pH (Low) Insertion Peptide (pHLIP) Targets Ischemic Myocardium

The pH (low) insertion peptide (pHLIP) family enables targeting of cells in tissues with low extracellular pH. Here, we show that ischemic myocardium is targeted, potentially opening a new route to diagnosis and therapy. The experiments were performed using two murine ischemia models: regional ischemia induced by coronary artery occlusion and global low-flow ischemia in isolated hearts. In both models, pH-sensitive pHLIPs [wild type (WT) and Var7] or WT-pHLIP–coated liposomes bind ischemic but not normal regions of myocardium, whereas pH-insensitive, kVar7, and liposomes coated with PEG showed no preference. pHLIP did not influence either the mechanical or the electrical activity of ischemic myocardium. In contrast to other known targeting strategies, the pHLIP-based binding does not require severe myocardial damage. Thus, pHLIP could be used for delivery of pharmaceutical agents or imaging probes to the myocardial regions undergoing brief restrictions of blood supply that do not induce irreversible changes in myocytes

Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration

The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA–CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway

Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration

AbstractThe coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA–CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway

Effect of immune drugs to treat acute viral nasopharyngitis

The task in treating acute nasopharyngitis (ANP) deals with reducing the disease symptoms and the risk of complications. The lack of reliable antiviral drugs makes it important to search for appropriate medicines among other pharmacotherapeutic groups.The study involves a comparative analysis of the efficiency and estimates potential: the recombinant interferon α2b and the compound containing fungal β-D-glucans used in treat ANPThe studies involved patients with ANP from 18 to 55 years old. As many as 152 people were examined including the following: 38 were practically healthy people (group 1); and 114 patients wuth ANP: 38 people (group 2) was subject to a standard therapy (vasoconstrictor nasal drops, nasal cavity irrigation using 0.1% Miramistine solution, gargling using the Furacilin solution); forty people (group 3) were administered application of intranasal interferon α2b of 105 IU, it was delivered with a spray into each nasal passage twice a day; 36 people (group 4) were administered an immunotropic drug containing β-D-glucans orally twice a day. The duration of drug administration lasted 7 days. Polymerase chain reaction (PCR) was used to identify the ANP etiological factor. Concentrations of cytokines IL-1β, IL-1ra were estimated using enzyme immunoassay (ELISA) technique. Clinical efficiency was assessed through score approach. The following symptoms were taken into account: general malaise, sore throat, character of nasal discharge, and the difficulty of nasal breathing. The results of the study were analyzed using parametric and nonparametric statistical methods. In 60.0% the nasal secretions of patients revealed RV. The distribution of cytokine concentrations in nasal secretions in group 1 indicated that the concentration of IL-1β was in the range of 20.0-25.0 pg/ml, and the concentration of IL-1ra was about 1250.0-2500.0 pg/ml. Developing ANP stimulated an increase in IL-1β concentration up to 30.0-70.0 pg/ml in nasal secretions of patients without affecting IL-1ra concentrations. On day 7 of treatment, the cytokine concentrations among the patients treated using the immunotropic drugs were the same as in the group of healthy individuals. There were no significant changes in cytokine production on day 7 in the group of patients undergoing the standard treatment. Application of proposed immunobiological medicines to ANP does not result in overproduction of proinflammatory cytokine IL-1β in nasal secretion. This confirms that these drugs are promising in the treating strategy including reduction of the risk of developing complications

Исследование свойств композитного материала для СВЧ-применений на основе PTFE с различной концентрацией и размером частиц керамического наполнителя

Introduction. The technology of printed circuit boards (PCBs) is widely used in modern electronic instrumentation. PCBs for the microwave frequency range are made based on foil composite materials, in particular, polytetrafluoroethylene (PTFE). At the moment, there is no domestic production of such a class of materials. Information concerning foreign manufacturing technologies in this field and the influence of the filler on the characteristics of the composite material remains confidential. Therefore, research into the properties of composite materials for microwave applications with properties similar to foreign analogues seems relevant.Aim. Experimental determination of the dependence of the electrical and mechanical properties of a composite material based on polytetrafluoroethylene depending on the concentration and size of the titanium dioxide fraction.Materials and methods. Experimental determination of the dependence of the electrical and mechanical properties of a composite material based on PTFE depending on the concentration and size of the titanium dioxide fraction.Results. The results of an experimental study of the mechanical properties and microwave parameters of experimental samples of composite material based on PTFE are presented, namely: composite material with 10 % content of ceramic titanium dioxide powders (fraction size 10, 49 and 126 µm); composite material with 5, 10 and 15 % content of ceramic titanium dioxide powder (fraction size 49 µm for polytetrafluoroethylene and 126 µm for titanium dioxide).Conclusion. The results obtained demonstrate prospects for using compositions based on PTFE and titanium dioxide powder as a basis for microwave materials. A correlation was established between the percentage of the introduced ceramic filler and the microwave parameters of the material. The studies demonstrated a slight difference in the microwave properties of the manufactured composite material samples with a different ratio between the particle sizes of titanium dioxide and PTFE. However, a significant decrease in their mechanical properties was observed.Введение. Технология печатных плат является наиболее распространенной в современном электронном приборостроении. Платы для СВЧ-диапазона частот изготавливаются на основе фольгированных композитных материалов, в частности на основе политетрафторэтилена. В данный момент отечественное производство подобного класса материалов отсутствует. Информация, касающаяся зарубежной технологии изготовления композитного материала и влияния наполнителя на его характеристики, является закрытой. Поэтому актуальной задачей является поиск и исследование свойств композитных материалов для СВЧ-применения со свойствами, аналогичными зарубежным аналогам.Цель работы. Экспериментальное определение зависимости электрических и механических свойств композитного материала на основе политетрафторэтилена от концентрации и размера фракции диоксида титана.Материалы и методы. Механические свойства образцов композитного материала измерялись методом гидростатического взвешивания. Исследовались прочность и относительное удлинение при разрыве с помощью разрывной машины РМИ-250. СВЧ-параметры определялись с помощью метода Николсона–Росса–Вейра.Результаты. Представлены результаты экспериментального исследования механических свойств и СВЧпараметров экспериментальных образцов композитного материала на основе политетрафторэтилена: с 10 %-м содержанием керамических порошков диоксида титана (размер фракции 10, 49 и 126 мкм); с 5, 10 и 15 %-м содержанием керамического порошка диоксида титана (размер фракций у политетрафторэтилена – 49 мкм и у диоксида титана – 126 мкм).Заключение. Результаты демонстрируют перспективность применения композиций на основе PTFE и порошка диоксида титана в качестве основы для СВЧ-материалов. Установлена корреляция между процентным содержанием вводимого керамического наполнителя и СВЧ-параметрами материала. Исследования продемонстрировали незначительное отличие в СВЧ-свойствах изготовленных образцов композитного материала при различном соотношении между размерами частиц диоксида титана и PTFE. Однако при этом наблюдается значительное снижение их механических свойств

In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression.In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation

The nucleotide addition cycle of RNA polymerase is controlled by two molecular hinges in the Bridge Helix domain

Abstract Background Cellular RNA polymerases (RNAPs) are complex molecular machines that combine catalysis with concerted conformational changes in the active center. Previous work showed that kinking of a hinge region near the C-terminus of the Bridge Helix (BH-HC) plays a critical role in controlling the catalytic rate. Results Here, new evidence for the existence of an additional hinge region in the amino-terminal portion of the Bridge Helix domain (BH-HN) is presented. The nanomechanical properties of BH-HN emerge as a direct consequence of the highly conserved primary amino acid sequence. Mutations that are predicted to influence its flexibility cause corresponding changes in the rate of the nucleotide addition cycle (NAC). BH-HN displays functional properties that are distinct from BH-HC, suggesting that conformational changes in the Bridge Helix control the NAC via two independent mechanisms. Conclusions The properties of two distinct molecular hinges in the Bridge Helix of RNAP determine the functional contribution of this domain to key stages of the NAC by coordinating conformational changes in surrounding domains.</p

Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers. Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic “microtubers”. A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells. Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC