Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs

Background: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Methods: Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. Results: Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. Conclusion: In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined

Small proteoglycans of normal adult human kidney: Distinct expression patterns of decorin, biglycan, fibromodulin, and lumican

Small proteoglycans of normal adult human kidney: Distinct expression patterns of decorin, biglycan, fibromodulin, and lumican.BackgroundAmong the members of the small leucine-rich proteoglycan family, decorin, biglycan, and fibromodulin have been proposed to be potent modulators of transforming growth factor-β (TGF-β) activity, thereby playing an important role in the pathogenesis of fibrotic kidney diseases. Furthermore, decorin expression influences the expression of p21WAF1/CIP1, which has been related to kidney hypertrophy and hyperplasia. However, none of the members of this proteoglycan family have been investigated in normal adult human kidney cortex, thus making it impossible to correlate disease-mediated alterations of their expression with the normal situation in vivo.MethodsThe chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, and the keratan sulfate proteoglycans, fibromodulin and lumican, were investigated in normal human adult renal cortex by immunohistochemistry on the light and electron microscopic level and by in situ hybridization. Northern blot and reverse transcription-polymerase chain reaction (RT-PCR) methods were used to get an estimate of their expression in isolated glomeruli. Decorin excretion with the urine was measured by Western blotting.ResultsTwo bands of decorin and a single band of biglycan mRNA were identified in Northern blots of isolated glomeruli. Amplification by RT-PCR was required to detect the signals for fibromodulin and lumican. All four proteoglycans were preferentially expressed in the renal interstitium with accumulations around tubules. Weak expression was found in the mesangial matrix. Biglycan was expressed by glomerular endothelial cells and, together with fibromodulin, was synthesized and deposited in distal tubular cells and collecting ducts. Immunogold labeling indicated the presence of the proteoglycans in the glomerular basement membrane, which was interpreted as a result of glomerular filtration. Indirect evidence suggested tubular reuptake of decorin after glomerular filtration.ConclusionThe data indicate that the different cells of the adult human kidney are characterized by a distinct expression pattern of the four small proteoglycans. It is suggested that these proteoglycans may have distinct pathophysiological roles depending upon whether they are expressed by mesangial cells, endothelial cells, epithelial cells, or cells of the tubulointerstitium

Disturbed Epidermal Structure in Mice with Temporally Controlled Fatp4 Deficiency

So far, little is known about the physiological role of fatty acid transport protein 4 (Fatp4, Slc27a4). Mice with a targeted disruption of the Fatp4 gene display features of a human neonatally lethal restrictive dermopathy with a hyperproliferative hyperkeratosis, a disturbed epidermal barrier, a flat dermal–epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis, demonstrating that Fatp4 is necessary for the formation of the epidermal barrier. Because Fatp4 is widely expressed, it is unclear whether intrinsic Fatp4 deficiency in the epidermis alone can cause changes in the epidermal structure or whether the abnormalities observed are secondary to the loss of Fatp4 in other organs. To evaluate the functional role of Fatp4 in the skin, we generated a mouse line with Fatp4 deficiency inducible in the epidermis. Mice with epidermal keratinocyte-specific Fatp4 deficiency developed a hyperproliferative hyperkeratosis with a disturbed epidermal barrier. These changes resemble the histological abnormalities in the epidermis of newborn mice with total Fatp4 deficiency. We conclude that Fatp4 in epidermal keratinocytes is essential for the maintenance of a normal epidermal structure

Проблемы повышения эффективности инвестиций в образование

Определяются масштабы и эффективность инвестиций в образование, научные исследования и разработки. Обосновывается необходимость изменения социального статуса системы образования и увеличения масштабов финансирования как необходимого условия повышения качества подготовки специалистов

Информационная система учета и анализа деятельности микрокредитной организации «Дос-Бай»

В период тяжелых экономических ситуаций в стране большее количество граждан ищут способы пополнить свою бюджет с помощью займов, усугубляет ситуацию и низкий рост заработной платы, относительно роста инфляции. В связи с этим растет роль микрокредитных организаций на рынке финансов.In a period of difficult economic situations in the country, more citizens are looking for ways to replenish their budget with loans, exacerbates the situation and low wage growth, relative to inflation. In this regard, the role of microcredit organizations in the financial market is growing

Источник бесперебойного питания для телекоммуникационного оборудования

Телекоммуникационное оборудование очень важно в наши дни. Все чаще встречается необходимость его бесперебойной работы в современном мире Разработан источник бесперебойного питания, работающий в трехфазной цепи. Показана необходимость построения источников бесперебойного питания телекоммуникационного оборудования для обеспечения его нормальной работы. Выполнен анализ принципов построения источника бесперебойного питания для ответственных потребителей электрической энергии. Осуществлен выбор функциональной схемы электропитания телекоммуникационного оборудования. Выполнен расчет и выбор основных элементов сети электропитания узла связи. Представлено компьютерное моделирование работы выпрямителя в составе ИБП.Telecommutation equipment is very important these days. More and more often there is a need for its uninterrupted work in the modern world  An uninterruptible power supply has been developed that operates in a three-phase circuit. The need to build uninterruptible power supplies for telecommunications equipment is shown to ensure its normal operation. The analysis of the principles of construction of an uninterruptible power supply for responsible consumers of electrical energy is performed. The functional scheme of power supply of telecommunication equipment has been selected. The calculation and selection of the main elements of the power supply network of the communication center have been performed. A computer simulation of rectifier operation in the UPS is presented

Hepatitis C Virus Induced Endothelial Inflammatory Response Depends on the Functional Expression of TNF alpha Receptor Subtype 2

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I: C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I: C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFa). HCV-RNA induces the endothelial expression of TNFa and TNFa receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections

Glucosylceramide Synthase Is Involved in Development of Invariant Natural Killer T Cells

Invariant natural killer T (iNKT) cells represent a unique population of CD1d-restricted T lymphocytes expressing an invariant T cell receptor encoded by Vα14-Jα18 and Vα24-Jα18 gene segments in mice and humans, respectively. Recognition of CD1d-loaded endogenous lipid antigen(s) on CD4/CD8-double positive (DP) thymocytes is essential for the development of iNKT cells. The lipid repertoire of DP thymocytes and the identity of the decisive endogenous lipid ligands have not yet been fully elucidated. Glycosphingolipids (GSL) were implicated to serve as endogenous ligands. However, further in vivo investigations were hampered by early embryonal lethality of mice deficient for the key GSL-synthesizing enzyme glucosylceramide (GlcCer) synthase [GlcCer synthase (GCS), EC 2.4.1.80]. We have now analyzed the GSL composition of DP thymocytes and shown that GlcCer represented the sole neutral GSL and the acidic fraction was composed of gangliosides. Furthermore, we report on a mouse model that by combination of Vav-promoter-driven iCre and floxed GCS alleles (VavCreGCSf/f) enabled an efficient depletion of GCS-derived GSL very early in the T cell development, reaching a reduction by 99.6% in DP thymocytes. Although the general T cell population remained unaffected by this depletion, iNKT cells were reduced by approximately 50% in thymus, spleen, and liver and showed a reduced proliferation and an increased apoptosis rate. The Vβ-chains repertoire and development of iNKT cells remained unaltered. The GSL-depletion neither interfered with expression of CD1d, SLAM, and Ly108 molecules nor impeded the antigen presentation on DP thymocytes. These results indicate that GlcCer-derived GSL, in particular GlcCer, contribute to the homeostatic development of iNKT cells

Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis