Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications

МЕТАБОЛИЧЕСКИЕ ЭФФЕКТЫ СУБСТРАТНОГО АНТИГИПОКСАНТА НА ОСНОВЕ ЯНТАРНОЙ КИСЛОТЫ

The paper discusses promises for clinical use of substrate antihypoxants.Objective: to investigate the efficacy of succinate containing  substrate  antihypoxants  on  systemic  oxygen  consumption,  blood  buffer  capacity,  and  changes  in  the  mixed venous blood level of lactate when they are used in gravely sick patients and victims with marked metabolic posthypoxic disorders.Subjects and methods. The trial enrolled 30 patients and victims who had sustained an episode of severe hypoxia of mixed genesis, the severity of which was evaluated by the APACHE II scale and amounted to 23 to 30 scores with a 46 to 70.3% risk of death. The standard infusion program in this group involved the succinate-containing drug 1.5% reamberin solution  in  a  total  dose  of  800  ml.  A  comparison  group  included  15  patients  who  had  undergone  emergency  extensive surgery for abdominal diseases. 400 ml of 10% glucose solution was used as an infusion medium. Oxygen consumption (VO2ml/min) and carbon dioxide production (VCO2ml/min) were measured before infusion and monitored for 2 hours. Arterial blood gases and acid-base balance (ABB) parameters and mixed venous blood lactate levels were examined. Measurements were made before and 30 minutes after the infusion of reamberin or glucose solution.Results. Infusion of 1.5% reamberin solution was followed by a significant increase in minute oxygen consumption from 281.5±21.2 to 310.4±24.4 ml/min. CO2 production declined (on average, from 223.3±6.5 to 206.5±7.59 ml/min). During infusion of 10% glucose solution, all the patients of the comparison group showed a rise in oxygen consumption from 303.6±33.86 to 443.13±32.1 ml/min, i.e. about 1.5-fold. VCO2 changed similarly. The intravenous infusion of 800 ml of 1.5% reamberin solution raised arterial blood buffer capacity, which was reflected by changes in pH, BE, and HCO3. There was a clear trend for lactate values to drop in the mixed venous blood. The intravenous injection of 400 ml of 10% glucose solution caused no significant changes in major ABB indicators, which reinforced the statement that there is a difference in the metabolism of these substrates.Conclusion. The succinate-containing drugs are able to compensate for metabolic acidosis. Their use is followed by increased oxygen consumption  and  activated  aerobic  oxidation  processes.  The  basis  of  their  antihypoxant  properties  was  thought  to  be recovered intracellular aerobic metabolic processes due to corrected intracellular metabolic acidosis and increased blood  buffer capacity.В статье обсуждаются перспективы клинического применения субстратных антигипоксантов.Цель — изучить влияние сукцинат-содержащих субстратных антигипоксантов на системное потребление кислорода, буферную емкость крови, динамику содержания в смешанной венозной крови лактата при их применении у тяжелобольных и пострадавших с выраженными метаболическими постгипоксическими нарушениями.Материалы и методы. В исследование включили 30 больных и пострадавших, перенесших эпизод тяжелой гипоксии смешанного генеза, тяжесть состояния которых оценивали по шкале APACHE II, она составила от 23 до 30 баллов с риском летального исхода от 46 до 70,3%. В состав стандартной инфузионной программы этой группы был включен сукцинат-содержащий препарат — реамберин 1,5% в суммарной дозе 800 мл. Группа сравнения (n=15) была представлена больными, которым в экстренном порядке выполняли обширные операции по поводу заболеваний органов брюшной полости. В качестве инфузионной среды был использован 10% раствор глюкозы в количестве 400 мл. До начала инфузии, а затем в мониторном режиме на протяжении двух часов измеряли потребление O2(VO2мл/мин) и выделение CO2(VCO2мл/мин). Изучался газовый состав, параметры КОС артериальной крови, содержание лактата в смешанной венозной крови. Измерения проводили до начала инфузии раствора реамберина или глюкозы, а также через 30 минут после ее завершения.Результаты. Инфузия  1,5%  раствора  реамберина  сопровождалась  достоверным  увеличением минутного  потребления  кислорода  с 281,5±21,2 мл/мин до 310,4±24,4 мл/мин. Выделение CO2 при этом снизилось (в среднем с 223,3±6,5 до 206,5±7,59 мл/мин). У всех больных группы сравнения во время инфузии 10% раствора глюкозы наблюдали увеличение потребления кислорода с 303,6±33,86 до 443,13±32,1 мл/мин, то есть почти в 1,5 раза. Аналогичным образом изменилосьVCO2. Внутривенная инфузия 800 мл 1,5% раствора реамберина повышала буферную емкость артериальной крови, что проявлялось изменением PH, BE и HCO3. Отмечали явную тенденцию к снижению содержания лактата в смешанной венозной крови. При внутривенном введении 400 мл 10% раствора глюкозы достоверных изменений основных показателей КОС не отмечали, что подтверждает предположение о различии в метаболизме этих субстратов.Заключение.  Препараты,  содержащие  в  своем  составе  сукцинат,  способны  компенсировать  метаболический  ацидоз.  Их применение сопровождается увеличением потребления кислорода и активацией процессов аэробного окисления. Полагаем, что основу их антигипоксантных качеств составляет восстановление процессов внутриклеточного аэробного метаболизма благодаря коррекции внутриклеточного метаболического ацидоза и увеличения буферной емкости крови.

Четверта міжнародна наукова-практична конференція «Комп’ютерне моделювання в хімії і технологіях та системах сталого розвитку»

Запропоновано підхід до визначення константи швидкості розкладання диборану та товщини дифузійного шару в проточному термохімічному реакторі ізобарного типу за умов осадження твердого осаду у вигляді кристалічного бору на поверхні вуглецевих волокон.Approach for determination of constant speed of decomposition of diborane and thickness deffusive layer in the running thermo-chemical reactor of isobar type at the conditions of setting of incrustation as the crystalline boron on the surface of carbon fibres is offered.Предложен подход для определения константы скорости разложения диборана и толщины дифузионного слоя в проточном термохимическом реакторе изобарного типа в условиях осаждения твердого осадка в виде кристаллического бора на поверхности углеродных волокон

Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo

Abstract Introduction Macrophages comprise an essential component of the mammary microenvironment necessary for normal gland development. However, there is no viable in vivo model to study their role in normal human breast function. We hypothesized that adding primary human macrophages to the murine mammary gland would enhance and provide a novel approach to examine immune-stromal cell interactions during the humanization process. Methods Primary human macrophages, in the presence or absence of ectopic estrogen stimulation, were used to humanize mouse mammary glands. Mechanisms of enhanced humanization were identified by cytokine/chemokine ELISAs, zymography, western analysis, invasion and proliferation assays; results were confirmed with immunohistological analysis. Results The combined treatment of macrophages and estrogen stimulation significantly enhanced the percentage of the total gland humanized and the engraftment/outgrowth success rate. Timecourse analysis revealed the disappearance of the human macrophages by two weeks post-injection, suggesting that the improved overall growth and invasiveness of the fibroblasts provided a larger stromal bed for epithelial cell proliferation and structure formation. Confirming their promotion of fibroblasts humanization, estrogen-stimulated macrophages significantly enhanced fibroblast proliferation and invasion in vitro, as well as significantly increased proliferating cell nuclear antigen (PCNA) positive cells in humanized glands. Cytokine/chemokine ELISAs, zymography and western analyses identified TNFα and MMP9 as potential mechanisms by which estrogen-stimulated macrophages enhanced humanization. Specific inhibitors to TNFα and MMP9 validated the effects of these molecules on fibroblast behavior in vitro, as well as by immunohistochemical analysis of humanized glands for human-specific MMP9 expression. Lastly, glands humanized with macrophages had enhanced engraftment and tumor growth compared to glands humanized with fibroblasts alone. Conclusions Herein, we demonstrate intricate immune and stromal cell paracrine interactions in a humanized in vivo model system. We confirmed our in vivo results with in vitro analyses, highlighting the value of this model to interchangeably substantiate in vitro and in vivo results. It is critical to understand the signaling networks that drive paracrine cell interactions, for tumor cells exploit these signaling mechanisms to support their growth and invasive properties. This report presents a dynamic in vivo model to study primary human immune/fibroblast/epithelial interactions and to advance our knowledge of the stromal-derived signals that promote tumorigenesis

MODERN CONCEPT OF PATHOGENESIS OF ALLERGIC DISEASES AND NEW POTENTIALITIES OF IMMUNOTHERAPY

Despite the undoubted success of specific immunotherapy of allergic diseases (desensitization), one should confess that its effectiveness is not always satisfactory, and this explains the ongoing search for new approaches to immunotherapy. This conclusion is based on the results of basic research in immunology and allergy which provide new opportunities for therapy. The analysis of relevant work related to the study of allergic processes makes it possible to allocate two items: 1) specific hyposensitization-therapeutic approach that is primarily aimed at the final stage of the allergic reaction development; 2) development of allergic phenotype begins at early stages of B lymphocyte development while its final stage, IgE hyperproduction, depends on multiple of pre- and accompanying factors. Unfortunately, we should say that there are many issues in the development of allergic reaction that are beyond our understanding. Nevertheless, today new mechanisms of pathogenesis are revealed and there is a real opportunity for new approaches to the treatment of this pathology. Some of such various mechanisms will be discussed below

MODERN CONCEPT OF PATHOGENESIS OF ALLERGIC DISEASES AND NEW POTENTIALITIES OF IMMUNOTHERAPY

Despite the undoubted success of specific immunotherapy of allergic diseases (desensitization), one should confess that its effectiveness is not always satisfactory, and this explains the ongoing search for new approaches to immunotherapy. This conclusion is based on the results of basic research in immunology and allergy which provide new opportunities for therapy. The analysis of relevant work related to the study of allergic processes makes it possible to allocate two items: 1) specific hyposensitization-therapeutic approach that is primarily aimed at the final stage of the allergic reaction development; 2) development of allergic phenotype begins at early stages of B lymphocyte development while its final stage, IgE hyperproduction, depends on multiple of pre- and accompanying factors. Unfortunately, we should say that there are many issues in the development of allergic reaction that are beyond our understanding. Nevertheless, today new mechanisms of pathogenesis are revealed and there is a real opportunity for new approaches to the treatment of this pathology. Some of such various mechanisms will be discussed below