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Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms.AOX expression did not compromise the function of the mammalian respiratory chain at physiological conditions, however the complex IV inhibitor cyanide only partially blocked respiration by AOX-containing mitochondria. The relative fraction of cyanide-insensitive respiration increased at lower temperatures, indicative of a temperature-controlled attenuation of mammalian respiratory enzyme activity.As AOX does not translocate protons, the mitochondrial transmembrane potential in AOX-containing mitochondria was more sensitive to cyanide during succinate oxidation than during malate/pyruvate-supported respiration. High concentrations of cyanide fully collapsed membrane potential during oxidation of either succinate or glycerol 3-phosphate, but not during malate/pyruvate-supported respiration. This confirms AOX's electroneutral redox activity and indicates differences in the proton-translocating capacity of dehydrogenases upstream of the ubiquinone pool. Our respiration data refutes previous proposals for quinone partitioning within the supercomplexes of the respiratory chain, instead supporting the concept of a single homogeneous, freely diffusing quinone pool.Respiration with either succinate or glycerol 3-phosphate promotes reverse electron transfer (RET) towards complex I. AOX expression significantly decreased RET-induced ROS generation, with the effect more pronounced at low temperatures. Inhibitor-sensitivity analysis showed that the AOX-induced decrease in H2O2 release is due to the lower contribution of complex I to net ROS production during RET.Overall, our findings provide new insights into the role of temperature as a mechanism to control respiration and highlight the utility of AOX as a genetic tool to characterize both the distinct pathways of oxygen reduction and the role of redox control in RET.

Background. Viral infections trigger transcription factors, including Nrf2, which regulate the expression of genes related to cytokines, chemokines, and more. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in complex regulatory networks controlling the expression of cytoprotective genes and immune responses. Recently, new roles have been attributed to Nrf2, including the regulation of antiviral responses. Objective. The aim of the study was to analyze Nrf2 activation in influenza virus infection in vivo and in transmissible gastroenteritis coronavirus (TGEV) infection in vitro, as well as the effects of the flavonoid compositions Proteflazidum® and Protoil on the Nrf2 expression in these two experimental models of viral infection. Methods. Outbred white mice were infected with influenza A virus (A/FM/1/47/H1N1 strain). Jurkat cells were infected with TGEV, previously adapted to these cells. Flavonoid compositions Proteflazidum® and Protoil (Ecopharm, Ukraine), containing the mixture of tricin, luteolin, apigenin, quercetin, and rhamnosin, were used in corresponding dilutions. Real-Time PCR was employed to analyze Nrf2 RNA expression in the lungs of mice and in both uninfected and virus-infected cells. Additionally, ELISA was used to assess the expression of Nrf2 peptide. Results. The Nrf2 expression in the lungs of influenza virus-infected mice showed a tendency to increase within a 100-fold range. In virus-infected mice treated with Proteflazidum® or Protoil, the level of Nrf2 expression in the lungs decreased about 10-fold compared to infected untreated mice. TGEV infection resulted in 100-fold increase in Nrf2 expression in Jurkat cells. Both Proteflazidum® and Protoil decreased Nrf2 expression in TGEV-infected cells, while their effects on Nrf2 expression in the intact cells on Day 1 were not detected. Conclusions. Flavonoid compositions have only a slight effect on Nrf2 expression in intact cells. However, in case of virus infection, both in vivo and in vitro, they counteract the extensive up-regulation of Nrf2 expression due to viral infection.

Проблематика. Як ароматотвірні ферменти для надання аромату переробленій сировині застосовують протеази, а також комплекси ферментів із різними комбінаціями ліпази, амілази та целюлази. Рослинні ферменти мають значний потенціал впливу на реакції утворення аромату. Мета. Дослідження реакцій цілеспрямованої зміни аромату цибулі, листя дерев липи та вишні шляхом активації (для листя липи та вишні) або гальмування (для цибулі) дії комплексу ферментів рослинного походження. Методика реалізації. Листя липи та вишні, а також плоди цибулі використано як об’єкти, що змінюють аромат під дією комплексу ферментів. Для дії власних ферментів листя дерев були створені умови ферментації за принципом переробки листя чаю. Як додаткове джерело ферментів застосовано насіння гірчиці та коріння хрону. Для впливу на реакції утворення аромату цибулі використовували імбир, екстракти чорного та зеленого чаю, кори дуба. Результати. Встановлено, що ароматотвірні ферменти листя дерев активні в різні періоди формування листя: комплекс ферментів листя вишні активний після цвітіння дерев, липи – до цвітіння. Для зміни аромату цибулі ефективними є рослинні ферменти, такі як мірозинази гірчиці, поліфенолоксидази хрону. Для гальмування процесу утворення цибулевого аромату ефективними є речовини, які містяться в екстрактах чорного, зеленого чаю, імбиру. Висновки. Уповільненню або гальмуванню утворення цибулевого аромату сприяють компоненти імбиру, екстрактів чорного та зеленого чаю. Аромат листя дерев вишні та липи змінюється ферментами самого листя з утворенням аромату плодів вишні та цвіту липи відповідно. Рослинні ароматотвір­ні ферменти листя липи більший вплив на аромат мають у період до цвітіння, ніж після цвітіння, а листя вишні – після плодоносіння.

Abstract Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.

Background. In modern cardiovasclar surgery, it is a promising method to use xenotissues, which in their properties are close to human tissues, in order to restore the integrity of the heart chambers, its walls or valves. Decellularization of extracellular matrix (EMC) is applied in the process of creation of such bioprotheses. In EMC, the elastin and collagen components are preserved, and antigenic molecules are eliminated resulting in reduction the risk of rejection. The study is devoted to assessment of the histological, molecular-genetic and cytotoxic properties of decellularized bovine pericardium, processed with various concentrations of trypsin enzyme. Objective. The aim of the work is evaluation of efficiency of bovine pericardial decellularization, based on the use of trypsin enzyme with 1% Sodium Dodecyl Sulfate (SDS) and 0.1% SDS. Methods. Bovine pericardium was used as a biomaterial for decellularization. Decellularization protocol 1 envisages processing of samples with 0.25% Trypsin solution at 24 °C with constant shaking (200 rpm) along with processing with 1% ionic SDS detergent. The samples, prepared according to protocol 2, were processed with a low concentration of 0.1% SDS. Histological and morphological properties along with detection of nucleic acids concentration in the samples were studied. Matrix samples were cultured in a human fibroblasts cell culture suspension in order to determine cytotoxicity. Results. Histological examination has not revealed any presence of cells in tissues, decellularized in accordance with both protocols. More than 99% of the nucleic acids was removed from decellularized bovine matrix. During our study, we have not observed cytotoxic effect in vitro for protocol 2 matrix samples, decellularized with only 0.1% SDS. Focal destruction of fibroblasts was observed in conditions of long-term cultivation in protocol 1 samples (Trypsin + 1% SDS). Cells formed abnormal morphological aggregates. Samples of this group have also demonstated sructural changes in collagen and elastin fibers. Conclusions. Studies have shown that pericardial matrix tissue, decellularized with low-concentration of 0.1% SDS, has the same biological properties as the native pericardium. Decellularization of bovine pericardium, using trypsin enzyme with 1% SDS, has a cytotoxic effect on human cells.

Metropolitan Nikodemus (Rotov), who headed the Leningrad Diocese in 1963–1978, was at the same time chairman of the Holy Synod Commission on Christian Unity (since August 3, 1963; since May 30, 1972 he headed the Commission on Christian Unity and Interchurch Relations). The Metropolitan made his cathedral city widely open to church delegations, not only for all those from over the Orthodox world, but also for other Christian confessions. In those years, for the sake of establishing and deepening fraternal inter-confessional relations and for participating in theological interlocutions, Leningrad was visited by Catholic Bishop Johannes Willebrands (Cardinal and Chairman of the Secretariat for Promoting Christian Unity since 1969) and Archbishop Martti Simojoki, head of the Evangelical Lutheran Church of Finland. By building and strengthening business and personal ties with high hierarchs of different confessions, Metropolitan Nicodemus sought to get the most out of such contacts for his native Church and for the Leningrad Theological Academy.

Background. Programs of preclinical safety studies of the health care products depend on the regulatory status of the investigated products. The classification of such products, in particular suppositories for rectal and vaginal use, is a critical step of developing tactics for their biological evaluation. Adaptation of biological evaluation methods for the medical devices based on the combination of biologically active substances, as well as evaluation of the results of such studies is urgent task of biomedicine. Objective. To substantiate the regulatory status and to carry out a biological evaluation of medical devices in the form of vaginal suppositories based on octenidine dihydrochloride ("Prodexyn") and in the form of rectal suppositories based on Saw palmetto, Levisticum officinale and Calendula officinalis extracts ("Pravenor"). Methods. Biological evaluation was conducted according to the requirements of ISO 10993 standards using in vitro and in vivo biological test systems (cytotoxicity in cell culture and the MTT test, sensitizing and irritating effect in guinea pigs). Results. The cytotoxicity (СС50) of the medical device "Prodexyn" extract in Vero cell culture was 8.35 μg/ml calculated as octenidine dihydrochloride and 416.65 μg/ml calculated as dexpanthenol. "Pravenor" medical device was found to be non-toxic in Vero cell culture. According to the results of MMT assay CC50 for octenidine dihydrochloride was 1.67 μg/ml, and 83.33 μg/ml – for dexpanthenol. CC50 indicators calculated for the different active ingredients of the medical device "Pravenor" were the following: 50 mg/ml for the dwarf palm berries extract (Saw palmetto), 16.67 mg/ml for the lovage roots extract (Levisticum officinale), and 16.67 mg/ml for the calendula flowers extract (Calendula officinalis). No sensitizing or skin irritating effects were observed in guinea pigs. Conclusions. Biological evaluation of medical devices in the form of rectal suppositories "Pravenor" and vaginal suppositories "Prodexyn" performed using in vitro and in vivo biological systems. It was demonstrated an acceptable level of safety of the products. The MTT test was 5 times more sensitive than the Vero cell culture method in determination of cytotoxicity.

Background. Prostate-specific antigen (PSA) is a key marker used in the monitoring of patients with prostate hyperplasia, risk of deve­lopment and cancer of prostate. Clinical laboratory diagnostics for such patients are implemented using appropriate serological tests. Enzyme immunoassay kits are bioanalytical products that are subject to the requirements for medical devices for in vitro diagnostics. Thus, the urgent task of modern analytical biotechnology is improving bioanalytical, technical, and economic indicators of diagnostic kits, as well as their validation, as a prerequisite for the admission of such products to the market. Objective. Scientific substantiation of the composition and technology of highly informative enzyme-linked immunosorbent assay (ELISA) test-kit for the quantitative determination of free PSA in human serum (blood), as well as its bioanalytical validation at the time of manufacture and expiry date. Methods. A previously prepared and characterized set of monoclonal antibodies (mAb) to different PSA epitopes was used to construct ELISA. Peroxidase conjugates of mAbs were synthesized by periodate oxidation. We used the WHO Prostate Specific Antigen International Standard and the human serum with different PSA amount. The validation of the developed ELISA was performed according to the conventional scheme used for quantitative bioanalytical methods. Results. At the first stage of the work, the determination of the optimal mAbs configuration was carried out for the development of a non-competitive sandwich ELISA. The mAbs studied were characterized by the following indicators: activity in ELISA (relative to PSA, its complex with α1-antihymotrypsin (α1-ACT) and related protein kallikrein-2), isotype, titer, affinity constant, comparative epitope specificity, degree of PSA enzymatic activity inhibition, source of origin (Balb/c or NZB mouse). Based on these characteristics, the principle of using mAbs to construct ELISA for the determination of various forms of PSA (free molecule and one associated with α1-ACT) was formed. For different ranges of PSA concentrations, it was assessed the feasibility of sharing different mAbs to determine free PSA. At the second stage of the work, a protocol for the quantitative ELISA was formulated (determination of the number of reagent components, optimal time, and temperature indicators for all stages of the analysis). At the final stage of the study, we carried out validation of the developed ELISA, de­termining the following indicators: diagnostic specificity, linearity, limit of detection and quantification (analytical sensitivity), precision, correctness (accuracy). Conclusions. The antibodies of the epitopes P2 and P4 (and different specificity groups) are the most optimal combination for the sandwich ELISA to determine free PSA. The sorption-detection ability of different mAb pairs correlates with their affinity. Antibodies 26B9, 21B7, and 11G5 of the P2 epitope (group II specificity) were the best antibodies for use in solid phase sorption, and antibodies 14C8 and 21D7 of the epitope P4 (group I specificity) were the best ones for detections. The pair of high-affinity mAbs 26B9 and 14C8 possessed the most pronounced sorption-detection properties. The combined use of the mAbs 14C8 and 21D7 enzyme conjugates leads to increased sensitivity in the study of PSA concentrations in the range of 1–10 ng/ml. Validation characteristics were determined at the time of kit release and at the end of the shelf life (1 year). The average value of diagnostic specificity is 100.6%. The technique is linear in the range of 0.1–30 ng/ml, the uncertainty of the calibration graph is insignificant. The estimated detection limit is 0.001782 ng/ml, and the limit of quantification (analytical sensitivity) coincides with the reproducibility limit and is 0.0054 ng/ml. The correctness (systematic error) is 0.03 ng/ml and is statistically insignificant.

Background. Prostate cancer incidence in the world and in Ukraine is steadily increasing due to the difficulties of early diagnosis and late detection of the disease. For a diagnosis of prostate cancer tests for specific blood markers detection in the human blood serum are used, first of all, tests for prostate-specific antigen (PSA) detection – glycoprotein with enzymatic activity, which is secreted by the cells of the prostate. Detection of PSA has a number of analytical features due to biochemical and serological properties of some PSA forms, which, in turn, results in the continuous improvement of methods for its detection. Objective. Analysis of modern scientific data on the biochemical and molecular biological properties of PSA, as well as methods for its measurement in human biological fluids. Methods. The literature data on the molecular bases of synthesis, biochemical features and the role of PSA in the human body are systematized and analyzed, modern data on methods for PSA measurement are analyzed critically. Results. PSA has peculiarities of the biosynthesis and post-translational modifications, which directly affect its functions in the human body and the activity of the serum marker in prostate cancer diagnostics. Modern methods of analysis allow to deteсt most of the forms of PSA with high sensitivity. The most common methods of clinical laboratory diagnosis are enzyme immunoassay and immunochromatography. Conclusions. Analysis of the literature has shown that in the future further studies on the role of PSA for other than the prostate organs of a person will be carried on, as well as the development and improvement of tests for prostate cancer diagnostic and detection of other oncological diseases with the use of PSA, for example, breast cancer, will take place.

Editorial

Background: Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models. Methods: We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation. Findings: Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function. Interpretation: Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation. Funding: detailed information can be found in Acknowledgments.

Mitochondrial Ca2+-independent phospholipase A2γ (iPLA2γ/PNPLA8) was previously shown to be directly activated by H2O2 and release free fatty acids (FAs) for FA-dependent H+ transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLA2γ in the brain is not completely understood. Here, using wild-type and iPLA2γ-KO mice, we demonstrate the ability of tert-butylhydroperoxide (TBHP) to activate iPLA2γ in isolated brain mitochondria, with consequent liberation of FAs and lysophospholipids. The liberated FA caused an increase in respiratory rate, which was fully inhibited by carboxyatractyloside (CATR), a specific inhibitor of ANT. Employing detailed lipidomic analysis, we also demonstrate a typical cleavage pattern for TBHP-activated iPLA2γ, reflecting cleavage of glycerophospholipids from both sn-1 and sn-2 positions releasing saturated FAs, monoenoic FAs, and predominant polyunsaturated FAs. The acute antioxidant role of iPLA2γ-released FAs is supported by monitoring both intramitochondrial superoxide and extramitochondrial H2O2 release. We also show that iPLA2γ-KO mice were more sensitive to stimulation by pro-inflammatory lipopolysaccharide, as reflected by the concomitant increase in protein carbonyls in the brain and pro-inflammatory IL-6 release in the serum. These data support the antioxidant and anti-inflammatory role of iPLA2γ in vivo. Our data also reveal a substantial decrease of several high molecular weight cardiolipin (CL) species and accumulation of low molecular weight CL species in brain mitochondria of iPLA2γ-KO mice. Collectively, our results support a key role of iPLA2γ in the remodeling of lower molecular weight immature cardiolipins with predominantly saturated acyl chains to high molecular weight mature cardiolipins with highly unsaturated PUFA acyl chains, typical for the brain.

Background. Acute respiratory viral infection (ARVI) is accompanied by a general intoxication syndrome and respiratory mucosa predominant damage. A significant number of viral nature pathogens from various nosological groups (influenza viruses, parainfluenza, adenoviruses, respiratory syncytial viruses, coronaviruses, picornaviruses, rhinoviruses, enteroviruses, herpesviruses, etc.) could cause development of ARVI at human respiratory tract. Methods of ethnoscience and non-traditional medicine can be used as part of integrated treatment and prevention of influenza and ARVI. With the help of anti-cold homeopathic remedies, people can be treated from the very beginning of the disease when an elevated temperature is observed and there are all signs of intoxication and inflammation. Objective. Scientific justification for the safety and efficacy of a complex homeopathic formulation in tablet form (Aconitum napellus D6, Ammonium bromatum D4, Atropa belladonna D6, Bryonia D6, Cinchona pubescens D6, Echinacea D3, Hydrargyrum bicyanatum D8, Rhustoxicodendron D6) intended to enhance the natural immunity in influenza and respiratory diseases, to normalize the functional state of the immune system and upper respiratory tract. Results. Most patients have acute febrile respiratory syndrome, and some population groups have an increased risk of complications in the form of severe illness or death. These groups include elderly people, very young people, and people with concomitant illnesses. Annually, every third inhabitant of the planet suffers from acute respiratory infections. We have conducted a scientific substantiation of the safety and efficacy of a complex homeopathic tablet formulation (Aconitum napellus D6, Ammonium bromatum D4, Atropa belladonna D6, Bryonia D6, Cinchona pubescens D6, Echinacea D3, Hydrargyrum bicyanatum D8, Rhustoxico­dendron D6), which can be used to treat and prevention of these diseases. Conclusions. Components of developed homeopathic preparation are used in medical practice as anti-cold and immunomodulating mono- and complex homeopathic preparations for more than 100 years. There are no restrictions on the use of the drug in the context of its safety profile, since the active ingredient concentrations used are completely non-toxic. The preparation enhances the body’s protective responses and promotes the relief of symptoms of acute respiratory infections and flu (headache, sneezing, runny nose, sore throat, body aches, fever) and rapid recovery.

Background. The risk management plan is the one of main documents of pharmacovigilance system – a document focuses on the planning of pharmacovigilance activities and minimization of risks. As the use of herbal medicines has increased, so too have the reports of suspected toxicity and adverse events. As many herbal products on the market have not been thoroughly tested for their pharmacology and toxicology, pharmacovigilance has paramount importance in detecting unwanted reactions. One of the herbal preparations widely used to support the cardiovascular system under stress, neurocirculatory dystonia, cardiac neurosis, in the complex treatment of arterial hypertension, angina pectoris, arrhythmia is a complex medicinal product Carvelis, oral drops, solution. The active pharmaceutical ingredients of the drug are: extract from a mixture of hawthorn leaves, flowers and fruit (Сrataegi folii cum flore, fructus extractum); herb extract of canine nettle (Leonuri herbae extractum); melissae herbia extract Melissae herbae extractum); valerian root extract (Valerianae radix extractum). Objective. Сritical analysis of current scientific data on the benefit/risk ratio of a complex herbal medicine with sedative and cardioprotective effects. Results. Pathophysiological and epidemiological characteristic of following nosological forms have been analyzed: stress, neurocirculatory dystonia, cardiac neurosis, arterial hypertension, angina pectoris, arrhythmia. Current data on phytopreparation safety and estimation benefit/risk ratio have been generalized. Available clinical data were analyzed for individual phytocomponents or its combinations. Conclusions. The prevalence, seriousness and severity of the course of all manifestations of neurocirculatory dystonia, stress, nervous excitement, heart neurosis, especially with disproportionate approaches to the treatment of these diseases, is a serious medical and social problem. Given the proven efficacy of the use of Carvelis preparation components, and also that the risks are predictable, and their occurrence can be countered, and if they occur it can be effectively suppress with other drugs, the benefit of using the phytopreparation prevails above the risks.

The funeral service for A.A. Akhmatova was organised in Leningrad by her son L.N. Gumilev with the help of Priest Vasily Butylo. Initially, it was planned to hold the funeral ceremony at the Transfiguration Cathedral. However, after L.N. Gumilev and Fr. Vasily had visited Vicar Bishop of Tikhvin Philaret (Vakhromeyev) St Nicholas Cathedral of the Epiphany was chosen. The service was officiated by Archpriest Alexander Medvedsky, the only clergyman of the city awarded with the Patriarch’s Cross, together with Deacon Pyotr Kolosov. G.S. Zharinov, Leningrad Plenipotentiary on Religious Affairs, forbid to let more than one priest and a big church choir take part in the service as well as to light up large chandeliers. The two last prohibitions were ignored. The involvement of Metropolitan Nikodim (Rotov) of Leningrad and Ladoga in realization of the most worthy funeral ceremony is discussed in the article.

Проблематика. Незважаючи на те що проблема педикульозу в дітей і дорослих існує дуже давно, вона не втрачає своєї актуальності. Актуальність педикульозу пояснюється тим, що підхопити це захворювання легко може кожен, але діти заражаються значно частіше. Завошивленість є показником соціального неблагополуччя, становить соціально-психологічну проблему для завошивлених та їхніх оточуючих, а також може створювати епідемічне неблагополуччя в суспільстві, оскільки воші можуть бути переносниками збудників небезпечних захворювань. Тому розробка засобів для профілактики та боротьби із завошивленістю, зокрема розробка нових педикуліцидів на основі натуральних ефірних олій, продовжує бути актуальною задачею. Мета. Вивчити та довести інсектицидну (педикуліцидну) й овіцидну активність лосьйонів для волосся, виготовлених на основі натуральних ефірних олій – лавандової та іланг-ілангу – в лабораторних умовах. Оцінити безпеку лосьйонів при використанні в інфестованих пацієнтів. Методика реалізації. Методом біологічного контролю якості проведено дослідження лосьйонів для волосся, виготовлених на основі натуральних ефірних олій – лавандової та іланг-ілангу, з визначення їх біологічної активності відносно вошей Pediculus humanus humanus лабораторної популяції на базі лабораторії рикетсійних інфекцій Львівського НДІ епідеміології та гігієни МОЗ України. Дослідження безпеки лосьйонів проводилась із залученням здорових добровольців та уражених педикульозом осіб на базі Київської міської дезінфекційної станції (відділення камерної дезінфекції та санітарних пропускників). Результати. Модельна рецептура лосьйону, виготовленого з використанням 3,5 % лавандової олії та 3,5 % олії іланг-ілангу, викликає загибель 100 % імаго вошей при експозиції 30 хв. За меншої експозиції загибель імаго вошей знижена. Овіцидні властивості виражені при експозиції 30 хв. Засіб є безпечним для людей, добре переноситься та забезпечує ефективну загибель вошей незалежно від ступеня інфестування пацієнта. Висновки. Результати дослідження модельних рецептур лосьйонів свідчать про їх високу інсектицидну та овіцидну активність відносно вошей лабораторної популяції при зануренні тест-інсектів у один із досліджуваних лосьйонів та при підсадці тест-інсектів на фільтрувальний папір, зволожений одним із зазначених лосьйонів, за експозиції 30 хв. Засіб не потребує додаткових заходів безпеки та може використовуватися відповідно до інструкції до застосування.

Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca2+-independent phospholipase A2γ (iPLA2γ), is addressed to the mitochondrial matrix (or peroxisomes), where it may manifest its unique activity to cleave phospholipid side-chains from both sn-1 and sn-2 positions, consequently releasing either saturated or unsaturated fatty acids (FAs), including oxidized FAs. Moreover, iPLA2γ is directly stimulated by H2O2 and, hence, is activated by redox signaling or oxidative stress. This redox activation permits the antioxidant synergy with mitochondrial uncoupling proteins (UCPs) or other SLC25 mitochondrial carrier family members by FA-mediated protonophoretic activity, termed mild uncoupling, that leads to diminishing of mitochondrial superoxide formation. This mechanism allows for the maintenance of the steady-state redox status of the cell. Besides the antioxidant role, we review the relations of iPLA2γ to lipid peroxidation since iPLA2γ is alternatively activated by cardiolipin hydroperoxides and hypothetically by structural alterations of lipid bilayer due to lipid peroxidation. Other iPLA2γ roles include the remodeling of mitochondrial (or peroxisomal) membranes and the generation of specific lipid second messengers. Thus, for example, during FA β-oxidation in pancreatic β-cells, H2O2-activated iPLA2γ supplies the GPR40 metabotropic FA receptor to amplify FA-stimulated insulin secretion. Cytoprotective roles of iPLA2γ in the heart and brain are also discussed.

Despite the significant interest in molecular hydrogen as an antioxidant in the last eight years, its quantitative metabolic parameters in vivo are still lacking, as is an appropriate method for determination of hydrogen effectivity in the mammalian organism under various conditions.Intraperitoneally-applied deuterium gas was used as a metabolic tracer and deuterium enrichment was determined in the body water pool. Also, in vitro experiments were performed using bovine heart submitochondrial particles to evaluate superoxide formation in Complex I of the respiratory chain.A significant oxidation of about 10% of the applied dose was found under physiological conditions in rats, proving its antioxidant properties. Hypoxia or endotoxin application did not exert any effect, whilst pure oxygen inhalation reduced deuterium oxidation. During in vitro experiments, a significant reduction of superoxide formation by Complex I of the respiratory chain was found under the influence of hydrogen. The possible molecular mechanisms of the beneficial effects of hydrogen are discussed, with an emphasis on the role of iron sulphur clusters in reactive oxygen species generation and on iron species-dihydrogen interaction.According to our findings, hydrogen may be an efficient, non-toxic, highly bioavailable and low-cost antioxidant supplement for patients with pathological conditions involving ROS-induced oxidative stress.