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3.
J Urol ; 205(1): 60-67, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32856962

RESUMO

PURPOSE: Androgen deprivation therapy is a standard therapy for some patients with localized and almost all patients with metastatic prostate cancer. Although several clinical cohort studies have identified an impact of androgen deprivation therapy on cognitive function, the previous reviews were not able to perform a well designed quantitative synthesis to summarize the risk of dementia and/or Alzheimer disease. Consequently there is still a lack of systematic review and meta-analysis regarding the impact of this risk including more recent studies. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of the literature assessing the differential incidence of dementia and/or Alzheimer disease as outcomes in patients with prostate cancer who did vs did not receive androgen deprivation therapy. We queried PubMed® and Web of Science™ databases from January 1 to 3, 2020. We used random or fixed effects meta-analytic models in the presence or absence of heterogeneity per the I2 statistic. We performed 6 meta-analyses for all cause dementia, Alzheimer disease and all cause dementia or Alzheimer disease according to the duration of androgen deprivation therapy (up to 12 or more than 12 months). RESULTS: A total of 14 studies were selected after considering inclusion and exclusion criteria. Nine of them reported all cause dementia (ie all types of dementia including Alzheimer disease), with 8 reporting Alzheimer disease. Five studies assessed these outcomes according to the duration of androgen deprivation therapy. The risk of new onset dementia (all cause) and Alzheimer disease was higher in patients with prostate cancer who received androgen deprivation therapy compared to those who did not (HR 1.21, 95% CI 1.11-1.33 and HR 1.16, 95% CI 1.09-1.24). The risk of dementia (all cause) was higher in patients with prostate cancer who received androgen deprivation therapy for more than 12 months (HR 1.36, 95% CI 1.07-1.72); however, for those who had less than 12 months of androgen deprivation therapy exposure the difference was not statistically significant 1.06 (95% CI 0.77-1.28). There was no association between the androgen deprivation therapy duration and the risk of Alzheimer disease (HR 1.21, 95% CI 0.97-1.51 for exposure up to 12 months and HR 1.39, 95% CI 0.69-2.79 for exposure greater than 12 months). CONCLUSIONS: Men who receive androgen deprivation therapy for prostate cancer have an increased risk of dementia and/or Alzheimer disease compared to men who do not receive androgen deprivation therapy; this was more pronounced when androgen deprivation therapy was given longer than 12 months.


Assuntos
Doença de Alzheimer/epidemiologia , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Demência/epidemiologia , Neoplasias da Próstata/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/prevenção & controle , Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Cognição/efeitos dos fármacos , Demência/induzido quimicamente , Demência/prevenção & controle , Esquema de Medicação , Humanos , Masculino , Neoplasias da Próstata/patologia , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Fatores de Tempo
4.
Chemosphere ; 263: 128238, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297185

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. The association between environmental factors (e.g., pesticide) and AD has attracted considerable attention. However, no systematic analysis has been performed and make it difficult to provide deeper insights of AD correlated with pesticide exposure. Hence, this study utilized a bibliometric and visual approach that included map collaborations, co-citations, and keywords, to identifying the knowledge structure, hot topics and the research trends based on 372 publications from the Web of Science Core Collection and PubMed databases. The results showed that 116 institutions from 52 countries published articles in this field. The United States and Israel played a leading role with numerous publications in related journals, as well as prolific institutions and authors, respectively. Three hot topics in pesticide-induced AD were recognized based on co-occurrence keywords detection, including acetylcholinesterase (AChE) inhibitor, oxidative stress, and AChE. Moreover, analysis of keywords burst suggests that some potential molecular mechanisms and therapy targets of pesticide-induced AD, especially for mitochondrial dysfunction and monoamine oxidase-B (MAO-B) that catalyzes the oxidative deamination and causes oxidative stress, are emerging trends. In addition, the study of various pesticides and the assessment method of pesticide exposure will step forward as well. To the best of our knowledge, this study is the first to specifically visualize the relationship between AD and pesticide exposure and to predict potential future research directions.


Assuntos
Doença de Alzheimer , Praguicidas , Doença de Alzheimer/induzido quimicamente , Bibliometria , Exposição Ambiental/efeitos adversos , Humanos , Israel , Praguicidas/toxicidade , Estados Unidos
5.
Environ Sci Pollut Res Int ; 27(36): 44724-44742, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32715424

RESUMO

Neurodegenerative disorders are commonly erratic influenced by various factors including lifestyle, environmental, and genetic factors. In recent observations, it has been hypothesized that exposure to various environmental factors enhances the risk of Alzheimer's disease (AD). The exact etiology of Alzheimer's disease is still unclear; however, the contribution of environmental factors in the pathology of AD is widely acknowledged. Based on the available literature, the review aims to culminate in the prospective correlation between the various environmental factors and AD. The prolonged exposure to the various well-known environmental factors including heavy metals, air pollutants (particulate matter), pesticides, nanoparticles containing metals, industrial chemicals results in accelerating the progression of AD. Common mechanisms have been documented in the field of environmental contaminants for enhancing amyloid-ß (Aß) peptide along with tau phosphorylation, resulting in the initiation of senile plaques and neurofibrillary tangles, which results in the death of neurons. This review offers a compilation of available data to support the long-suspected correlation between environmental risk factors and AD pathology. Graphical abstract .


Assuntos
Doença de Alzheimer , Poluentes Ambientais , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Neurônios/metabolismo , Estudos Prospectivos
6.
Sci Rep ; 10(1): 9487, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528016

RESUMO

Our recent study revealed that prenatal exposure to bisphenol A (BPA) disrupted the transcriptome profiles of genes in the offspring hippocampus. In addition to genes linked to autism, several genes associated with Alzheimer's disease (AD) were found to be differentially expressed, although the association between BPA-responsive genes and AD-related genes has not been thoroughly investigated. Here, we demonstrated that in utero BPA exposure also disrupted the transcriptome profiles of genes associated with neuroinflammation and AD in the hippocampus. The level of NF-κB protein and its AD-related target gene Bace1 were significantly increased in the offspring hippocampus in a sex-dependent manner. Quantitative RT-PCR analysis also showed an increase in the expression of Tnf gene. Moreover, the reanalysis of transcriptome profiling data from several previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with top AD candidate genes. The findings from this study suggest that maternal BPA exposure may increase AD risk in offspring by dysregulating genes associated with AD neuropathology and inflammation and reveal a possible relationship between AD and autism, which are linked to the same environmental factor. Sex-specific effects of prenatal BPA exposure on the susceptibility of AD deserve further investigation.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Compostos Benzidrílicos/agonistas , Fenóis/agonistas , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transcriptoma/efeitos dos fármacos , Animais , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/genética , Feminino , Perfilação da Expressão Gênica/métodos , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Exposição Materna , NF-kappa B/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Wistar
7.
J Oleo Sci ; 69(7): 771-782, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32522946

RESUMO

The role of fish oil, primrose oil and their mixture in ameliorating the changes in Alzheimer's like model was evaluated in rats. Primrose oil and primrose/fish oil mixture fatty acids composition was assessed by gas chromatography. The rat experiment consisted of 5 groups; the first fed on balanced diet as control normal (CN); the other four groups treated with intraperitoneal aluminum lactate and consumed dyslipidemic diet; one group served as control Alzheimer's like disease (CA) while the other three groups (test groups) received daily oral dose from primrose oil, fish oil and primrose/fish oil mixture separately for 5 weeks. Results showed primrose oil and primrose/ fish oil mixture to contain gamma linolenic acid as 9.15 and 4.3% of total fatty acids, respectively. Eicosapentaenoic and docosahexaenoic were present as 10.9 and 6.5 %, respectively in the oil mixture. Dyslipidemia and increased erythrocyte sedimentation rate (ESR), plasma butyrylcholinesterase (BChE), brain malondialdehyde (MDA) and NO with decrease in plasma magnesium, brain catalase, reduced glutathione, body weight gain and brain weight were demonstrated in CA compared to CN. Brain histopathology and immuno-histochemistry showed neuronal degeneration and neurofibrillary tangles with elevated myeloperoxidase and nuclear factor-kappa B in CA compared to CN. The tested oils demonstrated neuro-protection reflected in the variable significant improvement of biochemical parameters, immuno-histochemistry and brain histopathology. Primrose/fish oil mixture was superior in reducing ESR, brain MDA, plasma activity of BChE and brain histopathological changes along with elevating plasma magnesium. Primrose/fish oil mixture and fish oil were more promising in improving plasma high density lipoprotein cholesterol (HDL-C) than primrose. Fish oil was the most efficient in improving plasma total cholesterol (T-C), low density lipoprotein cholesterol and T-C /HDL-C. Primrose/fish oil mixture and primrose oil were superior in elevating brain catalase compared to fish oil. Other parameters were equally improved by the different oil treatments. Primrose oil, fish oil and their mixture reduced the progression of Alzheimer's disease in rats with superiority to primrose/fish oil mixture.


Assuntos
Compostos de Alumínio/efeitos adversos , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Óleos de Peixe/administração & dosagem , Lactatos/efeitos adversos , Óleos Vegetais/administração & dosagem , Primula , Ácido gama-Linolênico/análise , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Butirilcolinesterase/metabolismo , Catalase/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Progressão da Doença , Ácidos Docosa-Hexaenoicos/análise , Ácido Eicosapentaenoico/análise , Óleos de Peixe/química , Masculino , Malondialdeído/metabolismo , Óleos Vegetais/química , Ratos , Ratos Endogâmicos
8.
Psychopharmacology (Berl) ; 237(7): 2111-2124, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363440

RESUMO

INTRODUCTION: Gelsemine is a natural alkaloid extracted from Gelsemium elegans Benth., a traditional Chinese medicinal herb. Gelsemine has been shown to penetrate the brain, and could produce neurological activities, such as anxiolytic and neuralgia-alleviating effects, suggesting that this natural compound might be used for treating nervous system diseases. RESULTS: In this study, we have found, for the first time, that gelsemine at low concentrations (5-10 µg/kg) significantly alleviated cognitive impairments induced by ß-amyloid (Aß) oligomer, a main neurotoxin of Alzheimer's disease (AD). In addition, gelsemine substantially prevented Aß oligomer-induced over-activation of microglia and astrocytes, indicating that gelsemine might reduce AD-related gliosis. Consistently, gelsemine inhibited the over-expression of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in the brain of mice. Moreover, gelsemine largely increased the expression of pSer9-glycogen synthase kinase-3ß (GSK3ß), and decreased the hyper-phosphorylation of tau protein as evidenced by Western blotting analysis. Furthermore, gelsemine prevented Aß oligomer-induced reduction of PSD-95, a representative post-synaptic protein. CONCLUSION: All these results directly demonstrated the anti-Aß oligomer neuroprotective properties of gelsemine, opening a novel perspective for the development of gelsemine-based therapeutics against Aß-associated neurodegeneration disorders, including AD in particular.


Assuntos
Alcaloides/uso terapêutico , Peptídeos beta-Amiloides/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Gelsemium , Mediadores da Inflamação/antagonistas & inibidores , Fragmentos de Peptídeos/toxicidade , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR
9.
PLoS One ; 15(5): e0232233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365077

RESUMO

The physiological actions of orally ingested peptides on the brain remain poorly understood. This study examined the effects of 39 orally administered synthetic Tyr-containing dipeptides on the enhancement of brain norepinephrine metabolism in mice by comparing the concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Although Tyr-Tyr administration increased blood and cerebral cortex (Cx) Tyr concentrations the most, Tyr-Trp increased Cx MHPG concentration the most. The oral administration of Tyr-Trp ameliorated a short-term memory deficit of a mouse model of cognitive dysfunction induced by amyloid beta peptide 25-35. Gene expression profiling of mouse brain using a microarray indicated that Tyr-Trp administration led to a wide variety of changes in mRNA levels, including the upregulation of genes encoding molecules involved in catecholamine metabolism. A comparative metabolome analysis of the Cx of mice given Tyr-Trp or Tyr-Tyr demonstrated that Tyr-Trp administration yielded higher concentrations of Trp and kynurenine pathway metabolites than Tyr-Tyr administration, as well as higher L-dopa levels, which is the initial product of catecholamine metabolism. Catecholamines were not significantly increased in the Cx of the Tyr-Tyr group compared with the Tyr-Trp group, despite a marked increase in Tyr. Presumably, Tyr-Trp administration enhances catecholamine synthesis and metabolism via the upregulation of genes involved in Tyr and Trp metabolism as well as metabolites of Tyr and Trp. These findings strongly suggest that orally ingested Tyr-Trp modulates the brain metabolome involved in catecholamine metabolism and contributes to higher brain function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Dipeptídeos/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/análise , Administração Oral , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/efeitos adversos , Animais , Catecolaminas/biossíntese , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Fragmentos de Peptídeos/efeitos adversos
10.
Environ Sci Pollut Res Int ; 27(36): 44673-44700, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32424756

RESUMO

Ochratoxin A (OTA) is a naturally occurring mycotoxin mostly found in food items including grains and coffee beans. It induces DNA single-strand breaks and has been considered to be carcinogenic. It is recognized as a serious threat to reproductive health both in males and females. OTA is highly nephrotoxic and carcinogenic, and its potency changes evidently between species and sexes. There is a close association between OTA, mutagenicity, carcinogenicity, and genotoxicity, but the underlying mechanisms are not clear. Reports regarding genotoxic effects in relation to OTA which leads to the induction of DNA adduct formation, protein synthesis inhibition, perturbation of cellular energy production, initiation of oxidative stress, induction of apoptosis, influences on mitosis, induction of cell cycle arrest, and interference with cytokine pathways. All these mechanisms are associated with nephrotoxicity, hepatotoxicity, teratotoxicity, immunological toxicity, and neurotoxicity. OTA administration activates various mechanisms such as p38 MAPK, JNKs, and ERKs dysfunctions, BDNF disruption, TH overexpression, caspase-3 and 9 activation, and ERK-1/2 phosphorylation which ultimately lead to Alzheimer disease (AD) progression. The current review will focus on OTA in terms of recent discoveries in the field of molecular biology. The main aim is to investigate the underlying mechanisms of OTA in regard to genotoxicity and epigenetic modulations that lead to AD. Also, we will highlight the strategies for the purpose of attenuating the hazards posed by OTA exposure.


Assuntos
Doença de Alzheimer , Ocratoxinas , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Dano ao DNA , Epigênese Genética , Feminino , Humanos , Masculino
11.
Ageing Res Rev ; 60: 101062, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32304732

RESUMO

Although it has been initially synthesized for therapeutic purposes and currently FDA-approved and prescribed for obesity, attention-deficit/hyperactivity disorder, narcolepsy and depression, methamphetamine became a recreational drug that is nowadays massively manufactured illegally. Because it is a powerful and extremely addictive psychotropic agent, its abuse has turned out to become a major health problem worldwide. Importantly, the numerous effects triggered by this drug induce neurotoxicity in the brain ultimately leading to serious neurological impairments, tissue damage and neuropsychological disturbances that are reminiscent to most of the symptoms observed in Alzheimer's disease and other pathological manifestations in aging brain. In this context, there is a growing number of compelling evidence linking methamphetamine abuse with a higher probability of developing premature Alzheimer's disease and consequent neurodegeneration. This review proposes to establish a broad assessment of the effects that this drug can generate at the cellular and molecular levels in connection with the development of the age-related Alzheimer's disease. Altogether, the objective is to warn against the long-term effects that methamphetamine abuse may convey on young consumers and the increased risk of developing this devastating brain disorder at later stages of their lives, but also to discuss a more recently emerging concept suggesting a possible use of methamphetamine for treating this pathology under proper and strictly controlled conditions.


Assuntos
Doença de Alzheimer , Estimulantes do Sistema Nervoso Central , Metanfetamina , Envelhecimento , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Encéfalo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Humanos , Metanfetamina/efeitos adversos
12.
Phytother Res ; 34(9): 2351-2365, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32250498

RESUMO

The aim of the present study was to assess the neuroprotective effects of xanthotoxin and umbelliferone in streptozotocin (STZ)-induced cognitive dysfunction in rats. Animals were injected intracerebroventricularly (ICV) with STZ (3 mg/kg) once to induce a sporadic Alzheimer's disease (SAD)-like condition. Xanthotoxin or umbelliferone (15 mg/kg, i.p.) were administered 5 hr after ICV-STZ and daily for 20 consecutive days. Xanthotoxin or umbelliferone prevented cognitive deficits in the Morris water maze and object recognition tests. In parallel, xanthotoxin or umbelliferone reduced hippocampal acetylcholinestrase activity and malondialdehyde level. Moreover, xanthotoxin or umbelliferone increased glutathione content. These coumarins also modulated neuronal cell death by reducing the level of proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-6), inhibiting the overexpression of inflammatory markers (nuclear factor κB [NF-κB] and cyclooxygenase II), and upregulating the expression of NF-κB inhibitor (IκB-α). Interestingly, xanthotoxin diminished phosphorylated JAK2 and phosphorylated STAT3 protein expression, while umbelliferone markedly replenished nuclear factor erythroid-derived 2-like 2 (Nrf2) and haem oxygenase-1 (HO-1) levels. The current study provides evidence for the protective effect of xanthotoxin and umbelliferone in STZ-induced cognitive dysfunction in rats. This effect may be attributed, at least in part, to inhibiting acetylcholinestrase and attenuating oxidative stress, neuroinflammation and neuronal loss.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Metoxaleno/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Transcrição STAT3/metabolismo , Estreptozocina/efeitos adversos , Umbeliferonas/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Metoxaleno/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais , Umbeliferonas/farmacologia
13.
Toxicology ; 437: 152436, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169473

RESUMO

Alzheimer's disease (AD) is a public health crisis due to debilitating cognitive symptoms and lack of curative treatments, in the context of increasing prevalence. Thus, it is critical to identify modifiable risk factors. High levels of meat consumption may increase AD risk. Many toxins are formed during meat cooking such as heterocyclic aromatic amines (HAAs). Our prior studies have shown that HAAs produce dopaminergic neurotoxicity. Given the mechanistic and pathological overlap between AD and dopaminergic disorders we investigated whether exposure to 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a prevalent dietary HAA formed during high-temperature meat cooking, may produce AD-relevant neurotoxicity. Here, C57BL/6 mice were treated with 100 or 200 mg/kg PhIP for 8 h or 75 mg/kg for 4 weeks and 16 weeks. PhIP exposure for 8 h produced oxidative damage, and AD-relevant alterations in hippocampal synaptic proteins, Amyloid-beta precursor protein (APP), and ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1). PhIP exposure for 4 weeks resulted in an increase in BACE1. PhIP exposure for 16 weeks resulted in increased hippocampal oxidative damage, APP, BACE1, Aß aggregation, and tau phosphorylation. Quantification of intracellular nitrotyrosine revealed oxidative damage in cholinergic neurons after 8 h, 4 weeks and 16 weeks of PhIP exposure. Our study demonstrates that increase in oxidative damage, APP and BACE1 might be a possible mechanism by which PhIP promotes Aß aggregation. Given many patients with AD or PD exhibit neuropathological overlap, our study suggests that HAA exposure should be further studied for roles in mediating pathogenic overlap.


Assuntos
Doença de Alzheimer/patologia , Contaminação de Alimentos , Hipocampo/patologia , Imidazóis , Neurônios/patologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Estresse Oxidativo , Fosforilação , Agregação Patológica de Proteínas , Fatores de Tempo , Proteínas tau/metabolismo
14.
Eur J Med Chem ; 192: 112180, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32131034

RESUMO

In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent huAChE (IC50 = 0.36 µM) and huBChE (IC50 = 15.3 µM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aß1-42 aggregation (IC50 = 3.7 µM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu2+-induced Aß aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl3-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aß1-40-induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Desenvolvimento de Medicamentos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Cloreto de Alumínio , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila/síntese química , Donepezila/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra
15.
Toxicol Lett ; 326: 31-51, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145396

RESUMO

Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.


Assuntos
Doença de Alzheimer/induzido quimicamente , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Exposição Ambiental/efeitos adversos , Neurotoxinas/toxicidade , Praguicidas/toxicidade , Animais , Feminino , Humanos , Masculino , Modelos Animais , Medição de Risco/métodos
16.
Psychopharmacology (Berl) ; 237(6): 1851-1860, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32221697

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease. However, effective drugs for this disease have not yet been developed. The analysis of big data indicated that childhood herpes virus infection may be associated with the incidence of AD, suggesting that anti-herpetic drugs, such as acyclovir, may have preventive and suppressive effects in AD therapy. Moreover, short-term use of dexamethasone (DXMT), a clinical used synthetic corticosteroid, could effectively inhibit AD-related neuroinflammation. In this study, we have found that the combination of acyclovir and DXMT, but not acyclovir or DXMT alone, could protect against AD causing ß-amyloid (Aß) oligomer-induced spatial cognitive impairments. Moreover, acyclovir and DXMT could prevent Aß oligomer-induced over-activation of microglia and astrocytes, and over-expression of pro-inflammatory cytokines, indicating that anti-AD effects of drug combination might be at least partially via neuroinflammation inhibition and immunomodulation. Furthermore, Aß oligomer-induced decrease of PSD-95 and increase of pTau expression was prevented by the combination of acyclovir and DXMT, suggesting the involvement of synaptic protective effects of the drug combination. Taken together, our studies indicated that the combination of acyclovir and DXMT might be an alternative therapy for the treatment of AD.


Assuntos
Aciclovir/administração & dosagem , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/toxicidade , Disfunção Cognitiva/prevenção & controle , Dexametasona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Quimioterapia Combinada , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-32079163

RESUMO

Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson's and Alzheimer's diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies.


Assuntos
Doença de Alzheimer , Tauopatias , Xenobióticos , Doença de Alzheimer/induzido quimicamente , Humanos , Metais , Tauopatias/induzido quimicamente , Xenobióticos/toxicidade , Proteínas tau
18.
Int J Pharm ; 578: 119115, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32045690

RESUMO

Alzheimer's disease (AD) is a common and severe brain disease with a high mortality among the elders, but no highly efficient medications are currently available. For example, timosaponin BII, an efficient anti-AD agent, has low oral bioavailability. Here, timosaponin BII was formulated in a temperature/ion-sensitive in situ hydrogel (ISG) that was well transformed into gels in the nasal environment. Timosaponin BII protected the PC12 cells injured by lipopolysaccharides (LPS) by decreasing TNF-α and IL-1ß and stabilizing F-actin. Timosaponin BII ISGs were intranasally administered to the mice every day for 38 days. On Day 36, LPS was injected to the mice to establish an AD model. Morris water maze experiments showed that the number of the animals that were able to cross the platform returned to normal and the total distance over which the animals moved in the open field also increased, which demonstrated that the spatial memory and spontaneous behavior were improved after treatment compared to the model. Moreover, an AD improver, inducible nitric oxide synthase (iNOS) in the brain, was reduced after treatment. High brain targeting effect of timosaponin BII ISGs was confirmed by in vivo fluorescence imaging. The nasal timosaponin BII dually sensitive ISGs can serve as a promising medication for local prevention of AD.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Hidrogéis/administração & dosagem , Lipopolissacarídeos/farmacologia , Saponinas/administração & dosagem , Esteroides/administração & dosagem , Administração Intranasal , Doença de Alzheimer/metabolismo , Animais , Anuros , Linhagem Celular Tumoral , Feminino , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Nariz/efeitos dos fármacos , Células PC12 , Coelhos , Ratos , Ovinos , Fator de Necrose Tumoral alfa/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-32033400

RESUMO

Fe2O3, CuO and ZnO nanoparticles (NP) have found various industrial and biomedical applications. However, there are growing concerns among the general public and regulators about their potential environmental and health impacts as their physio-chemical interaction with biological systems and toxic responses of the latter are complex and not well understood. Herein we first reported that human SH-SY5Y and H4 cells and rat PC12 cell lines displayed concentration-dependent neurotoxic responses to insults of CuO nanoparticles (CuONP), but not to Fe2O3 nanoparticles (Fe2O3NP) or ZnO nanoparticles (ZnONP). This study provides evidence that CuONP induces neuronal cell apoptosis, discerns a likely p53-dependent apoptosis pathway and builds out the relationship between nanoparticles and Alzheimer's disease (AD) through the involvement of reactive oxygen species (ROS) and increased Aß levels in SH-SY5Y and H4 cells. Our results implicate that exposure to CuONP may be an environmental risk factor for AD. For public health concerns, regulation for environmental or occupational exposure of CuONP are thus warranted given AD has already become a pandemic.


Assuntos
Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/efeitos dos fármacos , Amiloidose/induzido quimicamente , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Cobre/toxicidade , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Exposição Ambiental/efeitos adversos , Humanos , Modelos Animais , Síndromes Neurotóxicas , Ratos , Oligoelementos/toxicidade
20.
Environ Health ; 19(1): 8, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964412

RESUMO

BACKGROUND: Emerging evidence links road proximity and air pollution with cognitive impairment. Joint effects of noise and greenness have not been evaluated. We investigated associations between road proximity and exposures to air pollution, and joint effects of noise and greenness, on non-Alzheimer's dementia, Parkinson's and Alzheimer's disease and multiple sclerosis within a population-based cohort. METHODS: We assembled administrative health database cohorts of 45-84 year old residents (N ~ 678,000) of Metro Vancouver, Canada. Cox proportional hazards models were built to assess associations between exposures and non-Alzheimer's dementia and Parkinson's disease. Given reduced case numbers, associations with Alzheimer's disease and multiple sclerosis were evaluated in nested case-control analyses by conditional logistic regression. RESULTS: Road proximity was associated with all outcomes (e.g. non-Alzheimer's dementia hazard ratio: 1.14, [95% confidence interval: 1.07-1.20], for living < 50 m from a major road or < 150 m from a highway). Air pollutants were associated with incidence of Parkinson's disease and non-Alzheimer's dementia (e.g. Parkinson's disease hazard ratios of 1.09 [1.02-1.16], 1.03 [0.97-1.08], 1.12 [1.05-1.20] per interquartile increase in fine particulate matter, Black Carbon, and nitrogen dioxide) but not Alzheimer's disease or multiple sclerosis. Noise was not associated with any outcomes while associations with greenness suggested protective effects for Parkinson's disease and non-Alzheimer's dementia. CONCLUSIONS: Road proximity was associated with incidence of non-Alzheimer's dementia, Parkinson's disease, Alzheimer's disease and multiple sclerosis. This association may be partially mediated by air pollution, whereas noise exposure did not affect associations. There was some evidence of protective effects of greenness.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Doença de Alzheimer/epidemiologia , Meio Ambiente , Ruído/efeitos adversos , Doença de Parkinson/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/induzido quimicamente , Colúmbia Britânica/epidemiologia , Estudos de Casos e Controles , Feminino , Geografia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etiologia , Modelos de Riscos Proporcionais , Análise de Regressão , Características de Residência
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