Mitochondrial dynamics keep balance of nutrient combustion in thermogenic adipocytes.

Non-shivering thermogenesis takes place in brown and beige adipocytes and facilitates cold tolerance and acclimation. However, thermogenesis in adipose tissue also was found to be activated in metabolic overload states for fast utilization of nutrients excess. This observation spurred research interest in mechanisms of thermogenesis regulation for metabolic overload and obesity prevention. One of proposed regulators of thermogenic efficiency in adipocytes is the dynamics of mitochondria, where thermogenesis takes place. Indeed, brown and beige adipocytes exhibit fragmented round-shaped mitochondria, while white adipocytes have elongated organelles with high ATP synthesis. Mitochondrial morphology can determine uncoupling protein 1 (UCP1) content, efficiency of catabolic pathways and electron transport chain, supplying thermogenesis. This review will highlight the co-regulation of mitochondrial dynamics and thermogenesis and formulate hypothetical ways for excessive nutrients burning in response to mitochondrial morphology manipulation.

Chemical Inducers of Obesity-Associated Metabolic Stress Activate Inflammation and Reduce Insulin Sensitivity in 3T3-L1 Adipocytes.

Obesity is accompanied by dyslipidemia, hypoxia, endoplasmic reticulum (ER) stress, and inflammation, representing the major risk factor for the development of insulin resistance (IR) and type 2 diabetes. We modeled these conditions in cultured 3T3-L1 adipocytes and studied their effect on insulin signaling, glucose uptake, and inflammatory response via activation of stress-dependent JNK1/2 kinases. Decreased insulin-induced phosphorylation of the insulin cascade components IRS, Akt, and AS160 was observed under all tested conditions (lipid overloading of cells by palmitate, acute inflammation induced by bacterial lipopolysaccharide, hypoxia induced by Co2+, and ER stress induced by brefeldin A). In all the cases, except the acute inflammation, glucose uptake by adipocytes was reduced, and the kinetics of JNK1/2 activation was bi-phasic exhibiting sustained activation for 24 h. By contrast, in acute inflammation, JNK1/2 phosphorylation increased transiently and returned to the basal level within 2-3 h of stimulation. These results suggest a critical role of sustained (latent) vs. transient (acute) inflammation in the induction of IR and impairment of glucose utilization by adipose tissue. The components of the inflammatory signaling can be promising targets in the development of new therapeutic approaches for preventing IR and type 2 diabetes.

[Fibrinolytics: from the thrombolysis to the processes of blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis].

One of the most outstanding scientific achievements in the thrombolysis is the development and administration of fibrinolysin - the first Soviet drug that lyses blood clots. Intracoronary administration of fibrinolysin reduced the mortality of patients with myocardial infarction by almost 20%. For his work in this field Yevgeny Chazov was awarded the Lenin Prize in 1982. Over the next decades, under his leadership, the Cardiology Center established scientific and clinical laboratories that created new generations of drugs based on fibrinolytics for treating patients with myocardial infarction, restoration of blood flow in ischemic tissue, and also studying the mechanisms of remodeling of blood vessels involving the fibrinolysis system. It have been found new mechanisms of regulation of the navigation of blood vessels and nerves growth, tumor growth and its metastasis with the participation of the fibrinolysis system proteins. The review reports the role of the fibrinolysis system in the thrombolysis, blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis. The article is dedicated to the 90th anniversary of academician E.I. Chazov.

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.

[The Role of Macrophages in Repair of Injured Myocardium and Perspectives of Metabolic Reprogramming of Immune Cells for Myocardial Post-Infarction Recovery].

A new trend in modern experimental cardiology is the development of approaches to correction of reparation after myocardial infarction (MI) with the use of specific effects on immune cells. One of the main targets for such interventions is the process of macrophage's polarization in the infarction zone. Proinflammatory M1­macrophages contribute to hampered myocardial repair, in contrast to M2­macrophages that promote regeneration. Currently, there are two main ways of targeted delivery of agents necessary for macrophage reprogramming - inlipoid and inglycan-encapsulated particles. As modulating agents, small interfering RNA and other genetic constructions are usually used. Both these approaches are currently awaiting their translation into cardiology. The most physiological approach to reprogramming of immune cells may consist in attempts to switch the metabolism of the immune cell from glycolytic to oxidative, which allows macrophages to switch from M1 to M2 phenotype. Among possible targets for macrophage reprogramming, it is worthwhile to isolate the protein complex mTORC1, the blocking of which promotes oxidative metabolism, and the transcription factor HIF-1α, the blocking of which also facilitates the switching of the metabolism from glycolytic to oxidative one.

Molecular Mechanisms of Latent Inflammation in Metabolic Syndrome. Possible Role of Sirtuins and Peroxisome Proliferator-Activated Receptor Type γ.

The problem of metabolic syndrome is one of the most important in medicine today. The main hazard of metabolic syndrome is development of latent inflammation in adipose tissue, which promotes atherosclerosis, non-alcoholic fatty liver disease, myocarditis, and a number of other illnesses. Therefore, understanding of molecular mechanisms of latent inflammation in adipose tissue is very important for treatment of metabolic syndrome. Three main components that arise during hypertrophy and hyperplasia of adipocytes underlie such inflammation: endoplasmic reticulum stress, oxidative stress, and hypoxia. Each of these components mediates activation in different ways of the key factor of inflammation - NF-κB. For metabolic syndrome therapy, it is suggested to influence a number of inflammatory signaling components by activating other cell factors to suppress development of inflammation. Such potential factors are peroxisome proliferator-activated receptors type γ that suppress transcription factor NF-κB through direct contact or via kinase of a NF-κB inhibitor (IKK), and also the antiinflammatory transcription factor AP-1. Other possible targets are type 3 NAD+-dependent histone deacetylases (sirtuins). There are mutually antagonistic relationships between NF-κB and sirtuin type 1 that prevent development of inflammation in metabolic syndrome. Moreover, sirtuin type 1 inhibits the antiinflammatory transcription factor AP-1. Study of the influence of these factors on the relationship between macrophages and adipocytes, macrophages, and adipose tissue-derived stromal cells can help to understand mechanisms of signaling and development of latent inflammation in metabolic syndrome.

Urokinase stimulates inflammatory response in damaged vascular wall during in vivo arterial remodeling.

Perivascular application of urokinase to the ballooned artery promoted the growth of neointima and constrictive remodeling of the vessel and stimulated the inflammatory response in the damaged vascular wall in vivo. Recombinant tissue plasminogen activator did not induce these changes. Our results indicate that urokinase is involved in the regulation of the inflammatory response during in vivo remodeling of the damaged vascular wall.

Plasmin-independent gelatinase B (matrix metalloproteinase-9) release by monocytes under the influence of urokinase.

It is shown that the release of matrix metalloproteinase-9 (gelatinase B) by THP-1 and U937 cells into conditioned media is increased under the action of recombinant single-chain urokinase. This effect is not accompanied by proteolytic activation of gelatinase B and is related to release of a pro-form of the enzyme. The action of urokinase on monocytes is time-dependent and becomes significant 12-24 h after the beginning of cell incubation. The dependence of the effect on the concentration of urokinase is characterized by half-maximum at about 20 nM and saturation at about 200 nM. The urokinase-induced gelatinase B release is not dependent on the action of plasmin because plasmin inhibitors aprotinin and alpha2-antiplasmin do not abolish this action. Additionally, tissue type plasminogen activator does not induce gelatinase B release by monocytes as observed under the action of urokinase. Nevertheless, the catalytic activity of urokinase participates in the development of the observed effect because it is significantly depressed by the natural urokinase inhibitor PAI-1. The effect of urokinase is completely abolished by actinomycin D and cycloheximide, indicating the participation of transcription and translation processes in its development.