Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity

Although the accumulation of the neurotoxic peptide {beta} amyloid ({beta}A) in the CNS is a hallmark of Alzheimer's disease, the mechanism of {beta}A neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide {beta}A (1–42) and the neurotoxic fragment (25–35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca2+]c)] signals in astrocytes that continued for hours, whereas adjacent neurons were completely unaffected. Nevertheless, after 24 hr, although astrocyte cell death was marginally increased, ~50% of the neurons had died. The [Ca2+]c signal was entirely dependent on Ca2+ influx and was blocked by zinc and by clioquinol, a heavy-metal chelator that is neuroprotective in models of Alzheimer's disease. Neuronal death was associated with Ca2+-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of {beta}A, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support

β-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase

β-Amyloid (βA) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of βA-induced neuronal death. βA causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca2+-dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks βA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents βA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of βA-induced neurodegeneration

Expression and modulation of an NADPH oxidase in mammalian astrocytes

Amyloid β peptides generate oxidative stress in hippocampal astrocytes through a mechanism sensitive to inhibitors of the NADPH oxidase [diphenylene iodonium (DPI) and apocynin]. Seeking evidence for the expression and function of the enzyme in primary hippocampal astrocytes, we confirmed the expression of the subunits of the phagocyte NADPH oxidase by Western blot analysis and by immunofluorescence and coexpression with the astrocyte-specific marker glial fibrillary acidic protein both in cultures and in vivo. Functional assays using lucigenin luminescence, dihydroethidine, or dicarboxyfluorescein fluorescence to measure the production of reactive oxygen species (ROS) demonstrated DPI and apocynin-sensitive ROS generation in response to the phorbol ester PMA and to raised [Ca2+]c after application of ionomycin or P2u receptor activation. Stimulation by PMA but not Ca2+ was inhibited by the protein kinase C (PKC) inhibitors staurosporine and hispidin. Responses were absent in transgenic mice lacking gp91phox. Expression of gp91phox and p67phox was increased in reactive astrocytes, which showed increased rates of both resting and stimulated ROS generation. NADPH oxidase activity was modulated by intracellular pH, suppressed by intracellular alkalinization, and enhanced by acidification. The protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone suppressed basal ROS generation but markedly increased PMA-stimulated ROS generation. This was independent of mitochondrial ROS production, because it was unaffected by mitochondrial depolarization with rotenone and oligomycin. Thus, the NADPH oxidase is expressed in astrocytes and is functional, activated by PKC and intracellular calcium, modulated by pHi, and upregulated by astrocyte activation. The astrocytic NADPH oxidase is likely to play important roles in CNS physiology and pathology

Investigation of using sulfur-containing gases in low-temperature fuel cell at sulfuric acid production site

The possibility and effectiveness of using sulfur dioxide and hydrogen sulfide as the fuel in lowtemperature fuel cells at the sulfuric acid production site has been investigated. A fuel cell has been designed and constructed using palladium as a catalyst, which enables conversion of the energy of oxidation of sulfur dioxide and hydrogen sulfide to the electric energy. The experimental data showed that the use of hydrogen sulfide and sulfur dioxide as a fuel allows achieving the power of 1.0 and 0.5 mW, respectively. The comparative studies with the use of hydrogen in the same fuel cell resulted in the power of about 2.0 mW, i.e. the use of hydrogen sulfide delivers a performance comparable with that of the hydrogen. The processes of oxidizing of the sulfur containing gases are used in our company in production of sulfuric acid. Oxidation of these gases conducted using the conventional technological processes. The use of these processes to produce energy as a byproduct could be an attractive way to reduce the energy consumption of the whole process. Considering the relatively high power obtained in this work for the sulfur containing gases fed fuel cells, the substitution of conventional oxidation of sulfur containing gases in this technological chain by the fuel cell oxidation, and by-producing the electric energy, could be very profitable for the energy efficiency enhancement of the main production process. In the future work, the design and development of fuel cell catalysts and membranes to enhance the performances of sulfur containing fuel cells will be significant

Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity

Feasibility studies for the measurement of time-like proton electromagnetic form factors from p¯ p→ μ+μ- at P ¯ ANDA at FAIR

This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, | GE| and | GM| , using the p¯ p→ μ+μ- reaction at P ¯ ANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at P ¯ ANDA , using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is p¯ p→ π+π-, due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distributions of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented

ORGANIZATIONAL AND METHODICAL PROBLEMS OF DISTANCE LEARNING OF MEDICAL STUDENTS IN THE COVID-19 PANDEMIC

In connection with the COVID-19 pandemic, since March 2020, medical universities in different countries have been forced to switch to distance or blended learning formats. The article discusses the limitations and advantages of distance learning through a meta-analysis of the research results and the authors' own experience. The article describes different options for conducting current classes, intermediate and final online certification, the peculiarities of establishing new methods of communication and changes in student-teacher communication. Practical recommendations are offered for solving organizational, methodical, educational, technical and informational problems of RUDN University and A. I. Yevdokimov MSMSU, associated with distance learning of future doctors

Introduction of tactile simulator virteasy dental to teach the students of dental faculty at Russian peoples friendship university

Modern rules applicable to educational process, require the introduction of innovative technologies into learning process from higher education institutions. During the last few years the teaching in the countries of Europe and America takes place with the introduction of new technologies for e-learning, the introduction of virtual technologies in educational process. The appearance of clinical situation virtual modeling simulators allowed to introduce the modern opportunities for student learning into the educational process. © 2016, International Journal of Pharmacy and Technology. All rights reserved

Simulation tasks in health care and public health training

Continuous medical education and accreditation of health care personnel and managers have become an urgent topic of discussion in Russia, Armenia and other countries. Discussion of these issues is based on the health care needs of highly skilled managers. It is necessary to assess the experience of other countries in using simulations to consolidate the practical skills of making managerial decisions. In this article use problems the simulations tasks in educational process of training of managers of health care and medical insurance are discussed. The analysis of ways of introduction the simulations of technologies is carried out to formation of competences of managers of health care and medical insurance. On the basis of own experience authors developed an algorithm of a multilevel technique the simulations tasks for training of administrator of public health, health care and medical insurance. Several levels of an algorithm of the simulations tasks on the basis of which skills of management are gained are offered: cases solutions, a training in a workplace, a mentoring. This problem remains important and relevant for health managers and teachers of all countries. The experience of Russia’s higher school in the issue of simulation training of medical organizations may be of interest to managers and trainers. Increase the effectiveness of health care is possible only with the help of successful management. The article substantiates important educational and methodological educational provisions and principles on which a continuous medical education in health care is identified: professional retraining in educational programs, internship at the workplace, a system of training in distance educational technologies and teaching materials to support the learning process. Simulation training will not solve all the problems of domestic healthcare, but it is an effective tool for increasing the effectiveness of medical education. In the article discusses the issues and proposes mechanisms for continuous medical education and accreditation of specialists of the health care organization and public health on the base of simulation, tasks. © 2020, Yerevan State Medical University. All rights reserved