Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer's disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review

Potencial citotóxico, genotóxico e citoprotetor de extratos aquosos de Caesalpinia pyramidalis Tul., Caesalpinia ferrea Mart. e Caesalpinia pulcherrima Sw.

The legumenous Caesalpinia pyramidalys, Caesalpinia ferrea and Caesalpinia pulcherrima are widely used in folk medicine in many countries. Thus, this study aimed to cytogenetically evaluate, through the use of meristematic roots cells of Allium cepa, after the exposure times 24 and 48 hours, the cytotoxic potential of aqueous extracts, at concentrations 1 g/500 mL and 1 g/1000 mL, obtained from the inner bark of Caesalpinia pyramidalis, the pod of Caesalpinia ferrea and the leaves of Caesalpinia pulcherrima, and also verify the modulatory potential of these extracts on cellular alterations induced by Paracetamol. The treatment groups used were: negative control – distilled water; positive control – 0.008 mg/mL Paracetamol solution; plant aqueous extract control – water fraction from the plants at concentrations 1 g/500 mL and 1 g/1000 mL; and simultaneous treatment – water fraction from the plants at concentrations 1 g/500 mL and 1g/1000 mL associated with 0.008 mg/mL Paracetamol solution. The Chi-square statistical test was used at 5% probability for data analysis. The results showed that C. pyramidalis and C. ferrea had a significant antiproliferative effect on the cells of the test organism, at both concentrations (1 g/500 mL and 1 g/1000 mL) and at both times of exposure, thus being cytotoxic. All three plants promoted significant cytoprotective effect on the Paracetamol-treated meristematic root cells of A. cepa, thus showing, under the studied conditions, antimutagenic potential. Further studies using these plants should be carried out in order to properly define the cytotoxic and cytoprotective potential of pau-ferro’s pod, catingueira’s inner bark and flamboyazinho’s leaves.Os objetivos do presente trabalho foram avaliar, por meio das células meristemáticas de raízes de Allium cepa, nos tempos de exposição 24 e 48 horas, o potencial citotóxico de extratos aquosos, nas concentrações de 1g/500ml e 1g/1000ml, provenientes da entrecasca de Caesalpinia pyramidalis, da vagem de Caesalpinia ferrea e das folhas de Caesalpinia pulcherrima, e verificar o potencial modulador destes extratos frente as aberrações celulares induzidas por Paracetamol a partir dos seguintes grupos tratamentos:  controle negativo – água destilada; controle positivo – solução de Paracetamol a 0,008mg/ml, controle extrato aquoso da planta – fração aquosa de uma das plantas na concentração de 1g/500ml ou 1g/1000ml,  tratamento simultâneo - fração aquosa de uma das plantas na concentração de 1g/500ml ou 1g/1000ml associada a solução de Paracetamol a 0,008mg/ml. As raízes de A. cepa após os tratamentos foram fixadas em solução de Carnoy, hidrolisadas em ácido e coradas com orceína acética a 2%. Em seguida fez-se o esmagamento dos meristemas e montagem das lâminas. Analisou-se 5.000 células para cada grupo tratamento em microscopia de campo claro (40x), e utilizou-se o teste estatístico Qui-quadrado a 5% para análise dos dados. A partir dos resultados obtidos verificou-se que C. pyramidalis e C. ferrea nas duas concentrações e nos dois tempos de exposição avaliados tiveram efeito antiproliferativo significativo as células do organismo de prova utilizado, mostrando-se citotóxicas. Também foi observado que os respectivos tratamentos simultâneos de cada planta, nas duas concentrações e nos dois tempos de exposição avaliados, não diferiram do índice de divisão celular do seu respectivo controle extrato aquoso da planta. As três plantas promoveram efeito citoprotetor significativo as células meristemáticas de raízes de A. cepa tratadas com Paracetamol, demonstrando, nas condições analisadas, potencial antimutagênico. Os resultados obtidos aqui com A. cepa sugerem a realização de mais estudos, com outros sistemas testes e diferentes esquemas de tratamento, para assim se definir, com propriedade, o real potencial citotóxico e antimutagênico destas plantas

Cirurgia bariátrica - aspectos epidemiológicos, fisiopatológicos e principais técnicas cirúrgicas empregadas

Nas últimas décadas, houve uma mudança no estilo de vida que contribuiu para um aumento alarmante da obesidade. Padrões alimentares ricos em calorias e comportamento sedentário têm levado a uma epidemia global, com números preocupantes tanto entre adultos quanto entre crianças e adolescentes. A cirurgia bariátrica é reconhecida como o tratamento mais eficaz para combater a obesidade e suas complicações. Esses procedimentos cirúrgicos, como o bypass gástrico, a banda gástrica ajustável, a gastrectomia vertical e a derivação biliopancreática, demonstraram ser altamente eficientes na redução de peso a longo prazo e no tratamento de problemas metabólicos associados. Embora ainda haja incertezas sobre os mecanismos exatos envolvidos na perda de peso resultante da cirurgia bariátrica, acredita-se que eles envolvam o controle do apetite, a influência de peptídeos intestinais, modificações na microbiota e alterações nos ácidos biliares. No geral, a cirurgia bariátrica é considerada a terapia mais eficaz disponível atualmente para alcançar e manter a perda de peso a longo prazo. Outrossim, intervenções endoscópicas minimamente invasivas têm ganhado espaço no manejo do paciente obeso; atualmente, existem três estratégias bariátricas endoscópicas comumente utilizadas: balões intragástricos (BIGs), gastroplastia endoscópica (GE) e bypass duodeno-jejunal endoscópico (BDJE). Esses procedimentos visam reduzir a capacidade do estômago e a absorção de nutrientes, resultando em perda de peso. Além disso, os procedimentos bariátricos endoscópicos têm mostrado resultados promissores devido às suas características, como baixo impacto traumático, possibilidade de reversão, recuperação rápida, custo-efetividade e eficácia na redução de peso

Plataforma Ensinando o Lattes / Platform teaching Lattes

O grupo do programa de educação tutorial em Odontologia (PET Odontologia - UNESP) da Universidade Estadual Paulista, UNESP, Faculdade de Odontologia de Araraquara, São Paulo, Brasil, com o apoio de seu tutor e vice-diretora, criaram e publicaram uma plataforma voltada para graduandos, intitulada “Plataforma Ensinando o Lattes”, em junho de 2020. Para ensinar o correto preenchimento da Plataforma Lattes, o material didático foi produzido em PDF e publicado via internet. Composto por tutoriais simples, instruções básicas e dividido em dez módulos, abordou os itens mais utilizados da produção curricular durante a graduação. A plataforma foi divulgada nas redes sociais do PET Odontologia - UNESP. Observou-se que a “Plataforma de Ensino Lattes” atingiu um grande público. Recebeu 1.051 acessos no Instagram e, entre eles, 106 usuários salvaram o documento. O site contabilizou 635 visitas. Os resultados mostraram que a “Plataforma Ensinando o Lattes” constitui um material instrucional de grande valor para os graduandos na construção e atualização do currículo

Niveaux d'ADAM10 dans le fluide cérébrospinal et le sérum d'individus avec la maladie d'Alzheimer

Researchers have pointed out that the identification of ADAM10 as a biomarker can be an important tool to aid in the clinical diagnosis of AD. The proposal of ADAM10 as a biomarker occurs because it is involved in different physiological and pathological processes, including AD. Studies indicate that ADAM10 platelet levels are lower in patients with AD compared to healthy subjects, however, there are few studies on the expression and activity of this protein in cerebrospinal fluid (CSF). This study was based on the hypothesis that levels of inactive ADAM10 in CSF and serum are increased in AD compared to cognitively healthy subjects. We evaluated levels and activity of ADAM10 in CSF and serum of patients with AD dementia and mild neurocognitive disorder (TNCL). The participants were submitted to clinical and neurological evaluations, and later CSF and serum samples were collected. The data obtained were analyzed in a database to perform descriptive statistical analyzes, considering statistical significance of 5% (p <0.05). It was possible to demonstrate that levels of soluble ADAM10 are elevated in the CSF and blood serum of patients with AD. Enzyme assays demonstrated absence of ADAM10 activity in serum and CSF, with the presence of ADAM10 activity in platelets. These results allow us to conclude that increased levels of ADAM10 in CSF and serum correspond to the inactive protein and strengthen ADAM10 as a biomarker for AD.Não recebi financiamentoPesquisadores têm apontado que a identificação da ADAM10 como biomarcador pode ser uma importante ferramenta para auxiliar no diagnóstico clínico de DA. A proposta da ADAM10 como biomarcador se dá por estar envolvida em diferentes processos fisiológicos e patológicos, incluindo a DA. Estudos apontam que os níveis plaquetários de ADAM10 são menores em pacientes com DA comparado a sujeitos saudáveis, entretanto são escassos estudos sobre a expressão e atividade dessa proteína no líquido cefalorraquidiano (LCR). Este estudo se baseou na hipótese de que os níveis de ADAM10 solúvel no LCR e soro estão aumentados na DA, comparados com sujeitos cognitivamente saudáveis. Avaliamos os níveis e a atividade da ADAM10 no LCR e soro de pacientes com demência da DA e transtorno neurocognitivo leve (TNCL). Os participantes foram submetidos a avaliações clínicas e neurológicas e posteriormente foram realizadas as coletas do LCR e soro. Os dados obtidos foram analisados e inseridos em um banco de dados para realização de análises estatísticas descritivas, considerando significância estatística de 5% (p < 0,05). Foi possível demonstrar que os níveis de ADAM10 solúvel estão elevados no LCR e soro sanguíneo de pacientes com DA. Ensaios enzimáticos demonstraram ausência da atividade da ADAM10 no soro e LCR, com presença atividade da ADAM10 em plaquetas. Níveis aumentados de ADAM10 no LCR e soro correspondem à proteína inativa e fortalecem a proposta da ADAM10 como biomarcador para DA

Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review

ADAM10 Plasma and CSF Levels Are Increased in Mild Alzheimer’s Disease

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers

Profile of the population use of household insecticides against mosquitoes

This study described the use of household insecticides in Picos (Piauí, Brazil), identify which are the most used types of insecticides and describes the incidence of poisoning and environmental awareness of the population. After home visits (n = 700), it was seen that the majority of respondents was represented by women (75%), with 31-55 years-old (49%), incomplete primary education (38.1%) and income between 1-2 earnings (64%). Most homes have between 1-3 residents (48%), 85% of the persons use insecticides mainly chosen in TV and radio and only 54% of them read the label before employing the product. The most used form of presentation is the aerosol (70.7%). Majority (79%) recognizes that insecticides are harmful to health, but 74% do not use any Personal Protective Equipment (PPE). Symptoms of toxicity were reported by 27% of people interviewed. Two women reported irritation, dizziness and respiratory problems and need for medical intervention and hospitalization. All interviewed discard the package as regular trash, since Picos does not has selective collection. In conclusion, most people use insecticides, know about the individual and collective risks to which they are exposed but do not use PPE, though they believe insecticides are toxic. It was noted that acquisition of knowledge does not necessarily result in behavioral changes, since learning does not translate into appropriate preventive attitudes and practices, emphasizing the requirement for awareness campaigns about toxicity and environmental risks, preparation of professionals and surveillance policy against indiscriminate sale