The interactions between inflammation and insulin resistance: molecular mechanisms in insulin-producing and insulin-dependent tissues

In the modern world the prevalence of obesity and type 2 diabetes mellitus (T2DM) significantly increases. In this light the risks of obesity-associated complications also grow up. The crucial linkage between obesity and its metabolic and cardiovascular complications is inflammatory process. The mechanism of this linkage is similar in pancreas and insulin-dependent tissues both on cells, cell-to-cell communication and signaling pathway levels: the catalysts are different lipids (cholesterol, free fatty acids, triglycerides), which are able to activate Toll-like receptors of innate immunity and inflammation. Nextly, IKK- and JNK-dependent cascades activate the secretion of inflammatory cytokines TNFa, IL-1b, IL-6 and others, which act by paracrine and autocrine manner and support inflammation both in local and systemic levels. Thus, insulin-producing and insulin-dependent tissues, which are involved in T2DM pathogenesis, through the inflammatory process integrate in pathogenic and self-maintaining cycle, which leads to the suppression of insulin secretion, pancreatic β-cell failure and the development of insulin-dependent tissues insulin resistance

The interactions between inflammation and insulin resistance: prospects of immunoregulation as a potential approach for the type 2 diabetes mellitus treatment

In the modern world the prevalence of obesity and type 2 diabetes mellitus (T2DM) significantly increases. In this light the risks of obesity-associated complications also grow up. The crucial linkage between obesity and its complications is inflammation, which is a convenient target for potential anti-diabetic therapy. There are some anti-inflammatory therapy strategies: action on secreted cytokines, circulating lipids or intracellular signaling cascades. Canakinumab (antibody to IL-1b receptor) and colchicine (IL-6 secretion blocker) have the most balanced anti-diabetic and cardioprotective action among cytokine anti-inflammatory therapy. Lipid-lowering therapy is very diverse, but bempedoic acid nowadays has the best combination of anti-inflammatory and cardioprotective effects. Salicylate is an inhibitor of IKK-dependent inflammatory signaling cascade and significantly lowers glycated hemoglobin and C-reactive protein levels among obese patients. The future of anti-inflammatory T2DM therapy can be related with anti-inflammatory cytokines (IL-4, IL-37), chimeric engineered cytokines (IC7Fc), novel inhibitors of inflammatory and cytokines signaling cascades (imatinib, CC90001) and cell-based therapy (mesenchymal stem cells). In summary, despite on the limitations of current clinical trials, anti-inflammatory drugs have a potential to become a part of modern combined T2DM therapy with anti-diabetic and cardioprotective properties. Novel findings in potential anti-inflammatory T2DM therapy have great perspectives in protection against T2DM and related complication prevention

Ways of implementation the interdisciplinary approach in physical education students

В работе представлено структурно-процессуальное содержание межпредметного подхода в физическом воспитании школьников и намечены пути его реализацииIn the work presented a structural and procedural content of interdisciplinary approach in physical education pupils and the ways of its realizatio

CLIPPERS. Обзор литературы и собственные наблюдения

CLIPPERS (Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is a rare inflammatory disease of the central nervous system, during which the pons of the brain is damaged. This disease was described for the first time in 2010 by S.J. Pittock et.al. At present, there have been around 50 described cases of the disease. Up to the present moment, there are difficulties diagnosing this disease. In the article, a literature review and three clinical cases are presented. Furthermore, the necessity of further research is shown for improving the accuracy and specificity of the diagnostic criteria, as well as for defining biomarkers and developing algorithms of effective therapy.CLIPPERS (Chronic lymphocytic inflammation with pontine perivascular enhancement responsive tosteroids) – хроническое лимфоцитарное воспаление с поражением моста, контрастным усилениемпериваскулярных пространств, отвечающее на терапию глюкокортикостероидными препаратами,представляет собой редкое воспалительное заболевание центральной нервной системы, вовлекающеепреимущественно мост головного мозга. Впервые заболевание было описано в 2010 г. S.J. Pittock исоавт. В настоящее время в литературе описано около 50 случаев. Заболевание до настоящего временивызывает диагностические проблемы. В статье приведен краткий обзор литературы и собственныенаблюдения трех клинических случаев. Показана необходимость дальнейших исследований дляповышения точности и специфичности диагностических критериев, определения биомаркеров иразработки алгоритмов эффективной терапии

Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves: BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo

Transplantation of adipose-derived mesenchymal stem cells (ASCs) induces tissue regeneration by accelerating the growth of blood vessels and nerve. However, mechanisms by which they accelerate the growth of nerve fibers are only partially understood. We used transplantation of ASCs with subcutaneous matrigel implants (well-known in vivo model of angiogenesis) and model of mice limb reinnervation to check the influence of ASC on nerve growth. Here we show that ASCs stimulate the regeneration of nerves in innervated mice's limbs and induce axon growth in subcutaneous matrigel implants. To investigate the mechanism of this action we analyzed different properties of these cells and showed that they express numerous genes of neurotrophins and extracellular matrix proteins required for the nerve growth and myelination. Induction of neural differentiation of ASCs enhances production of brain-derived neurotrophic factor (BDNF) as well as ability of these cells to induce nerve fiber growth. BDNF neutralizing antibodies abrogated the stimulatory effects of ASCs on the growth of nerve sprouts. These data suggest that ASCs induce nerve repair and growth via BDNF production. This stimulatory effect can be further enhanced by culturing the cells in neural differentiation medium prior to transplantation

Combined Transfer of Human VEGF165 and HGF Genes Renders Potent Angiogenic Effect in Ischemic Skeletal Muscle

Increased interest in development of combined gene therapy emerges from results of recent clinical trials that indicate good safety yet unexpected low efficacy of “single-gene” administration. Multiple studies showed that vascular endothelial growth factor 165 aminoacid form (VEGF165) and hepatocyte growth factor (HGF) can be used for induction of angiogenesis in ischemic myocardium and skeletal muscle. Gene transfer system composed of a novel cytomegalovirus-based (CMV) plasmid vector and codon-optimized human VEGF165 and HGF genes combined with intramuscular low-voltage electroporation was developed and tested in vitro and in vivo. Studies in HEK293T cell culture, murine skeletal muscle explants and ELISA of tissue homogenates showed efficacy of constructed plasmids. Functional activity of angiogenic proteins secreted by HEK293T after transfection by induction of tube formation in human umbilical vein endothelial cell (HUVEC) culture. HUVEC cells were used for in vitro experiments to assay the putative signaling pathways to be responsible for combined administration effect one of which could be the ERK1/2 pathway. In vivo tests of VEGF165 and HGF genes co-transfer were conceived in mouse model of hind limb ischemia. Intramuscular administration of plasmid encoding either VEGF165 or HGF gene resulted in increased perfusion compared to empty vector administration. Mice injected with a mixture of two plasmids (VEGF165+HGF) showed significant increase in perfusion compared to single plasmid injection. These findings were supported by increased CD31+ capillary and SMA+ vessel density in animals that received combined VEGF165 and HGF gene therapy compared to single gene therapy. Results of the study suggest that co-transfer of VEGF and HGF genes renders a robust angiogenic effect in ischemic skeletal muscle and may present interest as a potential therapeutic combination for treatment of ischemic disorders

Latent Inflammation and Insulin Resistance in Adipose Tissue

Obesity is a growing problem in modern society and medicine. It closely associates with metabolic disorders such as type 2 diabetes mellitus (T2DM) and hepatic and cardiovascular diseases such as nonalcoholic fatty liver disease, atherosclerosis, myocarditis, and hypertension. Obesity is often associated with latent inflammation; however, the link between inflammation, obesity, T2DM, and cardiovascular diseases is still poorly understood. Insulin resistance is the earliest feature of metabolic disorders. It mostly develops as a result of dysregulated insulin signaling in insulin-sensitive cells, as compared to inactivating mutations in insulin receptor or signaling proteins that occur relatively rare. Here, we argue that inflammatory signaling provides a link between latent inflammation, obesity, insulin resistance, and metabolic disorders. We further hypothesize that insulin-activated PI3-kinase pathway and inflammatory signaling mediated by several IκB kinases may constitute negative feedback leading to insulin resistance at least in the fat tissue. Finally, we discuss perspectives for anti-inflammatory therapies in treating the metabolic diseases