Pancreas Β-Cells in Type 1 and Type 2 Diabetes: Cell Death, Oxidative Stress and Immune Regulation. Recently Appearing Changes in Diabetes Consequences.

Diabetes mellitus type 1 (T1D) and type 2 (T2D) develop due to dysfunction of the Langerhans islet ß-cells in the pancreas, and this dysfunction is mediated by oxidative, endoplasmic reticulum (ER), and mitochondrial stresses. Although the two types of diabetes are significantly different, ß-cell failure and death play a key role in the pathogenesis of both diseases, resulting in hyperglycemia due to a reduced ability to produce insulin. In T1D, ß-cell apoptosis is the main event leading to hyperglycemia, while in T2D, insulin resistance results in an inability to meet insulin requirements. It has been suggested that autophagy promotes ß-cell survival by delaying apoptosis and providing adaptive responses to mitigate the detrimental effects of ER stress and DNA damage, which is directly related to oxidative stress. As people with diabetes are now living longer, they are more susceptible to a different set of complications. There has been a diversification in causes of death, whereby a larger proportion of deaths among individuals with diabetes is attributable to nonvascular conditions; on the other hand, the proportion of cancer-related deaths has remained stable or even increased in some countries. Due to the increasing cases of both T1D and T2D, these diseases become even more socially significant. Hence, we believe that search for any opportunities for control of this disease is an overwhelmingly important target for the modern science. We focus on two differences that are characteristic of the development of diabetes's last periods. One of them shows that all-cause death rates have declined in several diabetes populations, driven in part by large declines in vascular disease mortality but large increases in oncological diseases. Another hypothesis is that some T2D medications could be repurposed to control glycemia in patients with T1D.

The Possible Role of Β-Cell Senescence in the Development of Type 2 Diabetes Mellitus

This minireview discusses the very important biomedical problem of treating type 2 diabetes mellitus (T2D). T2D accounts for more than 90% of the total number of diagnosed cases of diabetes mellitus and can result from aging, inflammation, obesity and ß-cell senescence. The main symptom of both T2D and type 1 diabetes (T1D) is an increase in blood glucose concentration. While T1D is insulin-dependent and is associated with the destruction of pancreatic ß-cells, T2D does not require lifelong insulin administration. In this case, pancreatic ß-cells are not destroyed, but their functional activity is deregulated. In T2D, metabolic stress increases the number of senescent ß-cells while impairing glucose tolerance. The potential paracrine effects of senescent ß-cells highlight the importance of the ß-cell senescenceassociated secretory phenotype (SASP) in driving metabolic dysfunction. We believe that the main reason for the deregulation of the functional activity of pancreatic ß-cells in T2D is associated with their "aging" or senescence, which may be induced by various stressors. We propose the use of peroxiredoxin 6 as a new senolytic drug, and the role of ß-cell senescence in the development of T2D is discussed in this review.

Solid Xenon Carrier Based on α-Cyclodextrin: Properties, Preparation, and Application.

The inert gas xenon (Xe) is increasingly used in medicine as a universal anesthetic, a regulator of cellular metabolism, and a broad-spectrum organoprotector. Commonly utilized Xe inhalation requires expensive equipment that is not universally available. Here we describe the production process and physical characteristics of a solid, highly stable xenon carrier based on α-cyclodextrin (α-CD), developed for oral administration. It was found, that the interaction of α-CD with Xe in an aqueous solution and elevated pressure leads to precipitation of the α-CD-Xe complex. We have discovered three new properties of the resulting complex that promote long-term storage and oral delivery of Xe. (i) At temperatures below 0 °C, the precipitated α-CD-Xe complex containing water is so stable that it allows the removal of water by vacuum freeze-drying (lyophilization). (ii). Lyophilized α-CD-Xe remains stable for months at room temperature. (iii) Upon contact with water, α-CD-Xe rapidly releases gaseous Xe. As revealed in the forced swim test, after oral administration of lyophilized α-CD-Xe to rats, the duration of swimming was significantly increased. The obtained data open up prospects for the development of drugs based on the lyophilized α-CD-Xe complex suitable for storage, transportation, and medical use, including outside the hospital.

Cell Senescence and Central Regulators of Immune Response.

Pathways regulating cell senescence and cell cycle underlie many processes associated with ageing and age-related pathologies, and they also mediate cellular responses to exposure to stressors. Meanwhile, there are central mechanisms of the regulation of stress responses that induce/enhance or weaken the response of the whole organism, such as hormones of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic and parasympathetic systems, thymic hormones, and the pineal hormone melatonin. Although there are many analyses considering relationships between the HPA axis and organism ageing, we found no systematic analyses of relationships between the neuroendocrine regulators of stress and inflammation and intracellular mechanisms controlling cell cycle, senescence, and apoptosis. Here, we provide a review of the effects of neuroendocrine regulators on these mechanisms. Our analysis allowed us to postulate a multilevel system of central regulators involving neurotransmitters, glucocorticoids, melatonin, and the thymic hormones. This system finely regulates the cell cycle and metabolic/catabolic processes depending on the level of systemic stress, stage of stress response, and energy capabilities of the body, shifting the balance between cell cycle progression, cell cycle stopping, senescence, and apoptosis. These processes and levels of regulation should be considered when studying the mechanisms of ageing and the proliferation on the level of the whole organism.

Peroxiredoxin 6 Applied after Exposure Attenuates Damaging Effects of X-ray Radiation in 3T3 Mouse Fibroblasts.

Although many different classes of antioxidants have been evaluated as radioprotectors, none of them are in widespread clinical use because of their low efficiency. The goal of our study was to evaluate the potential of the antioxidant protein peroxiredoxin 6 (Prdx6) to increase the radioresistance of 3T3 fibroblasts when Prdx6 was applied after exposure to 6 Gy X-ray. In the present study, we analyzed the mRNA expression profiles of genes associated with proliferation, apoptosis, cellular stress, senescence, and the production of corresponding proteins from biological samples after exposure of 3T3 cells to X-ray radiation and application of Prdx6. Our results suggested that Prdx6 treatment normalized p53 and NF-κB/p65 expression, p21 levels, DNA repair-associated genes (XRCC4, XRCC5, H2AX, Apex1), TLR expression, cytokine production (TNF-α and IL-6), and apoptosis, as evidenced by decreased caspase 3 level in irradiated 3T3 cells. In addition, Prdx6 treatment reduced senescence, as evidenced by the decreased percentage of SA-ß-Gal positive cells in cultured 3T3 fibroblasts. Importantly, the activity of the NRF2 gene, an important regulator of the antioxidant cellular machinery, was completely suppressed by irradiation but was restored by post-irradiation Prdx6 treatment. These data support the radioprotective therapeutic efficacy of Prdx6.

Role of Innate Immunity and Oxidative Stress in the Development of Type 1 Diabetes Mellitus. Peroxiredoxin 6 as a New Anti-Diabetic Agent.

The review discusses information on the development of type 1 diabetes mellitus (T1D) as a systemic autoimmune and inflammatory disease. Focus of the review is on the role of innate immune system, including activation of some signaling cascades, cytokine response, and activity of the Toll-like receptors in the development of T1D. Dysfunction of innate immunity is the cause of the attack of pancreatic beta cells by the host T-lymphocytes, which leads to the death of pancreatic beta cells that produce insulin. Lack of insulin causes hyperglycemia and the need for lifelong injections of insulin in patients with T1D, which, nevertheless, does not exclude damage to many organs and tissues, given particular vulnerability of the blood vessels under conditions of hyperglycemia. The review discusses the role of oxidative stress as a factor that plays a major role in damage of vascular system and pancreatic tissue during the development of T1D. Considering high sensitivity of pancreatic beta cells to the action of reactive oxygen species (ROS), the possibility of using antioxidants for reducing the level of pathological consequences in the course of T1D development is discussed. New information on anti-diabetic activity of the exogenous antioxidant enzyme peroxiredoxin 6, which is capable of penetrating cells, activating insulin production in beta cells, reducing ROS levels, as well as decreasing activation of some signaling cascades, production of pro-inflammatory cytokines, and expression of Toll-like receptors in beta cells and in immune cells during T1D development is discussed.

Pharmacological torpor prolongs rat survival in lethal normobaric hypoxia.

Resistance to hypoxia is one of the most prominent features of natural hibernation and is expected to be present in the pharmacological torpor (PT) that simulates hibernation. We studied resistance to lethal hypoxia (3.5% oxygen content) in rats under PT. To initiate PT, we used the previously developed pharmacological composition (PC) which, after a single intravenous injection, can induce a daily decrease in Tb by 7 °C-8 °C at the environmental temperature of 22 °C-23 °C. Half-survival (median) time of rats in lethal hypoxia was found to increase from 5 ± 0.8 min in anesthetized control rats to 150 ± 12 min in rats injected with PC, which is a 30-fold increase. Behavioral tests after PT and hypoxia, including the traveling distance, the number of rearing and grooming episodes, revealed that animal responses are significantly restored within a week. It is assumed that the discovered unprecedented resistance of artificially torpid rats to lethal hypoxia may open up broad prospects for the therapeutic use of PT for preconditioning to various damaging factors, treatment of diseases, and extend the so-called "golden hour" for lifesaving interventions.

Thymulin and peroxiredoxin 6 have protective effects against streptozotocin-induced type 1 diabetes in mice.

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F ß-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. We assessed the effects of the drugs on the physiological status of diabetic mice by measuring blood glucose, body weight, and cell counts in several organs, as well as effects of thymulin and PRDX6 on the immune status of diabetic mice measuring concentrations of pro-inflammatory cytokines in blood plasma (TNF-α, interleukin-5 and 17, and interferon-γ), activity of NF-κB and JNK pathways, and Hsp90α expression in immune cells. Both thymulin and PRDX6 reduced the physiological impairments in diabetic mice at various levels. Thymulin and PRDX6 provide beneficial effects in the model of diabetes via very different mechanisms. Taken together, the results of our study indicated that the thymic peptide and the antioxidant enzyme have anti-inflammatory functions. As increasing evidences show diabetes mellitus as a distinct comorbidity leading to acute respiratory distress syndrome and increased mortality in patients with COVID-19 having cytokine storm, thymulin, and PRDX6 might serve as a supporting anti-inflammatory treatment in the therapy of COVID 19 in diabetic patients.

Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells.

Type 1 diabetes is associated with the destruction of pancreatic beta cells, which is mediated via an autoimmune mechanism and consequent inflammatory processes. In this article, we describe a beneficial effect of peroxiredoxin 6 (PRDX6) in a type 1 diabetes mouse model. The main idea of this study was based on the well-known data that oxidative stress plays an important role in pathogenesis of diabetes and its associated complications. We hypothesised that PRDX6, which is well known for its various biological functions, including antioxidant activity, may provide an antidiabetic effect. It was shown that PRDX6 prevented hyperglycemia, lowered the mortality rate, restored the plasma cytokine profile, reversed the splenic cell apoptosis, and reduced the ß cell destruction in Langerhans islets in mice with a severe form of alloxan-induced diabetes. In addition, PRDX6 protected rat insulinoma RIN-m5F ß cells, cultured with TNF-α and IL-1ß, against the cytokine-induced cytotoxicity and reduced the apoptotic cell death and production of ROS. Signal transduction studies showed that PRDX6 prevented the activation of NF-κB and c-Jun N-terminal kinase signaling cascades in RIN-m5F ß cells cultured with cytokines. In conclusion, there is a prospect for therapeutic application of PRDX6 to delay or even prevent ß cell apoptosis in type 1 diabetes.

Comparison of natural and pharmacological hypothermia in animals: Determination of activation energy of metabolism.

The constancy of the activation energy of metabolism (E) for all living organisms is one of the most impressive, though controversial, statements of the modern metabolic theory of evolution. According to WBE-theory suggested by West, Brown, and Enquist, E should be in the range from -0.6 to -0.7 eV. However, there are many examples of significant deviations of E from the predictions of the theory. Now we have conducted a study of this value using rats in different types of pharmacological hypothermia: 1. Short-term (for several hours) hypothermia induced by anesthetic xylazine; 2. Daily torpor-like state induced by the pharmacological composition developed in our previous study. It has been found that in pharmacological daily hypothermia E = -0.56 ± 0.03 eV, which was close to that in daily heterotherms found in literature, E = -0.57 ± 0.04 eV. In short-term hypothermia E was substantially lower, E = -0.17 ± 0.071 eV. Our analysis revealed that in short-term hypothermia, changes in body temperature may lag behind changes in metabolic rate for a period Δt, affecting E. We propose an approach for estimating Δt and obtaining an adjusted E = -0.68 ± 0.17 eV, which corresponds to theoretical predictions. We assume that a similar consideration of Δt should be done when calculating E of daily heterotherms. We assume that in ectotherms, when the ambient temperature changes rapidly, changes in metabolic rate may lag behind changes in body temperature for a period (-) Δt, that should also be considered in E calculations. The proposed approach may contribute to the further development of the metabolic theory of evolution and may be useful in comparing artificial and natural hypothermia, as well as in studying the energy transformations in ecosystems.

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice.

Relapsing-remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing-remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate (PBCA) nanoparticles. PBCA nanoparticles were used to prolong the presence of thymulin in the blood. Cytokine levels in blood were measured by ELISA; NF-κB and SAPK/JNK cascade activation, as well as Hsp72 and p53 protein expression, were measured by Western blotting. Animal health statuses were estimated using severity scores. Results showed that the cytokine response in rEAE was multi-staged: an early phase was accompanied by an increase in plasma interferon-γ, while the interleukin (IL)-17 response was markedly increased at a later stage. The stages were attributed to rEAE induction and maintenance phases. Thymulin significantly alleviated symptoms of rEAE and lowered plasma cytokine levels both in early and later stages of rEAE, and decreased NF-κB and SAPK/JNK cascade activation. Thymulin modulated NF-kappaB pathway activity via site-specific phosphorylation of RelA/p65 protein (at Ser276 and Ser536). The effect of nanoparticle-bound thymulin was more pronounced than the effect of free thymulin. Therefore, PBCA-thymulin can be considered a prospective treatment for this pathology.

A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats.

AIMS: To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor. MATERIALS AND METHODS: We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle. KEY FINDINGS: After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C-23 °C. The hypothermic state may continue on average for 16-17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4-8 days later they were restored. SIGNIFICANCE: Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.

Effects of low-level combined static and weak low-frequency alternating magnetic fields on cytokine production and tumor development in mice.

We investigated the effects of weak combined magnetic fields (MFs) produced by superimposing a constant MF (in the range 30 - 150 µT) and an alternating MF (100 or 200 nT) on cytokine production in healthy Balb/C male mice exposed 2 h daily for 14 days. The alternating magnetic field was a sum of several frequencies (ranging from 2.5 - 17.5 Hz). The frequencies of the alternating magnetic field were calculated formally based on the cyclotron resonance of ions of free amino acids (glutamic and aspartic acids, arginine, lysine, histidine, and tyrosine). The selection of different intensity and frequency combinations of constant and alternating magnetic fields was performed to find the optimal characteristics for cytokine production stimulation in immune cells. MF with a constant component of 60 µT and an alternating component of 100 nT, which was a sum of six frequencies (from 5 to 7 Hz), was found to stimulate the production of tumor necrosis factor-α, interferon-gamma, interleukin-2, and interleukin-3 in healthy mouse cells and induce cytokine accumulation in blood plasma. Then, we studied the effect of this MF on tumor-bearing mice with solid tumors induced by Ehrlich ascite carcinoma cells by observing tumor development processes, including tumor size, mouse survival rate, and average lifespan. Tumor-bearing mice exposed to a combined constant magnetic field of 60 µT and an alternating magnetic field of 100 nT containing six frequencies showed a strong suppression of tumor growth with an increase in survival rate and enhancement of average lifespan.

The role of mitochondrial KATP channel in anti-inflammatory effects of uridine in endotoxemic mice.

In this study, we examined the effects of uridine on plasma cytokine levels, heat shock protein (HSP) 72 expression, and nuclear factor (NF)-κB signaling in spleen lymphocytes after exposure of male BALB/c mice to Escherichia coli lipopolysaccharide (LPS). Mice were treated with uridine (30 mg/kg body weight, intraperitoneal injection [i.p.]) or saline solution of LPS (2.5 mg/kg, i. p.). Endotoxin increased plasma levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)-1, IL-2, and IL-6 by 2.1-, 1.9-, 1.7-, 1.6-, and 2.3-fold, respectively. Prior treatment with uridine prevented LPS-induced increases in all studied cytokines. In splenic lymphocytes, LPS treatment increased the expression of HSP 72 by 2.4-fold, whereas preliminary treatment with uridine completely prevented this effect. LPS also activated NF-κB signaling in splenic lymphocytes, and uridine decreased NF-κB pathway activity. Inhibitory analysis showed that the mechanism of uridine action was associated with the formation of the UDP-metabolic activator of the mitochondrial ATP-dependent potassium channel (mitoKATP) and the UTP-activator of glycogen synthesis in the tissues. A specific inhibitor of mitoKATP, 5-hydroxydecanoate (5 mg/kg), and an inhibitor of glycogen synthesis, galactosamine (110 mg/kg), prevented the effects of uridine. Thus, uridine itself or uridine phosphates, which increased after uridine treatment, appeared to inhibit pro-inflammatory responses induced by LPS application. Overall, these findings demonstrated that the mechanisms mediating the effects of uridine were regulated by activation of glycogen synthesis and opening of the mitoKATP, which in turn increased the energy potential of the cell and reduced oxidative stress.

Thymulin, free or bound to PBCA nanoparticles, protects mice against chronic septic inflammation.

In the present work, we aimed to study the effects of free and polybutylcyanoacrylate nanoparticle-bound thymulin on immune cell activity in mice with chronic inflammation. NF-κB, MAPK, and PKC-θ signaling pathway activity was assessed, alongside Hsp72, Hsp90-α, and TLR4 expression and levels of apoptosis. In addition, plasma cytokines and blood and brain melatonin and serotonin levels were measured. In mice treated with gradually raised doses of lipopolysaccharide, significant increases in the activity of the signaling pathways tested, heat-shock protein and TLR4 expression, lymphocyte apoptosis, and plasma proinflammatory cytokine levels were noted. Moreover, we observed significantly heightened serotonin concentrations in the plasma and especially the brains of mice with inflammation. In contrast, melatonin levels were reduced in the tissues examined, particularly so in the brain. Treatment of these mice with thymulin alleviated fever, reduced apoptosis, increased splenic cell number, and decreased cytokine production, Hsp72, Hsp90, and TLR4 expression, and the activity of the signaling pathways examined. In addition, thymulin partially restored brain and blood serotonin and melatonin levels. Thus, thymulin suppressed the proinflammatory response in LPS-treated mice, indicating the potential of thymulin co-therapy in the treatment of sepsis. Nanoparticle-bound thymulin was more effective in several respects.

Extrathymic production of thymulin induced by oxidative stress, heat shock, apoptosis, or necrosis.

Thymic peptides are immune regulators produced mainly in the thymus. However, thymic peptides such as thymosin-α and thymopoietin have precursors widely expressed outside the thymus, localized in cell nuclei, and involved in vital nuclear functions. In stress-related conditions, they can relocalize. We hypothesized that another thymic peptide, thymulin, could be similarly produced by non-thymic cells during stress and have a precursor therein. Non-thymic cells, including macrophages and fibroblasts, were exposed to oxidative stress, heat, apoptosis, or necrosis. Extracellular thymulin was identified in media of both cell types 2 h after exposure to stress or lethal signals. Therefore, thymulin is released by non-thymic cells. To examine possible thymulin precursors in non-thymic cells, macrophage lysates were analyzed by western blotting. Bands stained with anti-thymulin antibody were detected in two locations, approximately 60 kDa and 10 kDa, which may be a possible precursor and intermediate. All of the exposures except for heat were effective for induction of the 10 kDa protein. BLAST search using thymulin sequence identified SPATS2L, an intranucleolar stress-response protein with molecular weight of 62 kDa, containing thymulin-like sequence. Comparisons of blots stained with anti-thymulin and anti-SPATS2L antibodies indicate that SPATS2L may be a possible candidate for the precursor of thymulin.

Extremely low-level microwaves attenuate immune imbalance induced by inhalation exposure to low-level toluene in mice.

PURPOSE: To clarify whether extremely low-level microwaves (MW) alone or in combination with p38 inhibitor affect immune cell responses to inhalation exposure of mice to low-level toluene. MATERIALS AND METHODS: The cytokine profile, heat shock proteins expression, and the activity of several signal cascades, namely, NF-κB, SAPK/JNK, IRF-3, p38 MAPK, and TLR4 were measured in spleen lymphocytes of mice treated to air-delivered toluene (0.6 mg/m3) or extremely low-level microwaves (8.15-18 GHz, 1µW/cm2, 1 Hz swinging frequency) or combined action of these two factors. RESULTS: A single exposure to air-delivered low-level toluene induced activation of NF-κB, SAPK/JNK, IFR-3, p38 MAPK and TLR4 pathways. Furthermore, air toluene induced the expression of Hsp72 and enhanced IL-1, IL-6, and TNF-α in blood plasma, which is indicative of a pro-inflammatory response. Exposure to MW alone also resulted in the enhancement of the plasma cytokine values (e.g. IL-6, TNF-α, and IFN-γ) and activation of the NF-κB, MAPK p38, and especially the TLR4 pathways in splenic lymphocytes. Paradoxically, pre-exposure to MW partially recovered or normalized the lymphocyte parameters in the toluene-exposed mice, while the p38 inhibitor XI additionally increased protective activity of microwaves by down regulating MAPKs (JNK and p38), IKK, as well as expression of TLR4 and Hsp90-α. CONCLUSIONS: The results suggest that exposure to low-intensity MW at specific conditions may recover immune parameters in mice undergoing inhalation exposure to low-level toluene via mechanisms involving cellular signaling.

Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application.

Hypothermia and hypometabolism (hypometabothermia) normally observed during natural hibernation and torpor, allow animals to protect their body and brain against the damaging effects of adverse environment. A similar state of hypothermia can be achieved under artificial conditions through physical cooling or pharmacological effects directed at suppression of metabolism and the processes of thermoregulation. In these conditions called torpor-like states, the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases. Therefore, the development of therapeutic methods for different pathologies is a matter of great concern. With the discovery of the antipsychotic drug chlorpromazine in the 1950s of the last century, the first attempts to create a pharmacologically induced state of hibernation for therapeutic purposes were made. That was the beginning of numerous studies in animals and the broad use of therapeutic hypothermia in medicine. Over the last years, many new agents have been discovered which were capable of lowering the body temperature and inhibiting the metabolism. The psychotropic agents occupy a significant place among them, which, in our opinion, is not sufficiently recognized in the contemporary literature. In this review, we summarized the latest achievements related to the ability of modern antipsychotics to target specific receptors in the brain, responsible for the initiation of hypometabothermia.

Signaling, stress response and apoptosis in pre-diabetes and diabetes: restoring immune balance in mice with alloxan-induced type 1 diabetes mellitus.

The aim of this study was to compare immune imbalances in "pre-diabetic" and diabetic mice and to evaluate the efficacy of several agents in improving the immunity of mice with type 1 diabetes. Pre-diabetic and diabetic models generated by a single or double alloxan injection were monitored for plasma glucose and pancreas immunohistochemistry. To study the immunity in pre-diabetic and diabetic Balb/C male mice; the levels of cytokines; synthesis of inducible heat shock proteins HSP72 and HSP90α; activity of the NF-κB, IFR3, SAPK/JNK, and TLR4 pathways; and apoptosis levels in thymuses were measured. Pre-diabetes resulted in a decrease in IL-4, IL-5 and IL-10 in plasma; in diabetic mice, plasma IFN-gamma, IL-6, TNF-alpha, and IL-10 were decreased. The NF-κB alternative pathway activity and TLR4 expression were significantly increased only in pre-diabetic mice, whereas SAPK/JNK activation was observed at both stages of diabetes. Other measured parameters also showed distinct altered patterns in the immunity of pre-diabetic and diabetic mice. Treatment with an inhibitor of NF-κB, thymulin, or a diet with an antioxidant improved or normalized the immune balance in diabetic mice and also notably decreased pancreatic cell damage in pre-diabetic mice.

The role of the NF-κB, SAPK/JNK, and TLR4 signalling pathways in the responses of RAW 264.7 cells to extremely low-intensity microwaves.

PURPOSE: To investigate the role of the toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), and stress activated protein kinases/Jun N-terminal kinase (SAPK/JNK) signalling pathways in the responses of RAW 264.7 macrophages to low-intensity microwaves (MW). MATERIALS AND METHODS: Three inhibitors of TLR4, SAPK/JNK, and NF-κB signalling, namely CLI-095, SP600125, and IKK Inhibitor XII, respectively, were added to cultured RAW 264.7 macrophages before MW treatment. RESULTS: MW exposure resulted in stimulation of RAW 264.7 cell activity manifested by increases in cytokine production and the stimulation of cell signalling. The blocking of a key kinase of the NF-κB pathway by IKK Inhibitor XII resulted in decreased MW-induced TLR4 expression and increased SAPK/JNK and NF-κB phosphorylation in irradiated cells. In addition, IKK Inhibitor XII significantly decreased tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin 1α (IL-1α), interleukin 6 (IL-6), and interleukin 10 (IL-10) production in both exposed and unexposed RAW 264.7 macrophages. Inhibitor SP6000125 did not prevent an MW effect on signal proteins with the exception of decreased SAPK/JNK phosphorylation in RAW 264.7 cells. Cytokine production was markedly decreased in MW-exposed cells cultured with SP6000125. The inhibitor of TLR4, CLI-095, did not affect signal proteins and cytokine production changes in MW-exposed cells. CONCLUSIONS: The results suggest that low-intensity MW promotes macrophage activity via mechanisms involving cellular signalling, particularly the NF-κB pathway.