cell death mainly through the interruption of intracellular calcium homeostasis, which leads to calpain activation and mitochondrial damage. Baicalein prevents 6-OHDA/AA-induced intracellular calcium elevation as well as consequent mitochondria damage. Taken together, our study confirms that 6-OHDA/AA is a more sensitive model for inducing neuronal lesion in vitro and reveals the central role of intracellular calcium in 6-OHDA/AA-induced cell death. Our studies further show that baicalein prevents 6-OHDA/AA-induced cell death by inhibiting intracellular calcium elevation.
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Adrenérgicos/toxicidad , Ácido Ascórbico/toxicidad , Hormonas y Agentes Reguladores de Calcio/toxicidad , Muerte Celular/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Flavanonas/metabolismo , Oxidopamina/toxicidad , Calcio/metabolismo , Calpaína/metabolismo , Línea Celular , Neuronas Dopaminérgicas/fisiología , Homeostasis , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
Nonmotor symptoms (NMS) of Parkinson's disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I-IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (p = 0.019), mood/cognition (p = 0.005), and reduction in hallucinations (p = 0.024). In addition, post hoc analysis showed a significant reduction in constipation (p < 0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score (p = 0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation.
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BACKGROUND: Tianma-Gouteng-Yin (TGY), which is common Chinese medicine formulation consisting of 11 different herbs and being used in China for the treatment of Parkinson's disease, inflammatory conditions and cardiovascular diseases, was selected for full component analysis. The aim of this study was to quantitatively analyze the chemical profiles of ten commercial TGY samples and one sample produced in our laboratory. METHODS: Ultra-high performance liquid chromatography (UHPLC) coupled with quadrupole-tandem time-of-flight mass spectrometry (Q-TOF-MS) was used to analyze the non-saccharide small molecule components of the different TGY samples. The established method was validated in terms of its linearity, sensitivity, precision, accuracy and stability. High performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) was also used to quantify three major saccharides (fructose, glucose and sucrose). RESULTS: The relative standard deviations for the precision, repeatability and stability of these compounds were less than 5 %, while the accuracy of the method was 95-105 %. Twenty-eight of the compounds found in TGY were successfully identified, with 20 being quantified. The macromolecules present in these samples were also identified using an ethanol precipitation method, representing 294.68-696.64 mg/g of the total material depending on the batch. Notably, the components identified using this method represented up to 78 % of the total weight of the TGY samples. CONCLUSIONS: The developed UHPLC/Q-TOF-MS and HPLC-ELSD methods successfully identified 28 of the complex compounds found in TGY.
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Autophagy dysfunction is a common feature in neurodegenerative disorders characterized by accumulation of toxic protein aggregates. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models. Currently known TFEB activators are mainly inhibitors of MTOR (mechanistic target of rapamycin [serine/threonine kinase]), which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions. Thus, the identification of TFEB modulators acting without inhibiting the MTOR pathway would be preferred and probably less deleterious to cells. In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR-independent activator of TFEB. Compound C1 specifically binds to TFEB at the N terminus and promotes TFEB nuclear translocation without inhibiting MTOR activity. By activating TFEB, C1 enhances autophagy and lysosome biogenesis in vitro and in vivo. Collectively, compound C1 is an orally effective activator of TFEB and is a potential therapeutic agent for the treatment of neurodegenerative diseases.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Curcumina/química , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Células HeLa , Humanos , Lisosomas/metabolismo , Masculino , Ratones , Enfermedades Neurodegenerativas/metabolismo , Fosforilación , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. In addition, the neuroprotective effect of TGY was also evaluated in the human dopaminergic neuroblastoma SH-SY5Y cell line treated with rotenone and the rotenone intoxicated hemi-parkinsonian rats. In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. Conclusively, TGY is neuroprotective in PD models both in vivo and in vitro.
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Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional China , Fármacos Neuroprotectores/farmacología , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Recuento de Células , Línea Celular Tumoral , Cromatografía Liquida , Modelos Animales de Enfermedad , Dopamina/metabolismo , Drosophila , Antagonismo de Drogas , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Humanos , Masculino , Espectrometría de Masas , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Ratas , Rotenona/farmacología , alfa-Sinucleína/metabolismoRESUMEN
Pre-harvest desiccation may increase the efficiency of seed production. Field studies were conducted to determine the effects of diquat, paraquat, and ethephon applications on grain moisture, grain weight, and seed germination of hybrid rice Yanliangyou 88 (Oryza sativa ssp. indica) and conventional rice Wuyunjing 7 (Oryza sativa ssp. japonica). In 2013, we tested 12 treatments applied at four weeks (Yanliangyou 88) and six weeks (Wuyunjing 7) after heading. Results showed that reductions in moisture content were significant two and four days after chemical application. Chemical applications had no adverse effects on 1000-grain weight, germination percentage, or germination index, but there were negative effects on the percentage of normal seedlings. Desiccation effects increased with increase in the period after application, while the effect of ethephon combined with diquat or paraquat on desiccation was limited compared with that of diquat or paraquat alone in a short period after application. In 2013, chemical applications reduced the moisture content by from 0.5% to 6.4%, the germination percentage by from 0% to 3.3%, and the percentage of normal seedlings by from 13.3% to 100.0%. Among the treatments, diquat applied at 120 g/ha resulted in effective desiccation with fewer negative effects on grain weight and seed germination in 2013 and 2014. Therefore, diquat may have potential as a pre-harvest chemical desiccation treatment for rice. These results may provide a basis for developing and implementing protocols for large scale field trials.
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Desecación/métodos , Germinación/fisiología , Herbicidas/administración & dosificación , Oryza/efectos de los fármacos , Oryza/crecimiento & desarrollo , Semillas/crecimiento & desarrollo , Análisis de los Alimentos , Germinación/efectos de los fármacos , Semillas/efectos de los fármacosRESUMEN
Urine metabolic phenotyping has been associated with the development of Parkinson's disease (PD). However, few studies using a comprehensive metabolomics approach have investigated the correlation between changes in the urinary markers and the progression of clinical symptoms in PD. A comprehensive metabolomic study with robust quality control procedures was performed using gas chromatography - mass spectrometry (GC - MS) and liquid chromatography - mass spectrometry (LC - MS) to characterize the urinary metabolic phenotypes of idiopathic PD patients at three stages (early, middle and advanced) and normal control subjects, with the aim of discovering potential urinary metabolite markers for the diagnosis of idiopathic PD. Both GC-MS and LC-MS metabolic profiles of idiopathic PD patients differed significantly from those of normal control subjects. 18 differentially expressed metabolites were identified as constituting a unique metabolic marker associated with the progression of idiopathic PD. Related metabolic pathway variations were observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism. Comprehensive, successive metabolomic profiling revealed changes in the urinary markers associated with progression of idiopathic PD. This profiling relies on noninvasive sampling, and is complementary to existing clinical modalities.
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Biomarcadores/orina , Metaboloma , Metabolómica , Enfermedad de Parkinson/patología , Adulto , Anciano , Anciano de 80 o más Años , Aminoácidos/metabolismo , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Análisis Discriminante , Progresión de la Enfermedad , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Determine the efficacy and safety of classic Chinese medicine formula Ditan Decoction (, DTD) for the treatment of Alzheimer's disease (AD) by reviewing the methods and results reported in laboratory and clinical studies in order to suggest strategies for developing more effective drugs for AD. METHODS: Embase (OVID) and China Journal Net (CJN) were searched for articles published between 1947 to November 2011 and 1915 to November 2011 respectively. Articles that fulfilled the inclusion criteria and did not meet the exclusion criteria were collected and compared in terms of research method, interventions and outcomes. RESULTS: No articles were found in Embase (OVID); 8 were found in CJN (4 laboratory studies; 4 clinical studies). The laboratory studies showed that memory impairment of AD mice models were significantly improved by DTD. The clinical studies showed that Chinese medicine which include DTD, can also relieve the memory impairment of AD patients, however, the data about the exactly effectiveness of DTD was inconclusive. CONCLUSIONS: All the clinical trials have not been fully designed yet. The evidences for recommending DTD in clinical practice were methodologically flawed. Rigid randomization in controlled clinical trials of DTD with adequate blinding and rating methods are highly recommended.
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SNCA/α-synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease (PD). Wild-type (WT) SNCA has been shown to impair macroautophagy in mammalian cells and in transgenic mice. In this study, we monitored the dynamic changes in autophagy process and confirmed that overexpression of both WT and SNCA(A53T) inhibits autophagy in PC12 cells in a time-dependent manner. Furthermore, we showed that SNCA binds to both cytosolic and nuclear high mobility group box 1 (HMGB1), impairs the cytosolic translocation of HMGB1, blocks HMGB1-BECN1 binding, and strengthens BECN1-BCL2 binding. Deregulation of these molecular events by SNCA overexpression leads to autophagy inhibition. Overexpression of BECN1 restores autophagy and promotes the clearance of SNCA. siRNA knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of SNCA on autophagy while overexpression of HMGB1 restores autophagy. Corynoxine B, a natural autophagy inducer, restores the deficient cytosolic translocation of HMGB1 and autophagy in cells overexpressing SNCA, which may be attributed to its ability to block SNCA-HMGB1 interaction. Based on these findings, we propose that SNCA-induced impairment of autophagy occurs, in part, through HMGB1, which may provide a potential therapeutic target for PD.
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Alcaloides/farmacología , Autofagia/efectos de los fármacos , Proteína HMGB1/metabolismo , alfa-Sinucleína/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Supervivencia Celular , Citosol/efectos de los fármacos , Citosol/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Alcaloides Indólicos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Modelos Biológicos , Proteínas Mutantes/metabolismo , Células PC12 , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Ratas , Factores de TiempoRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the autophagy-lysosomal system has been linked to its accumulation. In our previous study, we identified an oxindole alkaloid Corynoxine B (Cory B), isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy inducer. In this work, we show that Cory, an enantiomer of Cory B, also induces autophagy in different neuronal cell lines, including N2a and SHSY-5Y cells, which is paralleled with increased lysosomal enzyme cathepsin D. In vivo, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T α-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduction in the levels of phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. Collectively, our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine, which may have potential application in the prevention or treatment of PD.
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Alcaloides/farmacología , Autofagia/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , alfa-Sinucleína/metabolismo , Animales , Animales Modificados Genéticamente , Autofagia/fisiología , Línea Celular Tumoral , Drosophila , Humanos , Alcaloides Indólicos , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiologíaRESUMEN
Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-ß (Aß) accumulation in an Alzheimer's disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-ß precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPß-Swedish and reduced the generation of Aß peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aß- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aß production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aß plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aß. Further study of HLJDT-M for therapeutic use in treating AD is warranted.
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Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Procesamiento Proteico-Postraduccional , Enfermedad de Alzheimer/patología , Animales , Berberina/farmacología , Berberina/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Flavanonas/farmacología , Flavanonas/uso terapéutico , Humanos , Espacio Intracelular/metabolismo , Ratones Transgénicos , Mutación/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Procesamiento Proteico-Postraduccional/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The 15 herbs for the screening have been traditionally used in Ayurvedic medicine or in Traditional Chinese medicine (TCM) for the treatment of cognitive disorders clinically. AIM OF THE STUDY: Fifteen plant species were investigated for the inhibition of amyloid peptide (Aß) production and modulation of amyloid precursor protein (APP) processing. MATERIALS AND METHODS: The selected plants were extracted successively with 70% ethyl alcohol and absolute alcohol concentrated with rotary evaporation then lyophilized. Using a mouse neuroblastoma cells expressing Swedish APP (N2a-SweAPP), MTT assay was performed to determine the toxicity concentration of each herbal extract. In order to evaluate the activity of ethanol extracts on Aß inhibition, the N2a-SweAPP cells were treated with a high and low dosage of different extracts for 24h, Aßs levels in the supernatant of conditioned media were assessed by ELISA. The most active extracts were then subjected to test the effect on APP modulation in N2a-SweAPP cells by determining their effect on sAPPα and sAPPß through western blot analysis. RESULTS: Among the screened herbal extracts, only Polygonum multiflorum Thunb. (root) and Convolvulus pluricaulis Choisy. (leaves) showed profound inhibition of Aß production. MTT assay demonstrated that the anti-Aß effect of these extracts was not a sequential consequence of their cytotoxicity. The extract of Polygonum multiflorum Thunb. (root) could reduce Aß production only through APP modulation, which was exhibited together with the up-regulation of sAPPα and down-regulation of sAPPß. CONCLUSION: The results show that extract of Polygonum multiflorum Thunb. (root) can lower Aß generation by modulating APP processing in the N2a-SwedAPP cell line. These results corroborate the traditional use of Polygonum multiflorum Thunb. (root) for the treatment of cognitive disorders including Alzheimer's disease (AD).
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Precursor de Proteína beta-Amiloide/metabolismo , Convolvulus , Medicamentos Herbarios Chinos/farmacología , Medicina Ayurvédica , Medicina Tradicional China , Memoria/efectos de los fármacos , Neuronas/efectos de los fármacos , Nootrópicos/farmacología , Polygonum , Withania , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Convolvulus/química , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/toxicidad , Ensayo de Inmunoadsorción Enzimática , Etanol/química , Ratones , Mutación , Neuronas/metabolismo , Nootrópicos/aislamiento & purificación , Nootrópicos/toxicidad , Hojas de la Planta , Raíces de Plantas , Plantas Medicinales , Polygonum/química , Procesamiento Proteico-Postraduccional , Solventes/química , Transfección , Withania/químicaRESUMEN
Accumulation of α-synuclein (α-syn) in the brain is a pathogenic feature and also a causative factor of Parkinson disease. Isorhynchophylline (IsoRhy) is a major tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.)Jacks (Gouteng in Chinese), which has been used for the treatment of neurological diseases in East Asia for centuries. Here we report a novel function of IsoRhy as a neuronal autophagy inducer. IsoRhy induced autophagy in different neuronal cell lines, including N2a, SH-SY5Y and PC12 cells, and also in primary cortical neurons. Furthermore, IsoRhy induced autophagy in the fat bodies of Drosophila. IsoRhy promoted clearance of wild-type, A53T and A30P α-syn monomers, α-syn oligomers and α-syn/synphilin-1 aggresomes in neuronal cells via the autophagy-lysosome pathway. More importantly, IsoRhy was able to decrease the expression levels of wild-type and A53T α-syn protein in differentiated human dopaminergic neurons. Notably, IsoRhy-induced autophagy was independent of the mTOR pathway but dependent on the function of Beclin 1. Taken together, data from this study raise the possibility that oxindole alkaloid derivatives may serve as a means to stimulate autophagy in neuronal cells, thereby exerting preventive and therapeutic values against neurodegenerative diseases such as Parkinson disease by reducing pathogenic protein aggregates in neurons.
Asunto(s)
Autofagia/efectos de los fármacos , Alcaloides Indólicos/farmacología , Neuronas/citología , Neuronas/metabolismo , Proteolisis/efectos de los fármacos , alfa-Sinucleína/metabolismo , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Drosophila melanogaster/citología , Células Madre Embrionarias/citología , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Cuerpo Adiposo/citología , Cuerpo Adiposo/efectos de los fármacos , Cuerpo Adiposo/metabolismo , Humanos , Alcaloides Indólicos/química , Larva/citología , Larva/efectos de los fármacos , Larva/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Neuronas/efectos de los fármacos , Oxindoles , Ratas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The accumulation of ß-amyloid (Aß) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble ß-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.