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Insulin Protects Apoptotic Cardiomyocytes from Hypoxia/Reoxygenation Injury through the Sphingosine Kinase/Sphingosine 1-Phosphate Axis  [PDF]
Huan Yu, Xiangxin Che, Xiaoyuan Xu, Meirong Zheng, Yong Zhao, Wei He, Jingmou Yu, Jianjun Xiong, Weidong Li
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080644
Abstract: Objective Experimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective, but the mechanisms underlying this effect are still unknown. In this study, the ability of insulin to protect apoptotic cardiomyocytes from hypoxia/reoxygenation injury using the sphingosine kinase/sphingosine 1-phosphate axis was investigated. Methods and Results Rat cardiomyocytes were isolated and subjected to hypoxia and reoxygenation. [γ-32P] ATP was used to assess sphingosine kinase activity. Insulin was found to increase sphingosine kinase activity. Immunocytochemistry and Western blot analysis showed changes in the subcellular location of sphingosine kinase 1 from cytosol to the membrane in cardiomyocytes. Insulin caused cardiomyocytes to accumulate of S1P in a dose-dependent manner. FRET efficiency showed that insulin also transactivates the S1P1 receptor. TUNEL staining showed that administration of insulin during reoxygenation could to reduce the rate of reoxygenation-induced apoptosis, which is a requirement for SphK 1 activity. It also reduced the rate of activation of the S1P receptor and inhibited hypoxia/reoxygenation-induced cell death in cardiomyocytes. Conclusion The sphingosine kinase 1/sphingosine 1-phosphate/S1P receptor axis is one pathway through which insulin protects rat cardiomyocytes from apoptosis induced by hypoxia/reoxygenation injury.
Effects of Acute Exercise and Chronic Exercise on the Liver Leptin-AMPK-ACC Signaling Pathway in Rats with Type 2 Diabetes  [PDF]
Xuejie Yi,Shicheng Cao,Bo Chang,Dalin Zhao,Haining Gao,Yihan Wan,Jiaojiao Shi,Wei Wei,Yifu Guan
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/946432
Abstract: Aim. To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ). Methods. Animals were classified into control (CON), diabetes (DC), diabetic chronic exercise (DCE), and diabetic acute exercise (DAE) groups. Results. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPKα1/2, AMPKα1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPKα1/2, AMPKα2, AMPKα1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC. Conclusion. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver. 1. Introduction Leptin deficiency or dysfunction is one of the main causes for insulin resistance (IR) and lipid metabolism disorders [1, 2]. However, patients with type 2 diabetes rarely have a leptin deficiency. It has been found that the majority of type 2 diabetes patients have higher levels of body fat, but normal or increased leptin in the plasma [3–6], indicating leptin resistance (LR). Certain levels of leptin effectively could stimulate AMP-activated protein kinase (AMPK) to phosphorylate acetyl-coA carboxylase (ACC), which in turn reduces the ACC activity, decreases fatty acid synthesis [7], and increases the oxidation of fatty acid (FA) [8], consequently, maintaining the balance of lipid metabolism in the body. Studies have shown that even one week of a high fat diet can cause leptin to increase rapidly, leading to fat accumulation in peripheral tissue IR [9]. Obese persons with high serum leptin levels tend to experience a downregulation of leptin receptor in hypothalamus, adipose tissue, and liver [10], which causes peripheral tissues to become LR and promotes lipid accumulation [11–13]. Excessive lipid deposition in nonfat tissue has been known to have a toxic effect on cells and to reduce sensitivity to insulin, eventually leading to
Downregulation of heat shock protein 70 protects rheumatoid arthritis fibroblast-like synoviocytes from nitric oxide-induced apoptosis
Eun Ha Kang, Dong Jo Kim, Eun Young Lee, Yun Jong Lee, Eun Bong Lee, Yeong Wook Song
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2797
Abstract: Targeted knock-down of Hsp70 was performed by RNA interference in RA FLSs at passage 3-7. After SNP treatment, the morphological features of apoptosis were observed by phase-contrast microscopy. Cell survival was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and by flow cytometric analysis after propidium iodide (PI) staining. Bcl-2 expression and signaling pathways (Akt, extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase) were examined with or without Hsp70 downregulation.Hsp70 downregulation in RA FLSs, induced by small interfering RNA (siRNA), was confirmed by reverse transcriptase-polymerase chain reaction and Western blotting. When treated with SNP, Hsp70 downregulated cells showed markedly less cell blebbing, cytoplasmic condensation, and nuclear shrinkage than non-downregulated control cells. Furthermore, Hsp70 downregulated cells were found to survive better than control cells in MTT assays (mean of absorbance ratio, 4.39 in target cells versus 1.00 in control siRNA-treated cells versus 1.09 in lipofectamine-treated cells, P = 0.001) and according to PI staining results (mean M1 ratio, 0.21 in target cells versus 1.00 in control siRNA-treated cells versus 1.03 in lipofectamine-treated cells, P = 0.001). Bcl-2 expression and Akt phosphorylation were higher in Hsp70 downregulated RA FLSs than in control cells. When cells were treated with LY294002, a potent phosphoinositide 3-kinase inhibitor, Akt phosphorylation and Bcl-2 levels were reduced and Hsp70 downregulation no longer had a cytoprotective effect.Knock-down of Hsp70 protects RA FLSs from nitric oxide-induced apoptosis by activating the Akt signaling pathway. These results suggest that Hsp70 has a pro-apoptotic role in RA FLSs.Rheumatoid arthritis (RA) is a chronic inflammatory disorder that involves mainly joint synovium. One of the major characteristics of RA synovium is the tumor-like growth of fibroblast-like synoviocytes (FLSs) that invade ad
Insulin receptor has tyrosine kinase activity toward Shc in rat liver
Páez-Espinosa, E.V.;Carvalho, C.R.O.;Velloso, L.A.;Saad, M.J.A.;
Brazilian Journal of Medical and Biological Research , 1998, DOI: 10.1590/S0100-879X1998001100008
Abstract: insulin induces tyrosine phosphorylation of shc in cell cultures and in insulin-sensitive tissues of the intact rat. however, the ability of insulin receptor (ir) tyrosine kinase to phosphorylate shc has not been previously demonstrated. in the present study, we investigated insulin-induced ir tyrosine kinase activity towards shc. insulin receptor was immunoprecipitated from liver extracts, before and after a very low dose of insulin into the portal vein, and incubated with immunopurified shc from liver of untreated rats. the kinase assay was performed in vitro in the presence of exogenous atp and the phosphorylation level was quantified by immunoblotting with antiphosphotyrosine antibody. the results demonstrate that shc interacted with insulin receptor after infusion of insulin, and, more important, there was insulin receptor kinase activity towards immunopurified shc. the description of this pathway in animal tissue may have an important role in insulin receptor tyrosine kinase activity toward mitogenic transduction pathways.
Insulin receptor has tyrosine kinase activity toward Shc in rat liver  [cached]
Páez-Espinosa E.V.,Carvalho C.R.O.,Velloso L.A.,Saad M.J.A.
Brazilian Journal of Medical and Biological Research , 1998,
Abstract: Insulin induces tyrosine phosphorylation of Shc in cell cultures and in insulin-sensitive tissues of the intact rat. However, the ability of insulin receptor (IR) tyrosine kinase to phosphorylate Shc has not been previously demonstrated. In the present study, we investigated insulin-induced IR tyrosine kinase activity towards Shc. Insulin receptor was immunoprecipitated from liver extracts, before and after a very low dose of insulin into the portal vein, and incubated with immunopurified Shc from liver of untreated rats. The kinase assay was performed in vitro in the presence of exogenous ATP and the phosphorylation level was quantified by immunoblotting with antiphosphotyrosine antibody. The results demonstrate that Shc interacted with insulin receptor after infusion of insulin, and, more important, there was insulin receptor kinase activity towards immunopurified Shc. The description of this pathway in animal tissue may have an important role in insulin receptor tyrosine kinase activity toward mitogenic transduction pathways.
Diapause Formation and Downregulation of Insulin-Like Signaling via DAF-16/FOXO Delays Axonal Degeneration and Neuronal Loss  [PDF]
Andrea Calixto ,Juan S. Jara,Felipe A. Court
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003141
Abstract: Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.
Aspartame in conjunction with carbohydrate reduces insulin levels during endurance exercise  [cached]
Siegler Jason,Howell Keith,Vince Rebecca,Bray James
Journal of the International Society of Sports Nutrition , 2012, DOI: 10.1186/1550-2783-9-36
Abstract: Background As most sport drinks contain some form of non-nutritive sweetener (e.g. aspartame), and with the variation in blood glucose regulation and insulin secretion reportedly associated with aspartame, a further understanding of the effects on insulin and blood glucose regulation during exercise is warranted. Therefore, the aim of this preliminary study was to profile the insulin and blood glucose responses in healthy individuals after aspartame and carbohydrate ingestion during rest and exercise. Findings Each participant completed four trials under the same conditions (45 min rest + 60 min self-paced intense exercise) differing only in their fluid intake: 1) carbohydrate (2% maltodextrin and 5% sucrose (C)); 2) 0.04% aspartame with 2% maltodextrin and 5% sucrose (CA)); 3) water (W); and 4) aspartame (0.04% aspartame with 2% maltodextrin (A)). Insulin levels dropped significantly for CA versus C alone (43%) between pre-exercise and 30 min, while W and A insulin levels did not differ between these time points. Conclusions Aspartame with carbohydrate significantly lowered insulin levels during exercise versus carbohydrate alone.
Myeloid Cell-Restricted Insulin Receptor Deficiency Protects Against Obesity-Induced Inflammation and Systemic Insulin Resistance  [PDF]
Jan Mauer,Bhagirath Chaurasia,Leona Plum,Thomas Quast,Brigitte Hampel,Matthias Blüher,Waldemar Kolanus,C. Ronald Kahn,Jens C. Brüning
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000938
Abstract: A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IRΔmyel-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IRΔmyel-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) α and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.
Downregulation of protein kinase C-α enhances intracellular survival of Mycobacteria: role of PknG
Shivendra K Chaurasiya, Kishore K Srivastava
BMC Microbiology , 2009, DOI: 10.1186/1471-2180-9-271
Abstract: Based on our earlier study, we have extrapolated for the first time that knockdown of PKCα, impairs phagocytosis of mycobacteria by macrophages while their intracellular survival is drastically increased. Mycobacterium bovis BCG (BCG) and Mycobacterium tuberculosis H37Ra (Ra) have also been shown to downregulate the expression of PKCα during the infection. Since PknG is uniquely expressed in BCG, Ra, Rv but not in MS and has been reported to promote intracellular survival of mycobacteria, led us to believe that PknG may be involved in such downregulation of PKCα. THP-1 cells infected with recombinant MS expressing PknG (MS-G), showed significant reduction in PKCα expression. In normal THP-1 cells survival of MS-G was enhanced as compared to MS, while their behavior in PKCα deficient cells could not be distinguished. The results strongly demonstrate that pathogenic mycobacteria recognize and then inhibit PKCα to circumvent phagocytosis and the hostile environment of macrophages. We emphasize that, this inhibition is controlled by PknG.All together, our data reveal a mechanism that shows substantial interdependence of PKCα with PknG, in sustaining mycobacterial infection.Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has infected billions of people worldwide. Phagocytic cells are critical for host defense against infection by capturing invading pathogens and killing them inside the bactericidal milieu of lysosomes as well as in processing and presenting the pathogen derived antigens. Based on the ability to infect and cause diseases, mycobacteria can be classified into species that cause TB in humans or in animals, including Mtb and M. bovis, and species that are generally non-pathogenic, such as MS and M. vaccae. The survival of pathogenic mycobacteria within macrophages involves the inhibition of several host cell processes which allow them unlike non-pathogenic species to survive inside host cells. Host processes manipulated by pathogenic my
Resveratrol Protects against Physical Fatigue and Improves Exercise Performance in Mice  [PDF]
Ruei-Er Wu,Wen-Ching Huang,Chen-Chung Liao,Yu-Kai Chang,Nai-Wen Kan,Chi-Chang Huang
Molecules , 2013, DOI: 10.3390/molecules18044689
Abstract: Resveratrol (RES) is a well-known phytocompound and food component which has antioxidative and multifunctional bioactivities. However, there is limited evidence for the effects of RES on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of trans-RES on fatigue and ergogenic functions following physiological challenge. Male ICR mice from four groups ( n = 8 per group) were orally administered RES for 21 days at 0, 25, 50, and 125 mg/kg/day, which were respectively designated the vehicle, RES-25, RES-50, and RES-125 groups. The anti-fatigue activity and exercise performance were evaluated using forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, and creatine kinase (CK) after a 15-min swimming exercise. The exhaustive swimming time of the RES-25 group (24.72 ± 7.35 min) was significantly ( p = 0.0179) longer than that of vehicle group (10.83 ± 1.15 min). A trend analysis revealed that RES treatments increased the grip strength. RES supplementation also produced dose-dependent decreases in serum lactate and ammonia levels and CK activity and also an increase in glucose levels in dose-dependent manners after the 15-min swimming test. The mechanism was related to the increased energy utilization (as blood glucose), and decreased serum levels of lactate, ammonia, and CK. Therefore, RES could be a potential agent with an anti-fatigue pharmacological effect.
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