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1.
Br J Pharmacol ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034757

RESUMO

BACKGROUND AND PURPOSE: Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aß1-42 aggregates (Aß42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively. EXPERIMENTAL APPROACH: EAE/AD mice were immunized with the Aß42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests. Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA. KEY RESULTS: In contrast to previous findings in conventional AD animal models, Aß42 immunization promoted neuroinflammation, enhanced Aß levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aß levels, and improved cognitive performance in EAE/AD mice. CONCLUSION AND IMPLICATIONS: These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aß oligomers may be safe and show clinical benefit for AD treatment.

2.
Food Funct ; 11(2): 1334-1348, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32043503

RESUMO

Huntington's disease (HD) is a genetic neurodegenerative disorder caused by a highly polymorphic CAG trinucleotide repeat expansion encoding an extended polyglutamine (polyQ) tract at the N-terminus of huntingtin protein (HTT). The polyQ tract promotes the formation of toxic oligomers and aggregates of HTT, which leads to neuronal dysfunction and death. Therapies to lower mutant HTT (mHTT) and its aggregates appear to be the most promising strategies. Ellagic acid (EA) has been marketed as a dietary supplement with various claimed benefits and neuroprotective effects on several neurodegenerative disorders, while its effect on mHTT pathology is still unknown. Here we reported that EA significantly attenuated motor and cognitive deficits in R6/2 mice. Moreover, EA significantly lowered mHTT levels, reduced neuroinflammation, rescued synapse loss, and decreased oxidative stress in R6/2 mouse brains. These findings indicated that EA has promising therapeutic potential for HD treatment.

3.
Int J Nanomedicine ; 14: 9497-9512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819446

RESUMO

Background: Critical-sized bone defects raise great challenges. Zein is of interest for bone regeneration, but it has limited ability to stimulate cell proliferation. In this regard, a poly (aspartic acid) (PAsp)-zein hybrid is promising, as PAsp can promote rat bone marrow stromal cell (rBMSCs) proliferation and osteogenic differentiation. This research aimed to develop electrospun PAsp-modified zein nanofibers to realize critical-sized bone defects repair. Methods: Three groups of PAsp-modified zein nanofibers were prepared, they were PAsp grafting percentages of 0% (zein), 5.32% (ZPAA-1), and 7.63% (ZPAA-2). Using rBMSCs as in vitro cell model and SD rats as in vivo animal model, fluorescence staining, SEM, CCK-8, ALP, ARS staining, µCT and histological analysis were performed to verify the biological and osteogenic activities for PAsp-modified zein nanofibers. Results: As the Asp content increased from 0% to 7.63%, the water contact angle decreased from 129.8 ± 2.3° to 105.5 ± 2.5°. SEM, fluorescence staining and CCK-8 assay showed that ZPAA-2 nanofibers had a superior effect on rBMSCs spreading and proliferation than did zein and ZPAA-1 nanofibers, ALP activity and ARS staining showed that ZPAA-2 can improve rBMSCs osteogenic differentiation. In vivo osteogenic activities was evaluated by µCT analysis, HE, Masson and immunohistochemical staining, indicating accelerated bone formation in ZPAA-2 SD rats after 4 and 8 weeks treatment, with a rank order of ZPAA-2 > ZPAA-1 > zein group. Moreover, the semiquantitative results of the Masson staining revealed that the maturity of the new bone was higher in the ZPAA-2 group than in the other groups. Conclusion: Electrospun PAsp-modified zein can provide a suitable microenvironment for osteogenic differentiation of rBMSCs, as well as for bone regeneration; the optimal membrane appears to have a PAsp grafting percentage of 7.63%.


Assuntos
Regeneração Óssea/fisiologia , Nanofibras/química , Peptídeos/química , Zeína/química , Fosfatase Alcalina/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Forma Celular , Células-Tronco Mesenquimais/citologia , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Crânio/diagnóstico por imagem , Microtomografia por Raio-X
4.
Curr Alzheimer Res ; 16(8): 710-722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368873

RESUMO

BACKGROUND: Alzheimer's Disease (AD) is characterized by the presence of extracellular amyloid-ß (Aß) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aß generation and Aß-induced neurocytotoxicity, while its effect on tau pathology is still unknown. METHODS: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1ß, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. RESULTS: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. CONCLUSION: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

5.
Clin Oral Implants Res ; 30(8): 760-776, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102416

RESUMO

OBJECTIVE: Periodontitis and peri-implantitis are oral infectious-inflammatory diseases that share similarities in their pathology and etiology. Our objective was to characterize the single-site subgingival and submucosal microbiomes of implant-rehabilitated, partially dentate Chinese subjects (n = 18) presenting with both periodontitis and peri-implantitis. MATERIALS AND METHODS: Subgingival/submucosal plaque samples were collected from four clinically distinct sites in each subject: peri-implantitis submucosa (DI), periodontal pocket (DT), clinically healthy (unaffected) peri-implant submucosa (HI), and clinically healthy (unaffected) subgingival sulcus (HT). The bacterial microbiota present was analyzed using Illumina MiSeq sequencing. RESULTS: Twenty-six phyla and 5,726 operational taxonomic units (OTUs, 97% sequence similarity cutoff) were identified. Firmicutes, Proteobacteria, Fusobacteria, Bacteroidetes, Actinobacteria, Synergistetes, TM7, and Spirochaetes comprised 99.6% of the total reads detected. Bacterial communities within the DI, DT, HI, and HT sites shared high levels of taxonomic similarity. Thirty-one "core species" were present in >90% sites, with Streptococcus infantis/mitis/oralis (HMT-070/HMT-071/HMT-638/HMT-677) and Fusobacterium sp. HMT-203/HMT-698 being particularly prevalent and abundant. Beta-diversity analyses (PERMANOVA test, weighted UniFrac) revealed the largest variance in the microbiota was at the subject level (46%), followed by periodontal health status (4%). Differing sets of OTUs were associated with periodontitis and peri-implantitis sites, respectively. This included putative "periodontopathogens," such as Prevotella, Porphyromonas, Tannerella, Bacteroidetes [G-5], and Treponema spp. Interaction network analysis identified several putative patterns underlying dysbiosis in periodontitis/peri-implantitis sites. CONCLUSIONS: Species (OTU) composition of the periodontal and peri-implant microbiota varied widely between subjects. The inter-subject variations in subgingival/submucosal microbiome composition outweighed differences observed between implant vs. tooth sites, or between diseased vs. healthy (unaffected) peri-implant/periodontal sites.


Assuntos
Placa Dentária , Microbiota , Peri-Implantite , Periodontite , Bactérias , Humanos
6.
Yi Chuan ; 41(5): 430-438, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31106779

RESUMO

Arabidopsis CKI1 (cytokinin independent 1) is a histidine kinase protein involved in the two-component system, which can activate two-component signaling via the downstream histidine phospho-transfer proteins, playing the essential roles in central cell fate determination and development regulation in embryo sacs. However, studies on CKI1 upstream transcription regulators are still limited. In the present study, promoter activities with varying fragments were investigated, and CKI1 upstream transcription regulators were screened and identified by the yeast-one hybrid technique. Results indicated F5/R2 fragments located in the intron region showed promoter activities in embryo sacs, which is consistent with CKI1 full-length promoters. Then three tandem repeats of F5/R2 fragments were used to construct the bait expression vector, and Arabidopsis pistils were collected for cDNA library construction. Totally, 226 positive clones were screened by the yeast-one hybrid technique, 66 readable sequences were retrieved after removing sequences with low quality and redundant repeats, among which eight proteins could act as DNA-binding proteins. These results provided some important clues to study the molecular function of CKI1 in the transcription regulation network.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas Quinases/genética , Flores/genética , Regulação da Expressão Gênica de Plantas
7.
J Geriatr Cardiol ; 16(2): 156-163, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30923548

RESUMO

Background: Few data on the combined effects of bifurcation and calcification on coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) are available. This study evaluated the impact of main vessel (MV) calcification on the procedural and long-term outcomes in patients with CAD who underwent provisional single stent PCI. Methods: This is a multicenter, prospective, observational study. Patients with bifurcation lesions were enrolled at 10 PCI centers in China from January 2015 to December 2017. Intravascular ultrasound or optical coherence tomography was performed in all patients to evaluate the MV calcification. Patients were treated with provisional single stent strategy using drug eluting stents and followed-up at 1 month, 6 months and 12 months after discharge by telephone contact or outpatient visit. Repeated coronary imaging was performed within one year. We compared the procedural success rates in MV and in side branch (SB), and target lesion failure (TLF), defined as a composite of cardiac death, non-fatal myocardial infarction, definite or possible stent thrombosis and target lesion revascularization between patients with and without MV calcification. Results: A total of 185 subjects were enrolled according to the inclusion and exclusion criteria of this study. MV calcification was detected in 119 (64.3%, calcification group) and not found in 66 (35.7%, non-calcification group) patients. The angiographic success rate of MV was 95.8% in the calcification group and 97.0% in the non-calcification group (P = 0.91); the angiographic success rate of SB was 32.8% in the calcification group and 53.0% in the non-calcification group (P < 0.05). During the one-year follow-up period, TLF occurred in 14 (11.8%) patients in the calcification group and in 13 (19.7%) in the non-calcification group (P = 0.31). Multivariate regression analysis showed the same result (HR = 1.23, 95% CI: 0.76-1.52, P = 0.47). Calcification on group had higher recurrent angina than non-calcification group (13.51% vs. 17.65%, P < 0.05). Conclusions: In patients with coronary bifurcation lesion treated with provisional one stent approach, calcification of MV is associated with lower SB procedural success rate, it could increase recurrence of angina; however, it was not associated with an increased risk of TLF.

8.
Brain Res ; 1707: 141-153, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30481502

RESUMO

It is widely accepted that amyloid oligomers are the most toxic species to initiate the pathologic processes of Parkinson's disease (PD) and Huntingdon's disease (HD). But there is no definitive diagnosis for PD and HD at their early stages. Here, we conjugated an amyloid oligomer-specific scFv antibody (W20) to PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) and detected the properties of the SPIONs conjugated with W20. The results showed that W20-SPIONs, with the size of around 11.8 nm in diameter, were stable and nontoxic, and had enough relaxation capacity to be used as an MRI contrast agent. When applied to the transgenic mouse models of PD and HD, W20-SPIONs crossed the blood-brain barrier and specifically bound to the oligomer area to give MRI signal, distinguishing PD and HD from healthy controls. These results indicated that W20-SPIONs had potential in early-stage diagnosis for PD and HD and also opened up a new strategy for evaluating the efficacy of new drugs.

9.
Neurobiol Dis ; 124: 202-217, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30481547

RESUMO

It has been suggested that aggregation of α-synuclein (α-syn) into oligomers leads to neurodegeneration in Parkinson's disease (PD), but intravenous immunoglobulin (IVIG) which contains antibodies against α-syn monomers and oligomers fails to treat PD mouse model. The reason may be because IVIG contains much low level of antibodies against α-syn, and of which only a small part can penetrate the blood-brain barrier, resulting in an extremely low level of effective antibodies in the brain, and limiting the beneficial effect of IVIG on PD mice. Here, we first isolated naturally occurring autoantibodies against α-syn (NAbs-α-syn) from IVIG. Our further investigation results showed that NAbs-α-syn inhibited α-syn aggregation and attenuated α-syn-induced cytotoxicity in vitro. Compared with vehicles, NAbs-α-syn significantly attenuated the memory and motor deficits by reducing the levels of soluble α-syn, total human α-syn and α-syn oligomers, decreasing the intracellular p-α-synser129 deposits and axonal pathology, inhibiting the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines, increasing the levels of PSD95, synaptophysin and TH in the brain of A53T transgenic mice. These findings suggest that NAbs-α-syn overcomes the deficiency of IVIG and exhibits a promising therapeutic potential for the treatment of PD.


Assuntos
Autoanticorpos/administração & dosagem , Encéfalo/imunologia , Atividade Motora , Doença de Parkinson/imunologia , Memória Espacial , alfa-Sinucleína/imunologia , Animais , Autoanticorpos/isolamento & purificação , Encéfalo/patologia , Modelos Animais de Doenças , Imunização Passiva , Imunoglobulinas Intravenosas/isolamento & purificação , Camundongos Transgênicos , Microglia/imunologia , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/imunologia
10.
Food Funct ; 9(12): 6414-6426, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30462117

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by Lewy pathology and progressive loss of dopaminergic neurons in the substantia nigra. Lewy pathology mainly consists of abnormal aggregates of α-synuclein, which play a pivotal role in PD pathophysiology. However, the complexity of PD leads to clinical challenges, and there are still no treatments to halt or slow the neurodegenerative process. Resveratrol (RV) is a natural polyphenol compound with multiple biological activities, which has been reported to exert neuroprotective effects on several neurological diseases. Here we first provided evidence that RV treatment alleviated motor and cognitive deficits in the A53T α-synuclein mouse model of PD in a dose-dependent manner. The beneficial effects of RV against PD resulted from inhibiting α-synuclein aggregation and cytotoxicity, lowering the levels of total α-synuclein and oligomers, reducing neuroinflammation and oxidative stress. These findings suggest that RV has promising therapeutic potential for PD and other synucleinopathies.


Assuntos
Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Resveratrol/administração & dosagem , alfa-Sinucleína/genética , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Mutação de Sentido Incorreto , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/psicologia , alfa-Sinucleína/metabolismo
11.
Chin Med J (Engl) ; 131(22): 2705-2712, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30425197

RESUMO

Background: Leigh syndrome (LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity. We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA (mtDNA) mutations. Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging (MRI) were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid (CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography-mass spectrometry and tandem mass spectrometry. The histopathological traits of skeletal muscles were analyzed under microscope. Results: Among 13 patients, mutations of MT-NDs (n = 8) and MT-ATP6 (n = 4) genes were most common. Strabismus (8/13), muscle weakness (8/13), and ataxia (5/13) were also common, especially for the patients with late-onset age after 2 years old. However, respiratory distress was common in patients with early-onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem (12/13), particularly the dorsal part of midbrain, followed by basal ganglia (6/13), thalamus (6/13), cerebellum (5/13), and supratentorial white matter (2/13). Besides, the elevated lactate levels in CSF (6/6) were more common than those in serum (7/13). However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results (0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late-onset patients but not in the early-onset ones. Conclusions: Noninvasive genetic screening is recommended for mtDNA mutations in MT-NDs and MT-ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.


Assuntos
DNA Mitocondrial/genética , Doença de Leigh/diagnóstico por imagem , Doença de Leigh/genética , Neuroimagem/métodos , Criança , Pré-Escolar , Creatina Quinase/sangue , Deficiência de Citocromo-c Oxidase , Jejum/sangue , Jejum/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Ácido Láctico/sangue , Ácido Láctico/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Masculino , Mutação/genética
12.
Int Immunopharmacol ; 65: 413-421, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30388515

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers. Our study showed that W20 significantly improved motor neuron survival and motor performance in SOD1-G93A mouse model of ALS when administrated even at low dose within short time. Further investigation demonstrated that the beneficial effects of W20 resulted from the reduction of SOD1 oligomer levels and the inhibition of gliosis and neuroinflammation in the spinal cords and brain stems of ALS model mice. These findings for the first time suggest that an oligomer-specific antibody has promising therapeutic potential for ALS and open a new way for ALS treatment.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Anticorpos/uso terapêutico , Gliose/terapia , Imunoterapia/métodos , Inflamação Neurogênica/terapia , Medula Espinal/patologia , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/genética , Animais , Modelos Animais de Doenças , Gliose/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurônios Motores/patologia , Inflamação Neurogênica/genética , Superóxido Dismutase/imunologia
13.
Brain Res ; 1697: 21-33, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29902468

RESUMO

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive movement disorders and cognitive deficits, which is caused by a CAG-repeat expansion encoding an extended polyglutamine (polyQ) tract in the huntingtin protein (HTT). Reduction of mutant HTT levels and inhibition of neuroinflammation has been proposed as a major therapeutic strategy in treating HD. Intravenous immunoglobulin (IVIg) therapy has been firmly established for the treatment of several autoimmune or inflammatory neurological diseases, either as adjunctive treatment or as first-line therapy. However, whether IVIg has therapeutic potential on HD remains unclear. Here we for the first time demonstrated that IVIg treatment remarkably rescued motor and cognitive deficits, prevented synaptic degeneration, attenuated neuroinflammation and oxidative stress in R6/2 mouse model. Further investigation showed that the beneficial effects of IVIg resulted from the reduced levels of mutant HTT and inhibition of NF-κB signalling pathway. These findings suggest that IVIg is a promising therapeutic potential for HD.


Assuntos
Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Animais , Encéfalo/metabolismo , Cognição/fisiologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Proteína Huntingtina/genética , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Doenças do Sistema Nervoso/patologia , Neuropatologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Superóxido Dismutase-1/efeitos dos fármacos
14.
Alzheimers Res Ther ; 10(1): 55, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29914543

RESUMO

BACKGROUND: Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau294-305, an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau294-305-targeted approach may have beneficial effects in the treatment of AD and FTD. METHODS: In this study, we genetically fused tau294-305 epitope to the hepatitis B virus core protein (HBc) major immunodominant region (MIR) (with the resultant protein termed T294-HBc), and we subcutaneously immunized a Tau.P301S transgenic mouse model of FTD and AD with T294-HBc four times. The levels and characteristics of antibodies induced by T294-HBc were determined by enzyme-linked immunosorbent assay. The effect of T294-HBc on the cognitive deficits of Tau.P301S mice was tested using the Morris water maze test, novel object recognition, and a Y-maze test. Western blot analysis and IHC were applied to measure the effect of T294-HBc on tau pathologies and neuroinflammation in the mouse brains. RESULTS: The results showed that T294-HBc self-assembled into HBc chimeric virus-like particles (VLPs) with tau294-305 displayed on the surface and that it induced high antibody titers specifically against the mis-disordered truncated tau. Further investigation showed that these antibodies simultaneously bound to microtubule-binding regions 1-4 (MTBR1-4) [tau263-274, tau294-305, tau325-336, tau357-368 and tau294-305(P301S)]. Moreover, T294-HBc VLP vaccination significantly ameliorated memory and cognitive decline; reduced the levels of AT8-positive tau, truncated tau monomer, and oligomer; attenuated microgliosis and astrogliosis; and rescued synaptic deficits in Tau.P301S transgenic mice. CONCLUSIONS: T294-HBc VLP vaccine elicited strong immune response and alleviated cognitive deficits and neuropathology progression in Tau.P301S mice, indicating that the T294-HBc VLP vaccine has promising therapeutic potential for the treatment of AD and FTD.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/terapia , Demência Frontotemporal/complicações , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Proteínas tau/imunologia , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Comportamento Exploratório , Feminino , Demência Frontotemporal/genética , Vacinas contra Hepatite B/química , Vacinas contra Hepatite B/metabolismo , Imunização/métodos , Epitopos Imunodominantes/uso terapêutico , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Prolina/genética , Serina/genética , Resultado do Tratamento , Proteínas tau/genética , Proteínas tau/metabolismo
15.
Curr Alzheimer Res ; 15(9): 856-868, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29623840

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Aß leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reducing Aß levels and inhibiting Aß-induced neurotoxicity are feasible therapeutic strategies for AD treatment. Wolfberry has been traditionally used as a natural antioxidant and anti-aging product. However, whether wolfberry species has therapeutic potential on AD remains unknown. METHOD: The effects of fruitless wolfberry-sprout extract (FWE) on Aß fibrillation and fibril disaggregation was measured by thioflavin T fluorescence and transmission electron microscope imaging; Aß oligomer level was determined by dot-blot; Cell viability and apoptosis was assessed by MTT and TUNEL assay. The levels of Aß40/42, oxidative stress biomarkers and inflammatory cytokines were detected by corresponding kits. 8-month-old male APP/PS1 mice and their age-matched WT littermates were treated with FWE or vehicle by oral administration (gavage) once a day for 4 weeks. Then the cognitive performance was determined using object recognition test and Y-maze test. The Aß burden and gliosis was evaluated by immunostaining and immunoblotting, respectively. RESULTS: FWE significantly inhibited Aß fibrillation and disaggregated the formed Aß fibrils, lowered Aß oligomer level and Aß-induced neuro-cytotoxicity, and attenuated oxidative stress in vitro. Oral administration of FWE remarkably improved cognitive function, reduced Aß burden, decreased gliosis and inflammatory cytokines release, and ameliorated oxidative stress in the brains of APP/PS1 mice. CONCLUSION: These findings indicate that FWE is a promising natural agent for AD treatment.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Lycium/química , Extratos Vegetais/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Interleucina-6/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Mutação/genética , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Life Sci ; 192: 68-74, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155303

RESUMO

AIMS: Inflammation is strongly associated with the mechanism of ß-cell failure in type 2 diabetes mellitus (T2DM). Blockade of the key proinflammatory cytokine IL-1ß has been implicated as a promising therapeutic strategy for the prevention and treatment of type 2 diabetes. In this study, we developed an IL-1ß-targeted therapeutic vaccine consisting of an IL-1ß epitope peptide (A1ß) and assessed its efficacy on a diabetic KK-Ay mouse model. MAIN METHODS: KK-Ay mice were immunized with A1ß for three injections at a 2-week interval. The induced antibody titers, body weights and blood glucose levels were monitored every two weeks. Then the intraperitoneal glucose tolerance test and insulin tolerance test were performed. The ß-cell mass, ß-cell apoptosis and proliferation were evaluated by immunofluorescence. IL-1ß gene expression in islets was also measured by quantitative RT-PCR. KEY FINDINGS: A1ß immunization induced robust antibody responses, reduced body weight gain, improved glucose tolerance and insulin sensitivity in KK-Ay mice. Moreover, A1ß restored ß-cell mass, inhibited ß-cell apoptosis, enhanced ß-cell proliferation and downregulated IL-1ß expression. SIGNIFICANCE: The novel IL-1ß-targeted epitope vaccine has the therapeutic potential for T2DM.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Interleucina-1beta/imunologia , Vacinas/uso terapêutico , Animais , Anticorpos/análise , Apoptose , Peso Corporal , Proliferação de Células , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Epitopos/imunologia , Teste de Tolerância a Glucose , Imunoglobulina G/análise , Imunoglobulina G/biossíntese , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vacinas/imunologia
17.
Int Immunopharmacol ; 54: 145-152, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29145032

RESUMO

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by ß-cell loss, insulin resistance, islet inflammation and amyloid deposits derived from islet amyloid polypeptide (IAPP). Reducing toxic IAPP oligomers and inhibiting islet inflammation may provide therapeutic benefit in treating T2DM. Intravenous immunoglobulin (IVIg) is an efficient anti-inflammatory and immunomodulatory agent for the treatment of several autoimmune or inflammatory neurological diseases. However, whether IVIg has therapeutic potential on T2DM remains unclear. In present study, we showed that IVIg treatment significantly improved glucose control and insulin sensitivity, and prevented ß-cell apoptosis by lowering toxic IAPP oligomer levels, attenuating islet inflammation and activating autophagy in human IAPP transgenic mouse model. These results suggest that IVIg is a promising therapeutic potential for T2DM treatment.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Glucose/metabolismo , Imunoglobulinas Intravenosas/uso terapêutico , Células Secretoras de Insulina/fisiologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/imunologia , Animais , Apoptose , Autofagia , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Masculino , Camundongos , Camundongos Transgênicos , Multimerização Proteica
18.
Sci Rep ; 6: 36631, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824125

RESUMO

Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson's disease and Huntington's disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson's disease, Huntington's disease, Alzheimer's disease, and other amyloidoses.


Assuntos
Amiloide/imunologia , Amiloidose/tratamento farmacológico , Cognição/efeitos dos fármacos , Epitopos/imunologia , Atividade Motora/efeitos dos fármacos , Anticorpos de Cadeia Única/farmacologia , Amiloidose/imunologia , Amiloidose/patologia , Amiloidose/fisiopatologia , Animais , Doença de Huntington/tratamento farmacológico , Doença de Huntington/imunologia , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora/imunologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/imunologia , Doença de Parkinson Secundária/fisiopatologia , Anticorpos de Cadeia Única/imunologia
19.
PLoS One ; 11(5): e0154298, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27152706

RESUMO

Interleukin-1ß (IL-1ß) has been implicated as a key proinflammatory cytokine involved in the pancreatic islet inflammation of type 2 diabetes mellitus (T2DM). Excess IL-1ß impairs islet function by inducing insulin resistance and ß-cell apoptosis. Therefore, specifically reducing IL-1ß activity provides a therapeutic improvement for T2DM by sustaining the inhibition of IL-1ß-mediated islet inflammation. In this study, we developed an IL-1ß-targeted epitope peptide vaccine adjuvanted with polylactic acid microparticles (1ßEPP) and applied it to a diabetic KK-Ay mouse model. Results showed that the 1ßEPP elicited high antibody responses, which neutralized the biological activity of IL-1ß, and induced barely detectable inflammatory activity. 1ßEPP immunization reduced body weight gain, protected KK-Ay mice from hyperglycemia, improved glucose tolerance and insulin sensitivity, and decreased the serum levels of free fatty acids, total cholesterol and triglyceride. Moreover, 1ßEPP restored ß-cell mass; inhibited ß-cell apoptosis; decreased the expression of IL-1ß; and interrupted NF-κB activation by reducing IKKß and pRelA levels. These studies indicated that the IL-1ß-targeted vaccine may be a promising immunotherapeutic for T2DM treatment.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Interleucina-1beta/metabolismo , Ilhotas Pancreáticas/fisiopatologia , Vacinas/administração & dosagem , Animais , Formação de Anticorpos , Ensaio de Imunoadsorção Enzimática , Teste de Tolerância a Glucose , Hiperglicemia/prevenção & controle , Resistência à Insulina , Camundongos , Ganho de Peso
20.
Neuropharmacology ; 105: 561-576, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26907803

RESUMO

Alzheimer's disease (AD) is characterized by memory loss, intracellular neurofibrillary tangles, and extracellular plaque deposits composed of ß-amyloid (Aß). Previous reports showed that naturally occurring autoantibodies, such as intravenous immunoglobulin (IVIG), benefited patients with moderate-stage AD who carried an APOE-ε4 allele. However, the mechanism underlying the role of IVIG remains unclear. In this study, we identified naturally occurring autoantibodies against Aß oligomers (NAbs-Aßo), which were purified by Aß42 oligomer or Cibacron Blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs, respectively. Oli-NAbs and Blue-NAbs recognized Aß42 oligomers or both Aß40 and 42 oligomers, differently. Both antibodies inhibited Aß42 aggregation and attenuated Aß42-induced cytotoxicity. Compared with vehicles, Oli-NAbs, Blue-NAbs and IVIG significantly improved the memory and cognition, and reduced the soluble and oligomeric Aß levels in APPswe/PS1dE9 transgenic mice. Further investigation showed that Blue-NAbs at increased doses effectively decreased plaque burden and insoluble Aß levels, whereas Oli-NAbs significantly declined the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines in vivo. Therefore, high levels of these antibodies against oligomeric Aß40 or Aß42 were required, correspondingly, to achieve the optimal effect. NAbs-Aßo could be condensed to a high concentration by affinity chromatography and its isolation from IVIG may not interfere with the normal function of conventional IVIG as its concentration is very low. Thus, the isolated NAbs-Aßo as an extra product of plasma required low cost and the enriched NAbs-Aßo may be more feasible than IVIG for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/imunologia , Autoanticorpos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Fragmentos de Peptídeos/imunologia , Doença de Alzheimer/patologia , Animais , Autoanticorpos/isolamento & purificação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Cromatografia de Afinidade , Citocinas/metabolismo , Modelos Animais de Doenças , Gliose/tratamento farmacológico , Gliose/metabolismo , Gliose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunoterapia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos Transgênicos , Neuroimunomodulação , Fármacos Neuroprotetores/isolamento & purificação , Nootrópicos/isolamento & purificação , Multimerização Proteica/efeitos dos fármacos , Sinaptofisina/metabolismo
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