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  • 1
    Language: English
    In: European Journal of Pharmacology, 15 August 2013, Vol.714(1-3), pp.498-506
    Description: Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hyperglycemia, but remain entirely responsive to exogenous insulin in adult age. Furthermore, as a consequence of MIF deficiency, the immune response in these mice is predominantly anti-inflammatory. Since MIF is a natural counter-regulator of glucocorticoid action, and it is known that excessive concentration of glucocorticoids contribute both to beta cell dysfunction and immunosuppression, we hypothesized that MIF absence enables elevation of glucocorticoids which in turn caused the observed condition. Our results confirm that MIF-knockout (MIF-KO) mice possess higher levels of circulating corticosterone, but lower expression of glucocorticoid receptor in pancreatic islets, liver and adipose tissue to the one observed in wild type (WT) mice. A significant up-regulation of glucocorticoid receptor expression was however noticed in MIF-deficient lymph node cells. The inhibition of glucocorticoid receptor by RU486 improved tolerance to glucose in MIF-KO mice and restored euglycemia. Although RU486 treatment did not alter the level of glucose receptor GLUT2, it enhanced insulin secretion and up-regulated insulin-triggered Akt phosphorylation within hepatic tissue. Finally, inhibition of glucocorticoid receptor changed anti-inflammatory phenotype of MIF-KO lymphocytes toward a physiological profile. Our results indicate that deregulated glucocorticoid secretion and glucocorticoid receptor expression in the absence of MIF possibly contributes to the development of glucose intolerance and immunosuppression in MIF-KO mice. However, since MIF-KO mice respond normally to insulin and their beta cell function is within physiological range, additional cause for glucose intolerance could be sought in the possible malfunction of their insulin.
    Keywords: Macrophage Migration Inhibitory Factor ; Glucocorticoids ; Diabetes ; Insulin ; Inflammation ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 2
    Language: English
    In: Diabetologia, 2014, Vol.57(5), pp.980-990
    Description: Byline: Ivana Nikolic (1), Tamara Saksida (1), Katia Mangano (2), Milica Vujicic (1), Ivana Stojanovic (1), Ferdinando Nicoletti (2), Stanislava Stosic-Grujicic (1) Keywords: Beta cell apoptosis; Carbon monoxide-releasing molecule-A1; Cytokines; Type 1 diabetes Abstract: Aims/hypothesis Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of autoimmune diseases owing to its anti-inflammatory and anti-apoptotic properties. We explored the efficacy and the mechanisms of action of the CO-releasing molecule (CORM)-A1 in preclinical models of type 1 diabetes. Methods The impact of CORM-A1 on diabetes development was evaluated in models of spontaneous diabetes in NOD mice and in diabetes induced in C57BL/6 mice by multiple low-dose streptozotocin (MLDS). Ex vivo analysis was performed to determine the impact of CORM-A1 both on T helper (Th) cell and macrophage differentiation and on their production of soluble mediators in peripheral tissues and in infiltrates of pancreatic islets. The potential effect of CORM-A1 on cytokine-induced apoptosis in pancreatic islets or beta cells was evaluated in vitro. Results CORM-A1 conferred protection from diabetes in MLDS-induced mice and reduced diabetes incidence in NOD mice as confirmed by preserved insulin secretion and improved histological signs of the disease. In MLDS-challenged mice, CORM-A1 attenuated Th1, Th17, and M1 macrophage response and facilitated Th2 cell differentiation. In addition, CORM-A1 treatment in NOD mice upregulated the regulatory arm of the immune response (M2 macrophages and FoxP3.sup.+ regulatory T cells). Importantly, CORM-A1 interfered with in vitro cytokine-induced beta cell apoptosis through the reduction of cytochrome c and caspase 3 levels. Conclusions/interpretation The ability of CORM-A1 to protect mice from developing type 1 diabetes provides a valuable proof of concept for the potential exploitation of controlled CO delivery in clinical settings for the treatment of autoimmune diabetes. Author Affiliation: (1) Department of Immunology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bul. Despota Stefana 142, 11060, Belgrade, Serbia (2) Department of Biomedical Sciences, School of Medicine, University of Catania, Via Androne 83, 95124, Catania, Italy Article History: Registration Date: 10/01/2014 Received Date: 19/07/2013 Accepted Date: 18/12/2013 Online Date: 02/02/2014 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00125-014-3170-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
    Keywords: Beta cell apoptosis ; Carbon monoxide-releasing molecule-A1 ; Cytokines ; Type 1 diabetes
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 3
    In: Journal of Food Science, July 2016, Vol.81(7), pp.H1846-H1853
    Description: Type 1 diabetes (T1D) is an autoimmune disease that develops as a consequence of pancreatic β‐cell death induced by proinflammatory mediators. Because L. ssp. (Greek oregano) contains antiinflammatory molecules, we hypothesized that it might be beneficial for the treatment of T1D. An ethyl acetate extract of oregano (EAO) was prepared from the leaves by a polar extraction method. Phytochemical composition was determined by liquid chromatography‐UV diode array coupled to ion‐trap mass spectrometry with electrospray ionization interface (LC/DAD/ESI‐MS). immunomodulatory effect of EAO was estimated by measuring proliferation (MTT) or cytokine secretion (ELISA) from immune cells. Diabetes was induced by multiple low doses of streptozotocin (MLDS) in male C57BL/6 mice and EAO was administered intraperitoneally for 10 d. Determination of cellular composition (flow cytometry) and cytokine production (ELISA) was performed on 12th d after diabetes induction. EAO suppressed the function of both macrophages and lymphocytes . , EAO treatment significantly preserved pancreatic islets and reduced diabetes incidence in MLDS‐challenged mice. Besides down‐modulatory effect on macrophages, EAO reduced the number of total CD4 and activated CD4CD25 T cells. Furthermore, EAO affected the number of T helper 1 (Th1) and T helper 17 (Th17) cells through downregulation of their key transcription factors T‐bet and RORγT. Because EAO treatment protects mice from development of hyperglycemia by reducing proinflammatory macrophage/Th1/Th17 response, this plant extract could represent a basis for future diabetes therapy. Through direct targeting of proinflammatory arm of the immune response, oregano extract enables preservation of healthy β cells during diabetes progression. This determines oregano extract as a possible candidate for the treatment of Type 1 diabetes.
    Keywords: Immune Modulation ; Macrophages ; Origanum Vulgare L. Ssp. Hirtum ; T Lymphocytes ; Type 1 Diabetes
    ISSN: 0022-1147
    E-ISSN: 1750-3841
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  • 4
    Language: English
    In: Megatrend Revija, 01 January 2015, Vol.12(1), pp.139-156
    Description: The paper examines the system of higher education in the Republic of Serbia in the context of educational paradigms and the development of the innovation and knowledge-based national economy. The subject of the research is higher education in Serbia in a life-long learning perspective as an essential component in achieving smart growth, capable enough to become a competent part of the European Higher Education Area. The aim of this paper is to examine the current situation in this area and the achievements of the new Strategy for Development of Education in Serbia by 2020 in the context of the expansion of higher education on the global level, as well as to emphasize the responsibility towards future generations for development of a more modern system of education based on the creativity of all participants in the learning process. In conclusion, the paper points out that the developmental orientation of educational system in the Republic of Serbia is building a new model of higher education.
    Keywords: Higher Education ; Sustainable Development ; Interactive Learning ; Evaluation Methodologies ; Teaching/Learning Model ; Serbia ; Economics
    ISSN: 1820-3159
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  • 5
    In: British Journal of Nutrition, 2015, Vol.113(5), pp.770-782
    Description: Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potent in vitro antioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved β-cells from in vitro apoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.
    Keywords: Full Papers; Nutritional Immunology; Type 1 Diabetes; Oregano; Il-17; T Helper 2 Cells; T Regulatory Cells
    ISSN: 0007-1145
    E-ISSN: 1475-2662
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  • 6
    In: Journal of Cellular Physiology, June 2018, Vol.233(6), pp.4990-5001
    Description: Carbonyl iron, a strong adjuvant, is able to prevent development of type 1 diabetes induced in mice and rats. It probably reduces the ability of antigen‐presenting cells to activate autoreactive T helper 1 cells that mediate destruction of pancreatic islets during diabetes progression.
    Keywords: Adjuvant ; Carbonyl Iron ; T Helper 17 ; T Regulatory Cells ; Type 1 Diabetes
    ISSN: 0021-9541
    E-ISSN: 1097-4652
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  • 7
    Language: English
    In: European Journal of Pharmacology, 05 October 2014, Vol.740, pp.683-689
    Description: Macrophage migration inhibitory factor is a multifunctional cytokine involved in the regulation of immune processes and also in apoptosis induction. Elevated MIF expression is detrimental for insulin-producing beta cells and MIF inhibition protected beta cells from several cytotoxic insults such as inflammatory cytokines, high fatty acids or high glucose concentrations. Therefore, the aim of this study was to investigate two newly synthesized small molecule MIF inhibitors (K664-1 and K647-1) and to compare them with previously established effects of the prototypical MIF inhibitor, ISO-1. Our results indicate that K664-1 and K647-1 are 160- and 40-fold more effective in inhibition of MIF׳s tautomerase activity than ISO-1. Also, new inhibitors confer beta cell protection from cytokine-triggered apoptosis at significantly lower concentrations than ISO-1. Although all three MIF inhibitors inhibit caspase 3 activity, K664-1 and K647-1 suppress pro-apoptotic BAX protein expression and up-regulate anti-apoptotic Bcl-2 mRNA. Finally, all three MIF inhibitors operate through blockade of nitric oxide production stimulated by cytokines. In conclusion, two novel MIF inhibitors are more potent than ISO-1 and operate through inhibition of the mitochondria-related apoptotic pathway. We propose that these compounds represent a unique class of anti-MIF antagonists that should be further tested for therapeutic use.
    Keywords: Macrophage Migration Inhibitory Factor ; Diabetes ; ISO-1 ; Cytokines ; Apoptosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 8
    Language: English
    In: Archives of Biological Sciences, 01 January 2017, Vol.69(4), pp.658-663
    Description: Type 1 diabetes (T1D) is an autoimmune disorder with a strong inflammatory component. Autoreactive cells specifically target insulin-producing β-cells, which leads to loss of glucose homeostasis. T1D remains incurable and versatile; potentially beneficial therapeutics are being tested worldwide. Possible candidates for the treatment of autoimmune diabetes are plants and their extracts since they are rich in biophenols, substances that act as secondary metabolites, and have verified antioxidant and antiinflammatory effects. Salvianolic acid B (SalB) is a biophenol and one of the major constituents of Origanum vulgare ssp. hirtum (Greek oregano) extracts which in our previous studies was shown to exhibit an antidiabetic effect in mice. The aim of the present study was to determine whether SalB is responsible for the observed effects of Greek oregano extracts. SalB was applied in vitro to macrophages and lymphocytes isolated from C57BL/6 mice, as well as in vivo in the model of T1D induced by multiple low doses (MLD) of streptozotocin (STZ). SalB did not affect the viability of cells, but it significantly decreased secretion of nitric oxide (NO) and TNF in lipopolysaccharide (LPS)-stimulated macrophages, as well as the secretion of IFN-γ in concanavalin A (ConA)-stimulated lymphocytes. However, when applied in vivo, SalB at a dose of 2.5 mg/kg b.w., applied for 10 consecutive days, failed to protect mice from diabetes development. In conclusion, SalB exerts immunomodulatory effects in vitro, but is not effective in prevention of T1D in vivo. It probably requires cooperation with some other substances for the maximum efficacy exhibited by oregano extracts. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. OI 173013]
    Keywords: Salvianolic Acid B ; Type 1 Diabetes ; Macrophage ; Lymphocyte ; Immune Modulation ; Biology
    ISSN: 0354-4664
    E-ISSN: 1821-4339
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  • 9
    Language: English
    In: Poslovna ekonomija, 2015, Vol.9(1), pp.95-118
    Description: The goal of this paper is to present current developments in the field of consumer protection of the Western Balkans. An analysis of problems and issues observed during the implementation of the basic principles, commitments, and legislation in accordance with European principles was studied. Consumer protection is a wide-ranging and significant policy. It is complex, dynamic, comprehensive and specific. It is important to develop a sustainable strategy for continuous improvement of the status of consumers. The preconditions for the protection of consumers in a sustainable, comprehensive and efficient way in the Balkans is development of consumer protection strategies that meet the EU standards.
    ISSN: 1820-6859
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  • 10
    In: Eastern European Countryside, 12/1/2013, Vol.19(1), pp.105-125
    Description: The purpose of this paper is to identify the main problems related to the sustainable development of rural communities, as well as the possible solutions to overcome them. This paper uses an analytical and synthetic approach, method of comparison and analogy, and descriptive analysis. The starting point of the research is actually a brief overview of the current situation in rural Serbia, while the central part of the paper presents an analysis concerning the development of the rural economy in the representative villages of Grabovica and Ribare in the Republic of Serbia. Research results are given in the form of specific guidelines for a new approach to local rural development and strengthening the role and responsibilities of local government in the development process. The main conclusion that follows from the results of the research is that continued and constant work is needed in order to empower local communities to take responsibility for their own development, as well as to support local initiatives to this end.
    Keywords: Serbia ; Sustainable Development ; Rural Development ; Social Psychology;
    ISSN: 1232-8855
    E-ISSN: 21995877
    Source: CrossRef
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