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Purpose Diabetes, as a group of metabolic diseases, can elevate blood glucose, thus leading to the development of life-threatening complications. It is difficult to define the outcome for diabetics with different BMI. This review will illustrate the adipose tissue macrophage-derived exosome in the diabetics with different BMI. Patients and Methods Insulin resistance in peripheral tissues can cause diabetes. The peripheral tissues include liver, muscle, or the adipose depots. Communication between these organs is fatal to the maintenance of glucose homeostasis. This review will illustrate this communication. Obesity is closely linked with diabetes. There are different changes in fat distribution in diabetic patients. Adipose tissue macrophages can secrete various hormones, including adiponectin, leptin, resistin and other classical cytokines, such as TNF-α and IL-6. Studies illustrated that exosomes from the adipose tissue, can modulate inter-organ cross-talk by regulating gene expression in other tissues. Results Adipose tissue macrophages exosomes links thin and fat individuals in the development of diabetes. Conclusion The molecular pathways initiated by exosomes such as miRNA in the situations of metabolic stress could help us gain a deeper knowledge of the pathophysiology of diabetes.

Insufficient Astrocyte-Derived BDNF Contributes to Propofol-Induced Neuron Death through Akt/GSK3u03b2/Mitochondrial Fission PathwayZeljko J. Bosnjak, Ph.D., Yanan Liu, Ph.D., Sarah Logan, B.S., Yasheng Yan, B.S., Xiaowen Bai, M.D., Ph.D.Background: Propofol causes neuron death in developing animals and there is little information regarding the role of astrocytes. Relative numbers of astrocytes to neurons are much less in neonatal rodent brains compared with adults. We hypothesize that insufficient levels of astrocyte-derived brain-derived neurotrophic factor (BDNF) may contribute to propofol-induced neuron death. Methods: Hippocampal astrocytes and neurons isolated from neonatal rats were either cultured alone or co-cultured at 1:9 and 1:1 ratios. The cultures were treated with propofol (3, 10, or 30 u03bcM) for 6 h with BDNF, TrkB inhibitor Cyclotraxin-B, GSK3u03b2 inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1. Cell death was measured by propidium iodide staining. BDNF concentration in astrocyte-conditioned medium was quantified using ELISA. Western blot was performed for Akt and GSK3u03b2 assay. Mitochondrial shape was visualized through TOM20 staining. Results: Propofol (10 and 30 u03bcM) increased cell death, mitochondrial fission, and activated GSK3u03b2; and decreased activated Akt in neurons, but did not influence astrocyte viability. The neuron death was attenuated by co-culturing with astrocytes at high-density (1:1) but not low-density (1:9). Administration of BDNF, CHIR99021, or Mdivi-1 prevented the increases of cell death and mitochondrial fission of neurons in neuron-alone cultures and 1:9 co-cultures. Blocking BDNF receptor and Akt activities abolished astrocyte-induced neuroprotection. Conclusions: We demonstrate for the first time that 1) astrocytes are more resistant to propofol than neurons and 2) insufficient BDNF secretion, due to low-density of astrocytes, contributes to propofol-induced neuron death through Akt/GSK3u03b2/mitochondrial fission pathway, suggesting potential neuroprotective strategies against propofol such as administration of BDNF or astrocyte-conditioned medium, decreasing mitochondrial fission, or inhibiting GSK3u03b2.

Reactive oxygen species (ROS) mediate the effects of anesthetic precondition to protect against ischemia and reperfusion injury, but the mechanisms of ROS generation remain unclear. In this study, the authors investigated if mitochondria-targeted antioxidant (mitotempol) abolishes the cardioprotective effects of anesthetic preconditioning. Further, the authors investigated the mechanism by which isoflurane alters ROS generation in isolated mitochondria and submitochondrial particles.Rats were pretreated with 0.9% saline, 3.0 mg/kg mitotempol in the absence or presence of 30 min exposure to isoflurane. Myocardial infarction was induced by left anterior descending artery occlusion for 30 min followed by reperfusion for 2 h and infarct size measurements. Mitochondrial ROS production was determined spectrofluorometrically. The effect of isoflurane on enzymatic activity of mitochondrial respiratory complexes was also determined.Isoflurane reduced myocardial infarct size (40 ± 9% = mean ± SD) compared with control experiments (60 ± 4%). Mitotempol abolished the cardioprotective effects of anesthetic preconditioning (60 ± 9%). Isoflurane enhanced ROS generation in submitochondrial particles with nicotinamide adenine dinucleotide (reduced form), but not with succinate, as substrate. In intact mitochondria, isoflurane enhanced ROS production in the presence of rotenone, antimycin A, or ubiquinone when pyruvate and malate were substrates, but isoflurane attenuated ROS production when succinate was substrate. Mitochondrial respiratory experiments and electron transport chain complex assays revealed that isoflurane inhibited only complex I activity.The results demonstrated that isoflurane produces ROS at complex I and III of the respiratory chain via the attenuation of complex I activity. The action on complex I decreases unfavorable reverse electron flow and ROS release in myocardium during reperfusion.

Generation of excessive reactive oxygen species (ROS) leads to mitochondrial dysfunction, apoptosis and necrosis in renal ischemia-reperfusion (IR) injury. Previously we showed that lentiviral vector mediated over-expression of superoxide dismutase-1 (SOD1) in proximal tubular epithelial cells (LLC-PK1) reduced cytotoxicity in an in vitro model of IR injury. Here, we examined the effects of SOD1 over-expression on mitochondrial signaling following ATP depletion-recovery (ATP-DR). To examine the role of mitochondrial ROS, a subset of cells were treated with the mitochondrial antioxidant, MitoTEMPO. ATP-DR-mediated increases in mitochondrial calcium ([Ca2+]m), loss of mitochondrial membrane potential (ΔΨm) and increase in mitochondrial permeability transition pore (MPTP) were attenuated by SOD1 and MitoTEMPO (P < 0.01). SOD1 prevented ATP-DR induced mitochondrial Bax translocation, although the release of pro-apoptotic proteins from mitochondria was not prevented by SOD1 alone and required the presence of both SOD1 and MitoTEMPO. SOD1 suppressed the increase in c-jun phosphorylation suggesting that JNK signaling regulates Bax translocation to mitochondria via ROS. ATP-DR-mediated changes in MPTP and mitochondrial signaling increased necrosis and apoptosis, both of which were partially attenuated by SOD1 and MitoTEMPO. These studies show that SOD1 and MitoTEMPO preserve mitochondrial integrity and attenuate ATP-DR mediated necrosis and apoptosis.

Ischemic preconditioning is an important intrinsic mechanism for neuroprotection. Preconditioning can also be achieved by exposure of neurons to K+ channel-opening drugs that act on adenosine triphosphate-sensitive K+ (K(ATP)) channels. However, these agents do not readily cross the blood-brain barrier. Inhalational anesthetics which easily partition into brain have been shown to precondition various tissues. Here, the authors explore the neuronal preconditioning effect of modern inhalational anesthetics and investigate their effects on K(ATP) channels.Neuronal-glial cocultures were exposed to inhalational anesthetics in a preconditioning paradigm, followed by oxygen-glucose deprivation. Increased cell survival due to preconditioning was quantified with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction test. Recombinant plasmalemmal K(ATP) channels of the main neuronal type (Kir6.2/SUR1) were expressed in HEK293 cells, and the effects of anesthetics were evaluated in whole cell patch clamp recordings.Both sevoflurane and the noble gas xenon preconditioned neurons at clinically used concentrations. The effect of sevoflurane was independent of K(ATP) channel activation, whereas the effect of xenon required the opening of plasmalemmal K(ATP) channels. Recombinant K(ATP) channels were activated by xenon but inhibited by halogenated volatiles. Modulation of mitochondrial K-ATP channels did not affect the activity of K(ATP) channels, thus ruling out an indirect effect of volatiles via mitochondrial channels.The preconditioning properties of halogenated volatiles cannot be explained by their effect on K(ATP) channels, whereas xenon preconditioning clearly involves the activation of these channels. Therefore, xenon might mimic the intrinsic mechanism of ischemic preconditioning most closely. This, together with its good safety profile, might suggest xenon as a viable neuroprotective agent in the clinical setting.