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The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aß) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aß and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aß and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP.
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AIMS: Cerebrovascular impairment contributes to the pathogenesis of Alzheimer's disease (AD). However, it still lacks effective intervention in clinical practice. Here, we investigated the efficacy of electroacupuncture (EA) in cerebrovascular repair in 3xTg-AD mice and its mechanism. METHODS: 3xTg-AD mice were employed to evaluate the protective effect of EA at ST36 acupoint (EAST36). Behavioral tests were performed to assess neurological disorders. Laser speckle contrast imaging, immunostaining, and Western blot were applied to determine EAST36-boosted cerebrovascular repair. The mechanism was explored in 3xTg mice and endothelial cell cultures by melatonin signaling modulation. RESULTS: EAST36 at 20/100 Hz effectively alleviated the olfactory impairment and anxiety behavior and boosted cerebrovascular repair in AD mice. EAST36 attenuated cerebral microvascular degeneration in AD mice by modulating endothelial cell viability and injury. Consequently, the Aß deposits and neural damage in AD mice were reversed after EAST36. Mechanistically, we revealed that EAST36 restored melatonin levels in AD mice. Melatonin supplement mimicked the EAST36 effect on cerebrovascular protection in AD mice and endothelial cell cultures. Importantly, blockage of melatonin signaling by antagonist blunted EAST36-induced cerebrovascular recovery and subsequent neurological improvement. CONCLUSIONS: These findings provided strong evidence to support EAST36 as a potential nonpharmacological therapy against cerebrovascular impairment in AD. Further study is necessary to better understand how EAST36 treatment drives melatonin signaling.
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Doença de Alzheimer , Eletroacupuntura , Melatonina , Camundongos , Animais , Doença de Alzheimer/terapia , Doença de Alzheimer/tratamento farmacológico , Melatonina/uso terapêutico , Eletroacupuntura/métodos , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
BACKGROUND: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD). PURPOSE: To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese). STUDY DESIGN: By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models. METHODS: Liquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro. RESULTS: Our pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS). CONCLUSION: We identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases.
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Doença de Alzheimer , Desacetilase 6 de Histona , Doença de Alzheimer/tratamento farmacológico , Animais , Benzofenantridinas , Alcaloides de Berberina , Modelos Animais de Doenças , Desacetilase 6 de Histona/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Proteínas tauRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid ß plaques (Aß) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology. PURPOSE: The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation. METHODS: QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro. RESULTS: Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aß and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro. CONCLUSION: QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery.
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Doença de Alzheimer , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , PPAR alfa/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas tauRESUMO
Recent studies have shown that impairment of autophagy is related to the pathogenesis of Parkinson's disease (PD), and small molecular autophagy enhancers are suggested to be potential drug candidates against PD. Previous studies identified corynoxine (Cory), an oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks, as a new autophagy enhancer that promoted the degradation of α-synuclein in a PD cell model. In this study, two different rotenone-induced animal models of PD, one involving the systemic administration of rotenone at a low dosage in mice and the other involving the infusion of rotenone stereotaxically into the substantia nigra pars compacta (SNpc) of rats, were employed to evaluate the neuroprotective effects of Cory. Cory was shown to exhibit neuroprotective effects in the two rotenone-induced models of PD by improving motor dysfunction, preventing tyrosine hydroxylase (TH)-positive neuronal loss, decreasing α-synuclein aggregates through the mechanistic target of the rapamycin (mTOR) pathway, and diminishing neuroinflammation. These results provide preclinical experimental evidence supporting the development of Cory into a potential delivery system for the treatment of PD.
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Alzheimer disease (AD) is the most prevalent neurodegenerative disorder leading to dementia in the elderly. Unfortunately, no cure for AD is available to date. Increasing evidence has proved the roles of misfolded protein aggregation due to impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) in the pathogenesis of AD, and thus making TFEB (transcription factor EB), which orchestrates ALP, as a promising target for treating AD. As a complementary therapy, acupuncture or electroacupuncture (EA) has been commonly used for treating human diseases. Although the beneficial effects of acupuncture for AD have been primarily studied both pre-clinically and clinically, the real efficacy of acupuncture on AD remains inconclusive and the underlying mechanisms are largely unexplored. In this study, we demonstrated the cognitive-enhancing effect of three-needle EA (TNEA) in an animal model of AD with beta-amyloid (Aß) pathology (5xFAD). TNEA reduced APP (amyloid beta (A4) precursor protein), C-terminal fragments (CTFs) of APP and Aß load, and inhibited glial cell activation in the prefrontal cortex and hippocampus of 5xFAD. Mechanistically, TNEA activated TFEB via inhibiting the AKT-MAPK1-MTORC1 pathway, thus promoting ALP in the brains. Therefore, TNEA represents a promising acupuncture therapy for AD, via a novel mechanism involving TFEB activation.Abbreviations Aß: ß-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; AKT1: thymoma viral proto-oncogene 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta (A4) precursor protein; BACE1: beta-site APP cleaving enzyme 1; CQ: chloroquine; CTFs: C-terminal fragments; CTSD: cathepsin D; EA: electroacupuncture; FC: fear conditioning; GFAP: glial fibrillary acidic protein; HI: hippocampus; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPT: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNEA: three-needle electroacupuncture.
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Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/terapia , Eletroacupuntura , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Eletroacupuntura/métodos , Feminino , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Teste do Labirinto Aquático de MorrisRESUMO
Neurodegenerative diseases (NDs) are common chronic diseases related to progressive damage of the nervous system. Globally, the number of people with an ND is dramatically increasing consistent with the fast aging of society and one of the common features of NDs is the abnormal aggregation of diverse proteins. Autophagy is the main process by which misfolded proteins and damaged organelles are removed from cells. It has been found that the impairment of autophagy is associated with many NDs, suggesting that autophagy has a vital role in the neurodegeneration process. Recently, more and more studies have reported that autophagy inducers display a protective role in different ND experimental models, suggesting that enhancement of autophagy could be a potential therapy for NDs. In this review, the evidence for beneficial effects of traditional Chinese medicine (TCM) regulate autophagy in the models of Alzheimer's disease (AD), Parkinson's disease (PD), and other NDs are presented and common autophagy-related mechanisms are identified. The results demonstrate that TCM which regulate autophagy are potential therapeutic candidates for ND treatment.
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Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Degeneração Neural , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologiaRESUMO
Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.
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Curcumina/uso terapêutico , Nanoestruturas/química , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Curcumina/síntese química , Curcumina/química , Liberação Controlada de Fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Doença de Parkinson/patologia , Tamanho da Partícula , Agregados Proteicos/efeitos dos fármacos , Ratos , Propriedades de Superfície , alfa-Sinucleína/metabolismoRESUMO
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-ß (Aß) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid ß (Aß) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-ß/α), Aß and 4G8 positive Aß burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas tau , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Medicina Tradicional Chinesa , Camundongos , Camundongos Transgênicos , Agregação Patológica de Proteínas/tratamento farmacológico , Proteínas tau/metabolismoRESUMO
Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-ß/α), ß-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.
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Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Curcumina/uso terapêutico , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular Tumoral , Pareamento Cromossômico/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Curcumina/farmacologia , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente PequenoRESUMO
BACKGROUND: Breast cancer remains the most common female malignancy and metastasis is the leading cause of death in breast cancer patients. Oldenlandia diffusa has been empirically and extensively used as an adjuvant therapy for metastatic breast cancer patients in Traditional Chinese Medicine (TCM) with proven efficacy. However, its anti-metastasis mechanism has been poorly revealed. METHODS: Multiple molecular biology experiments as well as network pharmacology, bioinformatics analysis were conducted to investigate the anti-metastasis mechanism of Oldenlandia diffusa in breast cancer. RESULTS: We demonstrated that ethanol extract of Oldenlandia diffusa (EEOD) significantly inhibited proliferation and induced apoptosis of high-metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-453, while having no obvious cytotoxic effect on multiple nonmalignant cells. Furthermore, EEOD remarkably suppressed the migration and invasion capacities of the above breast cancer cells by modulating the matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) pathway. More importantly, EEOD also significantly inhibited breast cancer metastasis in zebrafish xenotransplantation model in vivo. Network pharmacology and bioinformatics analysis further demonstrated that EEOD yielded 12 candidate compounds and 225 potential targets, and shared 85 putative targets associated with breast cancer metastasis. Mechanistically, RNA sequencing and experimental validation results suggested that EEOD might inhibit breast cancer metastasis by attenuating the expression of caveolin-1 (Cav-1) as overexpression of Cav-1 could weaken the anti-metastasis efficacy of EEOD. CONCLUSIONS: Overall, our findings proved that EEOD could inhibit breast cancer metastasis by attenuating the expression of Cav-1, highlighting the use of EEOD as an adjunctive therapy for metastatic breast cancer patients. This study also provides novel insights into network pharmacology and bioinformatics analysis as effective tools to illuminate the scientific basis of TCM.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caveolina 1/biossíntese , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/farmacologia , Oldenlandia , Animais , Animais Geneticamente Modificados , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Caveolina 1/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-ZebraRESUMO
Alzheimer's disease (AD) is a degenerative disorder typified by progressive deterioration of memory and the appearance of ß-amyloid peptide (Aß)-rich senile plaques. Recently we have identified a novel function of a patented formulation of modified Huanglian-Jie-Tu-Tang (HLJDT-M), a Chinese herbal medicine, in treating AD in in vitro studies (US patent No. 9,375,457). HLJDT-M is a formulation composed of Rhizoma Coptitis, Cortex Phellodendri and Fructus Gardeniae without Radix Scutellariae. Here, we assessed the efficacy of HLJDT-M on a triple transgenic mouse model of AD (3XTg-AD). Oral administration of HLJDT-M ameliorated the cognitive dysfunction of 3XTg-AD mice and lessened the plaque burden. In addition, biochemical assays revealed a significant decrease in levels of detergent-soluble and acid-soluble Aß via decreasing the levels of full length amyloid-ß precursor protein (FL-APP) and C-terminal fragments of APP (CTFs) in brain lysates of HLJDT-M-treated mice. HLJDT-M treatment also significantly reduced the levels of FL-APP and CTFs in N2a/SweAPP cells. In contrast, treatment using the classical formula HLJDT did not reduce the memory impairment of 3XTg-AD mice and, rather, increased the Aß/Fl-APP/CTFs in both animal and cell culture studies. Altogether, our study indicates that HLJDT-M is a promising herbal formulation to prevent and/or cure AD.
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Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/fisiologia , Medicamentos de Ervas Chinesas/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacocinética , Placa Amiloide/prevenção & controle , Presenilina-1/fisiologia , Proteínas tau/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/etiologia , Placa Amiloide/patologiaRESUMO
The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd.
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Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Lisossomos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Neurônios Dopaminérgicos/patologia , HumanosRESUMO
OBJECTIVE: Generation and accumulation of the amyloid-ß (Aß) peptide after proteolytic processing of the full length amyloid precursor protein (FL-APP) by ß-secretase (ß-site APP cleaving enzyme or BACE1) and γ-secretase are the main causal factors of Alzheimer's disease (AD). Thus, inhibition of BACE1, a rate-limiting enzyme in the production of Aß, is an attractive therapeutic approach for the treatment of AD. Recent studies suggest that salvianolic acid B (Sal B) is isolated from the radix of Salvia miltiorrhiza Bunge, a Chinese herbal medicine commonly used for the treatment of cardiovascular, cerebrovascular and liver diseases in China. METHOD: In this study, we discovered that Sal B acted as a BACE1 modulator and reduced the level of secreted Aß in two different Swedish APP (SwedAPP) mutant cell lines. Using N2a-mouse and H4- human neuroglioma cell lines expressing SwedAPP, it was demonstrated that Sal B significantly and dose-dependently decreased the generation of extracellular Aß, soluble APPß (by-product of APP cleaved by BACE1), and intracellular C-terminal fragment ß from APP without influencing α-secretase and γ-secretase activity and the levels of FL-APP. In addition, using protein-docking, we determined the potential conformation of Sal B on BACE1 docking and revealed the interactions of Sal B with the BACE1 catalytic center. RESULTS: The docking provides a feasible explanation for the experimental results, especially in terms of the molecular basis of Sal B's action. Our results indicate that Sal B is a BACE1 inhibitor and, as such, is a promising candidate for the treatment of AD.
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Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/farmacologia , Fármacos Neuroprotetores/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Benzofuranos/química , Catálise/efeitos dos fármacos , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/químicaRESUMO
Hippocampal neurogenesis plays a critical role in the formation of new neurons during learning and memory development. Attenuation of neurogenesis in the brain is one of the primary causes of dementia in Alzheimer's disease (AD), and, conversely, modulating the process of hippocampal neurogenesis benefit patients with AD. Traditional Chinese medicine (TCM), particularly herbal medicine, has been in use for thousands of years in Asia and many regions of the world for the treatment of cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the role of neurotrophic factors, signal transducing factors, epigenetic modulators and neurotransmitters in neurogenesis, and we also discuss the functions of several Chinese herbs and their active molecules in activating multiple pathways involved in neurogenesis. TCM herbs target pathways such as Notch, Wnt, Sonic Hedgehog and receptor tyrosine kinase pathway, leading to activation of a signaling cascade that ultimately enhances the transcription of several important genes necessary for neurogenesis. Given these pathway activating effects, the use of TCM herbs could be an effective therapeutic strategy for the treatment of AD.
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Doença de Alzheimer/tratamento farmacológico , Neurogênese , Animais , Humanos , Medicina Tradicional Chinesa , Transdução de SinaisRESUMO
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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Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Fármacos Neuroprotetores/farmacologia , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Contagem de Células , Linhagem Celular Tumoral , Cromatografia Líquida , Modelos Animais de Doenças , Dopamina/metabolismo , Drosophila , Antagonismo de Drogas , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Humanos , Masculino , Espectrometria de Massas , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Ratos , Rotenona/farmacologia , alfa-Sinucleína/metabolismoRESUMO
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.
Assuntos
Biomarcadores/urina , Metaboloma , Metabolômica , Doença de Parkinson/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Análise Discriminante , Progressão da Doença , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Análise dos Mínimos Quadrados , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Fenótipo , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is estimated that the global prevalence of dementia will rise from 24.3 million in 2005 to 81.1 million in 2040. AD has a devastating impact on sufferers, caregivers, their communities and the healthcare system in general. "Di-tan decoction" (DTD) is a traditional Chinese medicine (TCM) formula frequently used to treat symptoms that are now defined as AD in clinical treatment. However, the existing evidence for recommending DTD in clinical practice derives from studies that were methodologically flawed. In this study, we aim to determine the efficacy and safety of DTD in AD patients based on a rigidly randomized controlled trial. It will provide critical information on sample size and treatment regimen for conducting a full-scale clinical trial of DTD later. METHODS/DESIGN: This study will be a double-blind, randomized, placebo-controlled, add-on trial. After a 2-week run-in period, eligible patients with mild to moderate AD will be recruited and given either DTD or placebo twice daily for 24 weeks with follow-up 6 weeks after the last treatment. An increase of four points or greater on the scores of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAD-cog) will be considered as a positive primary outcome. Total scores of the ADAD-cog, the Chinese version of Mini-Mental State Examination (C-MMSE), and the Chinese version of the Disability Assessment for Dementia (C-DAD) score will be used as secondary outcomes. Adverse events will also be reported. DISCUSSION: This randomized trial will be the first rigorous empirical study on the efficacy of DTD for treating cognitive symptoms in AD patients. Its success will justify and warrant a large-scale clinical trial to further consolidate the evidence for DTD's efficacy in treating AD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR-TRC-12004548 , Date of registration: 22 November 2012).