Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity

All forms of dementia including Alzheimer's disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer's disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on β-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on β-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against β-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against β-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents

Erratum to : Analysis of the mitochondrial maxicircle of Trypanosoma lewisi, a neglected human pathogen

BACKGROUND The haemoflagellate Trypanosoma lewisi is a kinetoplastid parasite which, as it has been recently reported to cause human disease, deserves increased attention. Characteristic features of all kinetoplastid flagellates are a uniquely structured mitochondrial DNA or kinetoplast, comprised of a network of catenated DNA circles, and RNA editing of mitochondrial transcripts. The aim of this study was to describe the kinetoplast DNA of T. lewisi. METHODS/RESULTS In this study, purified kinetoplast DNA from T. lewisi was sequenced using high-throughput sequencing in combination with sequencing of PCR amplicons. This allowed the assembly of the T. lewisi kinetoplast maxicircle DNA, which is a homologue of the mitochondrial genome in other eukaryotes. The assembly of 23,745 bp comprises the non-coding and coding regions. Comparative analysis of the maxicircle sequence of T. lewisi with Trypanosoma cruzi, Trypanosoma rangeli, Trypanosoma brucei and Leishmania tarentolae revealed that it shares 78 %, 77 %, 74 % and 66 % sequence identity with these parasites, respectively. The high GC content in at least 9 maxicircle genes of T. lewisi (ATPase6; NADH dehydrogenase subunits ND3, ND7, ND8 and ND9; G-rich regions GR3 and GR4; cytochrome oxidase subunit COIII and ribosomal protein RPS12) implies that their products may be extensively edited. A detailed analysis of the non-coding region revealed that it contains numerous repeat motifs and palindromes. CONCLUSIONS We have sequenced and comprehensively annotated the kinetoplast maxicircle of T. lewisi. Our analysis reveals that T. lewisi is closely related to T. cruzi and T. brucei, and may share similar RNA editing patterns with them rather than with L. tarentolae. These findings provide novel insight into the biological features of this emerging human pathogen

РОССИЙСКОЕ РЕСПИРАТОРНОЕ ОБЩЕСТВО ФЕДЕРАЛЬНЫЕ КЛИНИЧЕСКИЕ РЕКОМЕНДАЦИИ ПО ДИАГНОСТИКЕ И ЛЕЧЕНИЮ БРОНХИАЛЬНОЙ АСТМЫ

Asthma is a chronic inflammatory airway disease with bronchial hyperresponsivenes causing recurrent episodes of wheezing, dyspnea, chest tightness and cough which typically occur at nighttime or early in the morning. These episodes are due to generalized airway obstruction which is commonly reversible spontaneously or with treatment. Asthma is mainly diagnosed clinically and should be based on the patient's symptoms and signs, lung function testing with investigations of bronchial obstruction reversibility, allergy testing and after exclusion of other diseases. The aim of asthma therapy is achievement and maintenance of asthma control that is maximal resolution of clinical symptoms of the disease.Бронхиальная астма (БА) – хроническое воспалительное заболевание дыхательных путей с развитием бронхиальной гиперреактивности, которая обусловливает повторяющиеся эпизоды свистящих хрипов, одышки, чувства заложенности в груди и кашля, в особенности по ночам или ранним утром. Эти эпизоды связаны с распространенной обструкцией дыхательных путей, которая часто бывает обратимой спонтанно или под влиянием лечения. Диагноз БА является клиническим и устанавливается на основании жалоб и анамнеза пациента, клинико-функционального обследования с оценкой обратимости бронхиальной обструкции, специфического аллергологического обследования и при исключении других заболеваний. Целью лечения стабильной БА является достижение и поддержание контроля над симптомами БА, другими словами, максимальное устранение клинических проявлений заболевания