РЕДКИЙ ПЕРВИЧНЫЙ ИММУНОДЕФИЦИТ — ГИПЕР-IGE-СИНДРОМ: ПРЕЗЕНТАЦИЯ СЛУЧАЯ И ОБЗОР ЛИТЕРАТУРЫ

The article is dedicated to one of the rare primary immunodeficiency pathologies – hyper-IgE-syndrome. The authors present a clinical case from their own practice and a literature review on this disease. Inheritance, pathogenesis, clinical manifestations and hyper-IgE-syndrome diagnostics issues are also examined in the article. The article shows differences of disease course at different inheritance types – autosomal-dominant and autosomal-recessive.Статья посвящена одной из редких патологий из группы первичных иммунодефицитов — гипер-IgE-синдрому. Авторы представляют клинический случай из собственной практики, а также обзор современных литературных данных по данной болезни. Рассмотрены вопросы наследования, патогенеза, клинических проявлений, а также диагностики гипер-IgE-синдрома. Показаны различия в течении болезни при разных типах наследования — аутосомнодоминантном, аутосомно-рецессивном

Does the SARS-CoV-2 Spike Receptor-Binding Domain Hamper the Amyloid Transformation of Alpha-Synuclein after All?

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our work was to analyze the effect of the receptor-binding domain of the coronavirus S-protein domain (RBD) on alpha-synuclein amyloid aggregation. Molecular modeling showed that the predicted RBD complex with monomeric alpha-synuclein is stable over 100 ns of molecular dynamics. Analysis of the interactions of RBD with the amyloid form of alpha-synuclein showed that during molecular dynamics for 200 ns the number of contacts is markedly higher than that for the monomeric form. The formation of the RBD complex with the alpha-synuclein monomer was confirmed immunochemically by immobilization of RBD on its specific receptor ACE2. Changes in the spectral characteristics of the intrinsic tryptophans of RBD and hydrophobic dye ANS indicate an interaction between the monomeric proteins, but according to the data of circular dichroism spectra, this interaction does not lead to a change in their secondary structure. Data on the kinetics of amyloid fibril formation using several spectral approaches strongly suggest that RBD prevents the amyloid transformation of alpha-synuclein. Moreover, the fibrils obtained in the presence of RBD showed significantly less cytotoxicity on SH-SY5Y neuroblastoma cells

Does the SARS-CoV-2 Spike Receptor-Binding Domain Hamper the Amyloid Transformation of Alpha-Synuclein after All?

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our work was to analyze the effect of the receptor-binding domain of the coronavirus S-protein domain (RBD) on alpha-synuclein amyloid aggregation. Molecular modeling showed that the predicted RBD complex with monomeric alpha-synuclein is stable over 100 ns of molecular dynamics. Analysis of the interactions of RBD with the amyloid form of alpha-synuclein showed that during molecular dynamics for 200 ns the number of contacts is markedly higher than that for the monomeric form. The formation of the RBD complex with the alpha-synuclein monomer was confirmed immunochemically by immobilization of RBD on its specific receptor ACE2. Changes in the spectral characteristics of the intrinsic tryptophans of RBD and hydrophobic dye ANS indicate an interaction between the monomeric proteins, but according to the data of circular dichroism spectra, this interaction does not lead to a change in their secondary structure. Data on the kinetics of amyloid fibril formation using several spectral approaches strongly suggest that RBD prevents the amyloid transformation of alpha-synuclein. Moreover, the fibrils obtained in the presence of RBD showed significantly less cytotoxicity on SH-SY5Y neuroblastoma cells

Hydroxycinnamic Acid Derivatives from Coffee Extracts Prevent Amyloid Transformation of Alpha-Synuclein

Earlier we showed that derivatives of hydroxycinnamic acids prevent amyloid transformation of alpha-synuclein and prion protein. The aim of this work was to determine the content of 3-hydroxycinnamic acid derivatives in coffee extracts and to evaluate their activity in relation to alpha-synuclein amyloid aggregation. Hydroxycinnamic acid derivatives were identified in aqueous and ethanol extracts of coffee beans by quantitative mass spectrometric analysis. Only 3,4-dimethoxycinnamic acid (13–53 μg/mL) was detected in significant amounts in the coffee extracts, while ferulic acid was present in trace amounts. In addition, 3-methoxy-4-acetamidoxycinnamic acid (0.4–0.8 μg/mL) was detected in the roasted coffee extracts. The half-maximum inhibitory concentrations of alpha-synuclein fibrillization reaction in the presence of coffee extracts, as well as inhibitory constants, were determined using thioflavin T assay. The inhibitory effect of black and green coffee extracts on alpha-synuclein fibrillization is dose-dependent, and in a pairwise comparison, the constants of half-maximal inhibition of fibrillization for green coffee extracts are comparable to or greater than those for black coffee. Thus, coffee extracts prevent pathological transformation of alpha-synuclein in vitro, probably due to the presence of 3,4-dimethoxycinnamic acid in them. Consequently, coffee drinks and coffee extracts can be used for the prevention of synucleinopathies including Parkinson’s disease

Natural and synthetic derivatives of hydroxycinnamic acid modulating the pathological transformation of amyloidogenic proteins

This review presents the main properties of hydroxycinnamic acid (HCA) derivatives and their potential application as agents for the prevention and treatment of neurodegenerative diseases. It is partially focused on the successful use of these compounds as inhibitors of amyloidogenic transformation of proteins. Firstly, the prerequisites for the emergence of interest in HCA derivatives, including natural compounds, are described. A separate section is devoted to synthesis and properties of HCA derivatives. Then, the results of molecular modeling of HCA derivatives with prion protein as well as with α-synuclein fibrils are summarized, followed by detailed analysis of the experiments on the effect of natural and synthetic HCA derivatives, as well as structurally similar phenylacetic and benzoic acid derivatives, on the pathological transformation of prion protein and α-synuclein. The ability of HCA derivatives to prevent amyloid transformation of some amyloidogenic proteins, and their presence not only in food products but also as natural metabolites in human blood and tissues, makes them promising for the prevention and treatment of neurodegenerative diseases of amyloid nature

Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins

This review presents the main properties of hydroxycinnamic acid (HCA) derivatives and their potential application as agents for the prevention and treatment of neurodegenerative diseases. It is partially focused on the successful use of these compounds as inhibitors of amyloidogenic transformation of proteins. Firstly, the prerequisites for the emergence of interest in HCA derivatives, including natural compounds, are described. A separate section is devoted to synthesis and properties of HCA derivatives. Then, the results of molecular modeling of HCA derivatives with prion protein as well as with α-synuclein fibrils are summarized, followed by detailed analysis of the experiments on the effect of natural and synthetic HCA derivatives, as well as structurally similar phenylacetic and benzoic acid derivatives, on the pathological transformation of prion protein and α-synuclein. The ability of HCA derivatives to prevent amyloid transformation of some amyloidogenic proteins, and their presence not only in food products but also as natural metabolites in human blood and tissues, makes them promising for the prevention and treatment of neurodegenerative diseases of amyloid nature

Alzheimer's Amyloidopathy: An Alternative Aspect.

From PubMed via Jisc Publications RouterPublication status: aheadofprintThe 'amyloid hypothesis' dominates Alzheimer's disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1 (PSEN1) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12. These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials