Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin.</p> <p>Results</p> <p>We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met.</p> <p>Conclusion</p> <p>Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.</p

Matrix metalloproteinase-13 refines pathological staging of precancerous colorectal lesions

An exact classification of precancerous stages of colorectal polyps might improve therapy and patients´ outcome. Here we investigate the association between grade of dysplasia and Matrix metalloproteinase-13 (MMP-13) expression in 137 biopsies from patients with cancerous and non-cancerous colorectal adenomas. A reproducible staining procedure for histologic MMP-13 analysis in routinely fixed colorectal biopsy specimens has been established. A newly adopted immunoreactive scoring system for MMP-13 was demonstrated as reliable readout. The strength of the association between pathologic stage and immunoreactive MMP-13 scoring emphasizes its eligibility for diagnosis in precancerous colorectal lesions

Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD

Marketing As Tool of Resource Efficiency

This paper shows the role of marketing in ensuring resource efficiency. It is found that the marketing is one of the methods of saving resources, making them effective in use. The conclusion about the need to use marketing to increase the efficiency of resource management in the organization is justified. It is suggested to use SWOT-analysis as a marketing technique for choosing a particular strategy, significant for the company in the management of resource efficiency. The forecasting of demand allows receiving evidence-based options in tendencies of change, indicators of quality, expenses and other indicators. Therefore, the system of the resource efficiency at an enterprise has to be guided by forecasting the demand and its task. Improved analysis cost methods (such as the factorial analysis, the functional and cost analysis) help to solve a problem of resource efficiency at the stage of design or production improvement. It is proved that application of the concept of social and ethic marketing promotes development of the resource efficiency program in management

Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice

Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4-/- and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c. Liver injury, serum bile acid concentration, hepatic fibrosis, and carcinogenesis were enhanced by the combination of simultaneous damage in line with activation of c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, and Signal transducer and activator of transcription 3 (STAT3). Activation of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) and Eukaryotic translation initiation factor 2A (eIF2a) indicated unfolded protein response (UPR) in HBsAg-expressing mice and even in Abcb4-/- without HBsAg-expression. CONCLUSION: Cholestasis-induced STAT3- and JNK-pathways may predispose HBsAg-associated tumorigenesis. Since STAT3- and JNK-activation are well characterized critical regulators for tumor promotion, the potentiation of their activation in hybrids suggests an additive mechanism enhancing tumor incidence

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis

Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration

4 páginas, 2 figuras -- PAGS nros. 383-386B-cell chronic lymphocytic leukemia (B-CLL) progression is frequently accompanied by clinical lymphadenopathy, and the CCL21 chemokine may play an important role in this process. Indeed, CCR7 (the CCL21 receptor), as well as matrix metalloproteinase-9 (MMP-9), are overexpressed in infiltrating B-CLL cells. We have studied whether MMP-9 is regulated by CCL21 and participates in CCL21-dependent migration. CCL21 significantly increased B-CLL MMP-9 production, measured by gelatin zymography. This was inhibited by blocking extracellular signal-regulated kinase-1/2 (ERK1/2) activity or by cell transfection with CCR7-siRNA. Accordingly, CCL21/CCR7 interaction activated the ERK1/2/c-Fos pathway and increased MMP-9 mRNA. CCL21-driven B-CLL cell migration through Matrigel or human umbilical vein endothelial cells (HUVEC) was blocked by anti-CCR7 antibodies, CCR7-siRNA transfection, or the ERK1/2 inhibitor U0126, as well as by anti-MMP-9 antibodies or tissue inhibitor of metalloproteinase 1 (TIMP-1). These results strongly suggest that MMP-9 is involved in B-CLL nodal infiltration and expand the roles of MMP-9 and CCR7 in B-CLL progression. Both molecules could thus constitute therapeutic targets for this diseaseThis work was supported by grants PI060400 (to A.G.P.) and PI061637 (to M.J.T.) from the Ministerio de Sanidad y Consumo, and by the Fundación de Investigación Médica Mutua Madrileña (FMM; to A.G.P.). J.R.M. was supported by FMM and the Fundación Ramón ArecesPeer reviewe

Проект реконструкции ОРУ 220 кВ подстанции 500 кВ Томская

В процессе работы проводились расчеты затрат на оборудование и монтаж, расчёт экономической эффективности капиталовложений. Расчет показателей надежности распределительных устройств. Полученными результатами являются числовые значения необходимости реконструкции. Область применения: результаты данной работы могут быть использованы как образец для дальнейших реконструкций.In the process of work carried out calculations of the cost of equipment and installation, the calculation of the economic efficiency of investment. Calculation of reliability of switchgear. The results obtained are the numerical values of the need for reconstruction. Scope: the results of this work can be used as a model for further reconstruction

Мотивирование трудовой деятельности как фактор стабильности персонала ( на примере ООО Стоматологической поликлиники «Классик-Дент» г. Абакан)

Бакалаврская работа 93 с., 3 рис., 17 табл., 42 источников, 2 прил. Ключевые слова: мотивация, персонал, организация, управление персоналом, анализ, стабильность, эффективность. Объектом исследования является система мотивирования персонала в ООО «Стоматологическая поликлиника «Классик-Дент». Цель работы – анализ и разработка рекомендаций по совершенствованию системы мотивирования труда в организации. В результате исследования были разработаны мероприятия направленные на повышение мотивации персонала. Степень внедрения: разработанные рекомендации могут быть использованы руководством предприятия с целью улучшения трудовой деятельности персонала. Область применения: мотивирование трудовой деятельности как фактор стабильности персонала может быть использовано на предприятии, организацBachelor work 93 p., 3 Fig., 17 tab., 42 sources, 2 ADJ. Key words: motivation, personnel, organization, personnel management, analysis, stability, efficiency. The object of study is the system of motivation of the personnel OOO "STOMATOLOGICHESKAYA POLIKLINIKA Klassik-dent". The work purpose – analysis and development of recommendations on improvement of system of motivation of labor in the organization. The study activities were designed to increase staff motivation. Level of implementation: the guidelines may be used by management to improve work activities of staff. Scope: the motivation of labour activity as the factor of stability of personnel can be used in the enterprise, organization, company any industry. Economic efficiency and significance of the work: the effectiveness of the implementation of measures aimed at improving staff motivation is obvious, which will increase the work activity of staff and reduce staff turnover. In the future it is planned to develop new models aimed at increasing staff motivation, improving social-psychological climate in the team and reduce turnover