Mitochondria-targeted antioxidant SkQ1 reverses glaucomatous lesions in rabbits

Original article is published in: Frontiers in Bioscience, Landmark, 20, 892–901, January 1, 2015Glaucoma is the main cause of irreversible blindness worldwide. This disease is characterized by apoptosis of retinal ganglion cells (RGC) and visual field loss that seems to be related to elevated intraocular pressure (IOP). Several lines of evidences have implicated the crucial role of mitochondrial dysfunction in the pathogenesis of glaucoma. Increased mitochondrial oxidative stress in RGC may underlie or contribute to susceptibility of RGC to apoptosis. In our work we (i) designed a rabbit model of chronic, moderately elevated IOP for studying glaucoma and (ii) demonstrated efficacy of mitochondria-targeted antioxidant SkQ1 as a tool to reverse several traits of experimental glaucoma induced by a series of injections of hydroxypropylmethylcellulose (HPMC) to the anterior chamber of the rabbit eye. It is shown that 6 months instillations of drops of 0.2.5–5 µM solution of SkQ1 normalize IOP and eye hydrodynamics and abolish an increase in lens thickness that accompanies glaucoma.Original article is published in: Frontiers in Bioscience, Landmark, 20, 892–901, January 1, 2015Glaucoma is the main cause of irreversible blindness worldwide. This disease is characterized by apoptosis of retinal ganglion cells (RGC) and visual field loss that seems to be related to elevated intraocular pressure (IOP). Several lines of evidences have implicated the crucial role of mitochondrial dysfunction in the pathogenesis of glaucoma. Increased mitochondrial oxidative stress in RGC may underlie or contribute to susceptibility of RGC to apoptosis. In our work we (i) designed a rabbit model of chronic, moderately elevated IOP for studying glaucoma and (ii) demonstrated efficacy of mitochondria-targeted antioxidant SkQ1 as a tool to reverse several traits of experimental glaucoma induced by a series of injections of hydroxypropylmethylcellulose (HPMC) to the anterior chamber of the rabbit eye. It is shown that 6 months instillations of drops of 0.2.5–5 µM solution of SkQ1 normalize IOP and eye hydrodynamics and abolish an increase in lens thickness that accompanies glaucoma

Исследование антиоксидантного эффекта митохондриально-направленного антиоксиданта SkQ1 на модели изолированного сердца крысы

Mitochondrially targeted antioxidants based on Skulachev ions (SkQ1) are extremely attractive for neutralizing reactive oxygen species directly in the mitochondrial matrix.The aim was to examine the antioxidant and cardioprotective status of the SkQ1 mitochondrially targeted antioxidant in an isolated rat heart model of ischemia and reperfusion after cold cardioplegia.Material and methods. The effects of different concentrations of SkQ1 (1200 ng/ml, 120 ng/ml, 12 ng/ml) were explored on isolated hearts of Wistar rats (n=50) during 240-min cold cardioplegia. The levels of oxidative stress, changes in myocardial damage markers (classical and highly specific) and cardiac function (coronary flow velocity, heart rate, systolic pressure) were assessed.Results. The use of SkQ1 at 12 ng/ml resulted in a significant neutralization of oxidative stress manifestations (P<0.05). The minimum concentration of NO metabolites (nitrates and nitrites) (36.2 [30.8; 39.8] µmol/ml) was maintained at pre-ischemic level throughout the 30-minute reperfusion period, while the malonic dialdehyde concentration (49.5 [41.1; 58.9] µmol/g) was lower compared with SkQ1 use at 120 ng/ml dose. Due to the «mitigation» of oxidative stress, intracellular enzymes and highly specific markers of myocardial damage rose more slowly during reperfusion, while cardiac function recovery occurred at a higher rate and showed stability upon restoration of perfusion.Conclusion. SkQ1 at 12 ng/ml concentration showed strong antioxidant and cardioprotective properties in an ex vivo study.Митохондриально-направленные антиоксиданты на основе ионов Скулачёва (SkQ1) крайне привлекательны для нейтрализации активных форм кислорода непосредственно в матриксе митохондрий.Цель — изучить антиоксидантный и кардиопротективный эффект митохондриально-направленного антиоксиданта — SkQ1 на модели ишемии и реперфузии изолированного сердца крысы в условиях холодовой кардиоплегии.Материалы и методы. Исследование эффектов SkQ1 (1200 нг/мл, 120 нг/мл, 12 нг/мл) провели на изолированных сердцах крыс линии Wistar (n=50) в условиях 240-минутной холодовой кардиоплегии. Оценили уровень окислительного стресса, динамику маркеров повреждения миокарда (классические и высокоспецифичные) и функцию сердечной мышцы (скорость коронарного протока, частоту сердечных сокращений, систолическое давление).Результаты. Использование SkQ1 в концентрации 12 нг/мл привело к статистически значимой нейтрализации проявлений окислительного стресса (р<0,05): минимальное содержание NO-метаболитов — нитратов и нитритов (36,2 [30,8; 39,8] мкмоль/мл) поддерживалось на доишемическом уровне всю 30-минутную реперфузию, а концентрация малонового диальдегида (49,5 [41,1; 58,9] мкмоль/г) была ниже в сравнении с применением SkQ1 в концентрации 120 нг/мл. Вследствие «смягчения» окислительного стресса внутриклеточные ферменты и высокоспецифичные маркеры повреждения миокарда при реперфузии нарастали медленно, а восстановление сердечной функции произошло более высокими темпами и показало свою стабильность при возобновлении перфузии.Заключение. SkQ1 в концентрации 12 нг/мл проявил выраженные антиоксидантные и кардиопротективные свойства в исследовании ex vivo

Oxidative Distress in Patients with Polytrauma

Polytrauma is a serious threat to human life not only due to its direct damage to vital organs, but also to the development of significant oxidative distress that gives rise to multiple organ dysfunction. At the same time, the risk of lifethreatening infectious complications increases.Objective: to study oxidative distress over time and its association with early pulmonary infectious complications in patients with polytrauma.Subjects and methods. The authors examined 35 patients with polytrauma in the first 6—12 and 12—24 hours and 3, 5—7, and 10 days after injury and 25 healthy volunteers. Having regard to the development of pulmonary infectious complications, they formed two comparison groups of patients: 1) 15 patients without pneumonia and 2) 20 patients with pneumonia. The investigation used the antioxidant  index  (AOI)  considering  the  activity  of  erythrocyte  enzymes  (superoxide  dismutase,  catalase,  glutathione peroxidase, and glutathione reductase) and the degree of lipid peroxidation in the plasma (dienic conjugates and malonic dialdehyde) to estimate the balance between oxidative lesions and the performance of the body's antioxidant systems.Results. In both groups, the AOI reflects the oxidative stress state, as substantiated by negative values for the AOI with its normal value equal to zero. However, with the virtually parallel nature of AOI changes after injury in the patients with pneumonia, the values of the index were significantly lower than in those without complications within the first 6—12 and 12—24 hours and 5—7 days (p<0.05).Conclusion. This investigation has indicated that the AOI is an early candidate biomarker for the risk of infectious complications and its values are of prognostic value just within the first hours after injury

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

Observation of Photovoltaic Action from Photoacid-Modified Nafion Due to Light-Driven Ion Transport

Replacing passive ion-exchange membranes, like Nafion, with membranes that use light to drive ion transport would allow membranes in photoelectrochemical technologies to serve in an active role. Toward this, we modified perfluorosulfonic acid ionomer membranes with organic pyrenol-based photoacid dyes to sensitize the membranes to visible light and initiate proton transport. Covalent modification of the membranes was achieved by reacting Nafion sulfonyl fluoride poly(perfluorosulfonyl fluoride) membranes with the photoacid 8-hydroxypyrene-1,3,6-tris(2-aminoethylsulfonamide). The modified membranes were strongly colored and maintained a high selectivity for cations over anions. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and ion-exchange measurements together provided strong evidence of covalent bond formation between the photoacids and the polymer membranes. Visible-light illumination of the photoacid-modified membranes resulted in a maximum power-producing ionic photoresponse of ∼100 μA/cm2 and ∼1 mV under 40 Suns equivalent excitation with 405 nm light. In comparison, membranes that did not contain photoacids and instead contained ionically associated RuII-polypyridyl coordination compound dyes, which are not photoacids, exhibited little-to-no photoeffects (∼1 μA/cm2). These disparate photocurrents, yet similar yields for nonradiative excited-state decay from the photoacids and the RuII dyes, suggest temperature gradients were not likely the cause of the observed photovoltaic action from photoacid-modified membranes. Moreover, spectral response measurements supported that light absorption by the covalently bound photoacids was required in order to observe photoeffects. These results represent the first demonstration of photovoltaic action from an ion-exchange membrane and offer promise for supplementing the power demands of electrochemical processes with renewable sunlight-driven ion transport

Клиническое исследование эффективности и безопасности препарата Визомитин®, глазные капли, у пациентов с возрастной катарактой

PURPOSE: The assessment of possibility to add a new indication for the registered pharmaceutical. Evaluation of safety and efficacy of Visomitin® compared to placebo in patients with age-related cataracts. METHODS: A randomized, double-blind, placebo-controlled clinical study of Visomitin® eye drops in patients with age-related cataracts was conducted in accordance with Good Clinical Practice guidance, the Declaration of Helsinki and the Russian regulatory requirements. The study included 80 patients (23 men and 57 women) aged 45 to 75 years with diagnosed age-related cataract. All subjects were randomized into two groups of 40 patients each. In the treatment group patients received Visomitin® eye drops and in the control group, patients were given placebo (vehicle, i.e. eye drops with the same composition as Visomitin® except for the active substance SkQ1) in the form of instillations of one drop per each eye three times daily for six months. The study comprised 7 monthly visits. The following standard ophthalmological examinations were used to evaluate the effectiveness of the therapy: visual acuity measurement, refractometry, biomicroscopy of the eye, ophthalmoscopy, tonometry, computer perimetry, densitometry. At certain visits lacrimal fluid was taken for evaluation of its antioxidant activity. Blood pressure and heart rate were measured as a part of safety evaluation which also included documentation of complaints and adverse events. Concomitant therapies were also documented. RESULTS: Analysis of safety parameters showed Visomitin® to be safe and well tolerated for patients with age-related cataract. Practically no adverse effects were documented during the study. In both groups a decrease of the number of patients with subjective complaints was observed. These complaints included: visual deterioration, dryness, grittiness, burning eyes, eye fatigue. The decrease of the number of complaints in the Visomitin® group was more pronounced than in the placebo group. During the first months of treatment an improvement of visual acuity was observed in both groups. This result can be explained by a protective effect of hypromellose contained in both Visomitin® and placebo. However, between the 4th and the 6th months, the improvement in visual acuity significantly slowed down in the placebo group, while positive dynamics remained the same in the Visomitin® group. At the end of the treatment visual acuity increased by more than 50% in Visomitin® group and remained at the level of 10-15% in the placebo group (statistically significant difference between placebo and Visomitin® groups,

Митохондриально-направленный антиоксидант SkQ1 предотвращает глаукомные повреждения у кроликов

Original article is published in: Frontiers in Bioscience, Landmark, 20, 892–901, January 1, 2015Glaucoma is the main cause of irreversible blindness worldwide. This disease is characterized by apoptosis of retinal ganglion cells (RGC) and visual field loss that seems to be related to elevated intraocular pressure (IOP). Several lines of evidences have implicated the crucial role of mitochondrial dysfunction in the pathogenesis of glaucoma. Increased mitochondrial oxidative stress in RGC may underlie or contribute to susceptibility of RGC to apoptosis. In our work we (i) designed a rabbit model of chronic, moderately elevated IOP for studying glaucoma and (ii) demonstrated efficacy of mitochondria-targeted antioxidant SkQ1 as a tool to reverse several traits of experimental glaucoma induced by a series of injections of hydroxypropylmethylcellulose (HPMC) to the anterior chamber of the rabbit eye. It is shown that 6 months instillations of drops of 0.2.5–5 µM solution of SkQ1 normalize IOP and eye hydrodynamics and abolish an increase in lens thickness that accompanies glaucoma.Оригинальная статья опубликована: Frontiers in Bioscience, Landmark, 20, 892-901, January 1, 2015.Глаукома — основная причина необратимой слепоты в мире. Это заболевание характеризуется апоптозом ганглиозных клеток сетчатки (ГКС) и изменениями поля зрения, что, по-видимому, связано с повышенным внутриглазным давлением (ВГД). Есть основания полагать, что важную роль в патогенезе глаукомы играет митохондриальная дисфункция. Повышенный митохондриальный окислительный стресс в ГКС может лежать в основе или способствовать восприимчивости ГКС к апоптозу. В нашей работе мы (а) разработали модель хронического умеренно повышенного ВГД на кроликах для изучения глаукомы и (б) продемонстрировали эффективность митохондриально-направленного антиоксиданта SkQ1 в качестве инструмента для воздействия на некоторые проявления экспериментальной глаукомы, вызванной серией инъекций гидроксипропилметилцеллюлозы (ГПМЦ) в переднюю камеру глаза кролика. Показано, что инстилляции 0,2,5–5 мкМ раствора SkQ1 в течение 6-ти месяцев нормализуют ВГД и гидродинамику глаза, а также предотвращают увеличение толщины хрусталика, сопровождающее развитие экспериментальной глаукомы

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

A Gestational High Protein Diet Affects the Abundance of Muscle Transcripts Related to Cell Cycle Regulation throughout Development in Porcine Progeny

BACKGROUND: In various animal models pregnancy diets have been shown to affect offspring phenotype. Indeed, the underlying programming of development is associated with modulations in birth weight, body composition, and continual diet-dependent modifications of offspring metabolism until adulthood, producing the hypothesis that the offspring's transcriptome is permanently altered depending on maternal diet. METHODOLOGY/PRINCIPAL FINDINGS: To assess alterations of the offspring's transcriptome due to gestational protein supply, German Landrace sows were fed isoenergetic diets containing protein levels of either 30% (high protein--HP) or 12% (adequate protein--AP) throughout their pregnancy. Offspring muscle tissue (M. longissimus dorsi) was collected at 94 days post conception (dpc), and 1, 28, and 188 days post natum (dpn) for use with Affymetrix GeneChip Porcine Genome Arrays and subsequent statistical and Ingenuity pathway analyses. Numerous transcripts were found to have altered abundance at 94 dpc and 1 dpn; at 28 dpn no transcripts were altered, and at 188 dpn only a few transcripts showed a different abundance between diet groups. However, when assessing transcriptional changes across developmental time points, marked differences were obvious among the dietary groups. Depending on the gestational dietary exposure, short- and long-term effects were observed for mRNA expression of genes related to cell cycle regulation, energy metabolism, growth factor signaling pathways, and nucleic acid metabolism. In particular, the abundance of transcripts related to cell cycle remained divergent among the groups during development. CONCLUSION: Expression analysis indicates that maternal protein supply induced programming of the offspring's genome; early postnatal compensation of the slight growth retardation obvious at birth in HP piglets resulted, as did a permanently different developmental alteration and responsiveness to the common environment of the transcriptome. The transcriptome modulations are interpreted as the molecular equivalent of developmental plasticity of the offspring that necessitates adaptation and maintenance of the organismal phenotype

Selective Uncoupling of Individual Mitochondria within a Cell Using a Mitochondria-Targeted Photoactivated Protonophore

Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity