Prolactin-signal transduction in neonatal rat pancreatic islets and interaction with the insulin-signaling pathway

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICODuring pregnancy, pancreatic islets undergo structural and functional changes in response to an increased demand for insulin. Different hormones, especially placental lactogens, mediate these adaptive changes. Prolactin (PRL) mainly exerts its biological effects by activation of the JAK2/STAT5 pathway. PRL also stimulates some biological effects via activation of IRS-1, IRS-2, PI 3-kinase, and MAPK in different cell lines. Since IRS-2 is important for the maintenance of pancreatic islet cell mass, we investigated whether PRL affects insulin-signaling pathways in neonatal rat islets. PRL significantly potentiated glucose-induced insulin secretion in islets cultured for 7 days. This effect was blocked by the specific PI 3-kinase inhibitor wortmannin. To determine possible effects of PRL on insulin-signaling pathways, fresh islets were incubated with or without the hormone for 5 or 15 min. Immunoprecipitation and immunoblotting with specific antibodies showed that PRL induced a dose-dependent IRS-1 and IRS-2 phosphorylation compared to control islets. PRL-induced increase in IRS-1/-2 phosphorylation was accompanied by an increase in the association with and activation of PI 3-kinase. PRL-induced IRS-2 phosphorylation and its association with PI 3-kinase did not add to the effect of insulin. PRL also induced JAK2, SHC, ERK1 and ERK2 phosphorylation in neonatal islets, demonstrating that PRL can activate MAPK. These data indicate that PRL can stimulate the IRSs/PI 3-kinase and SHC/ERK pathways in islets from neonatal rats355282289FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçãosem informaçã

Isolation And Characterization Of A Convulxin-like Protein From Crotalus Durissus Collilineatus Venom

A convulxin (Cvx)-like protein was isolated from Crotalus durissus collilineatus venom by a combination of molecular exclusion and reversed-phase HPLC chromatographies. The molecular mass of the Cvx-like protein in the absence and presence of DTT was 78 kDa and 12-13 kDa, respectively. The Cvx-like protein consisted of two nonidentical polypeptide chains (α and β). The N-terminal amino-acid sequences of the α and β subunits were GLHCPSDWYAYDGHCYKIFNEEMNWED and GFCCPSHWSSYSRYCYKFFSQEMNWEDAEK, respectively, with both subunits having a high content of Glu, Ser, Cys, and Asp. The Cvx-like protein showed high homology with other venom C-type lectins, but had low hemagglutinating activity on intact and trypsinized erythrocytes. The Cvx-like protein stimulated insulin receptor phosphorylation and potentiated insulin secretion from isolated islets in the presence of sub- (2.8 mM) or supra-physiological (16.7 mM) glucose concentrations. These results suggest that the increase in insulin secretion induced by Cvx-like protein may be mediated by a protein tyrosine kinase-dependent pathway and may involve other membrane receptors, such as GP VI or Scr family proteins.207585591Aragon-Ortiz, F., Mentele, R., Auerswald, E.A., (1996) Toxicon, 34, pp. 763-769Aspinwall, C.A., Qian, W.J., Roper, M.G., Kulkami, R.N., Kahn, C.R., Kennedy, R.T., (2000) J. Biol. Chem., 275, pp. 22331-22338Boschero, A.C., Szpak-Glasman, M., Carneiro, E.M., Bordin, S., Paul, I., Rojas, E., Atwater, I., (1995) Am. J. Physiol., 268, pp. E336-E342Carvalho, D.D., Marangoni, S., Oliveira, B., Novello, J.C., (1998) Biochem. Mol. Biol. Internat., 44, pp. 933-938Cicmil, M., Thomas, J.M., Sage, T., Barry, F.A., Leduc, M., Bon, C., Gibbins, J.M., (2000) J. Biol. Chem., 275, pp. 27339-27347Drickamer, K., (1988) J. Biol. Chem., 263, pp. 9557-9560Francischetti, I.M., Saliou, B., Leduc, M., Carlini, C.R., Hatmi, M., Randon, J., Faili, A., Bon, C., (1997) Toxicon, 35, pp. 1217-1228Francischetti, I.M., Carlini, C.R., Guimaräes, J.A., (1998) Biochem. Biophys., 354, pp. 255-262Francischetti, I.M., Ghazaleh, F.A., Reis, R.A., Carlini, C.R., Guimaräes, J.A., (1998) Arch. Biochem. Biophys., 353, pp. 239-250Henrikson, R.L., Meredith, S.C., (1984) Analyt. Biochem., 136, pp. 65-71Hirabayashi, J., Kusunoki, T., Kasai, K., (1991) J. Biol. Chem., 266, pp. 2320-2326Hori, K., Matsubara, K., Miyazawa, K., (2000) Biochim. Biophys. Acta, 1474, pp. 226-236Komori, Y., Nikai, T., Tohkai, T., Sugihara, H., (1999) Toxicon, 37, pp. 1053-1064Lennon, B.W., Kaiser, I., (1990) Comp. Biochem. Physiol. B, 97, pp. 695-699Liener, I.E., Sharon, N., Goldstein, I.J., (1986), Academic Press, LondonMarangoni, S., Toyama, M.H., Arantes, E.C., Giglio, J.R., Da Silva, C.A., Carneiro, E.M., Gonçalves, A.A., Oliveira, B., (1995) Biochem. Biophys. Acta, 1243, pp. 309-314Marlas, G., (1985) Biochimie, 67, pp. 1231-1239Marlas, G., Joseph, D., Huet, C., (1983) Biochimie, 65, pp. 619-628Matsuzaki, R., Yoshida, E., Yamada, M., Atoda, H., Morita, T., (1996) Biochem. Biophys. Res. Commun., 220, pp. 382-387Niedergang, F., Alcover, A., Knight, C.G., Farndale, R.W., Barnes, M.J., Francischetti, I.M., Bon, C., Leduc, M., (2000) Biochem. Biophys. Res. Commun., 273, pp. 246-250Nikai, T., Suzuki, J., Komori, Y., Ohkura, M., Ohizumi, Y., Sugihara, H., (1995) Biol. Pharm. Bull., 18, pp. 620-622Nikai, T., Kato, S., Komori, Y., Sugihara, H., (2000) Toxicon, 38, pp. 707-711Prado-Franceschi, J., Tavares, D.Q., Hertel, R., Lobo de Araújo, A., (1981) Toxicon, 19, pp. 661-666Sakurai, Y., Fujimura, Y., Kokubo, T., Imamura, K., Kawasaki, T., Handa, M., Suzuki, M., Yoshioka, A., (1998) Thromb. Haemost., 79, pp. 1199-1207Santoro, M.L., Sousa-E-Silva, M.C., Gonçalves, L.R., Almeida-Santos, S.M., Cardoso, D.F., Laporta-Ferreira, I.L., Saiki, M., Sano-Martins, I.S., (1999) Comp. Biochem. Physiol. C, 122, pp. 61-73Schagger, H.G., Von Jagow, H.G., (1987) Anal. Biochem., 166, pp. 368-379Shin, Y., Okuyama, I., Hasegawa, J., Morita, T., (2000) Thromb. Res., 99, pp. 239-247Toyama, M.H., Leite, G.B., Rodrigues-Simioni, L., Saraguacy-Hemandez, O.S., Novello, J.C., Marangoni, S., (2000) Protein Pept. Lett., 7, pp. 381-388Toyama, M.H., Soares, A.M., Novello, J.C., Oliveira, B., Giglio, J.R., Marangoni, S., (2000) Biochimie, 82, pp. 245-250Usami, Y., Suzuki, M., Yoshida, E., Sakurai, Y., Hirano, K., Kawasaki, T., Fujimura, Y., Titani, K., (1993) Biochem. Biophys. Res. Commun., 219, pp. 727-733Usami, Y., Fujimura, Y., Suzuki, M., Ozeki, Y., Nishio, K., Fukui, H., Titani, K., (1996) Proc. Natl. Acad. Sci. USA, 90, pp. 928-93

Effect of atorvastatin on wound healing in rats

CNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOSkin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-α when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways.Skin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-α when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways172159168CNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãosem informaçã

Low Protein Diet Confers Resistance To The Inhibitory Effects Of Interleukin 1β On Insulin Secretion In Pancreatic Islets

High protein content in the diet during childhood and adolescence has been associated to the onset insulin-dependent diabetes mellitus. We investigated the effect of interleukin-1β (IL-1β) on insulin secretion, glucose metabolism, and nitrite formation by islets isolated from rats fed with normal protein (NP, 17%) or low protein (LP, 6%) after weaning. Pretreatment of islets with IL-1β for 1 h or 24 h inhibited the insulin secretion induced by glucose in both groups, but it was less marked in LP than in NP group. Islets from LP rats exhibited a decreased IL-1β-induced nitric oxide (NO) production, lower inhibition of D-[U14C]-glucose oxidation to 14CO2 and less pronounced effect of IL-1β on α-ketoisocaproic acid-induced insulin secretion than NP islets. However, when the islets were stimulated by high concentrations of K+ the inhibitory effect of IL-1β on insulin secretion was not different between groups. In conclusion, protein restriction protects β-cells of the deleterious effect of IL-1β, apparently, by decreasing NO production. The lower NO generation in islets from protein deprived rats may be due to increased free fatty acids oxidation and consequent alteration in Ca2+ homeostasis. © 2001 Elsevier Science Inc.125285291Corbett, J.A., MacDaniel, M.L., Does nitric oxide mediate autoimmune destruction of β-cells? (1992) Diabetes, 41, pp. 897-903Eizirik, D.L., Flodström, M., Karlsen, A.E., Welsh, N., The harmony of the spheres: Inducible nitric oxide synthase and related genes in pancreatic β-cells (1996) Diabetologia, 39, pp. 875-890Rabinovitch, A., Role of cytokines in IDDM pathogenesis and islet β-cell destruction (1993) Diabetes Rev, 1, pp. 215-240Arnush, M., Scarim, A.L., Heitmeier, M.R., Kelly, C.B., Corbett, J.A., Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes (1998) J Immunol, 160, pp. 2684-2691Southern, C., Schulster, D., Green, I.C., Inhibition of insulin secretion by interleukin IL-1β and tumor necrosis factor-α via L-arginine dependent nitric oxide generating mechanism (1990) FEBS Lett, 276, pp. 42-44Welsh, N., Eizirik, D.L., Bendtzen, K., Sandler, S., IL-1β induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase (1991) Endocrinology, 129, pp. 3167-3173Eizirik, D.L., Sandler, S., Welsh, N., Cetkovic-Curlje, M., Nieman, A., Geller, D.A., Pipeleers, D.G., Hellerström, C., Cytokines suppress human islet function irrespective of their effects on nitric oxide generation (1994) J Clin Invest, 93, pp. 1968-1974Delaney, C.A., Green, M.H.L., Lowe, J.E., Green, I.C., Endogenous nitric oxide induced by IL-1β in rat islets of Langerhans and HIT-T15 cells causes significant DNA damage as measured by the "comet assay," (1993) FEBS Lett, 333, pp. 291-295Fehsel, K., Jalowy, A., Qi, S., Burkart, V., Harmann, B., Kolb, H., Islet cell DNA is a target of inflammatory attack by nitric oxide (1993) Diabetes, 42, pp. 496-500Bhaskaram, P., Sivakumar, B., Interleukin-1 in malnutrition (1986) Arch Disease Childhood, 61, pp. 182-185Dorner, G., Thoeke, H., Mohnike, A., Schneider, H., High food supply in perinatal life appears to favor the development of insulin-treated diabetes mellitus (IDDM) in later life (1985) Exp Clin Endocrinol, 85, pp. 1-6Kalits, J., Podar, T., Incidence and prevalence of type 1 (insulin-dependent) diabetes in Estonia in 1988 (1988) Diabetologia, 33, pp. 346-349Elliott, R.B., Epidemiology of diabetes in Polynesia and New Zeland (1992) Pediatr Adolesc Endocrinol, 21, pp. 66-71Blom, L., Persson, L.A., Dahlquist, G., A high linear growth and risk for diabetes (1992) Diabetologia, 35, pp. 528-533Reeves, P.G., Nielsen, F.H., Fahey G.C., Jr., AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet (1993) J Nutr, 123, pp. 1939-1951Trinder, P., Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen (1969) J Clin Pathol, 22, pp. 158-161Doumas, B.T., Watson, W.A., Biggs, H.G., Albumin standards and measurement of serum albumin with bromocresol green (1971) Clin Chim Acta, 31, pp. 87-96Gornall, A.G., Bardawill, C.J., David, M.M., Determination of serum proteins by means of the biuret reagent (1949) J Biol Chem, 177, pp. 751-766Scott, A.M., Atwater, I., Rojas, E., A method for the simultaneous measurement of insulin release and β-cell membrane potential in single mouse islets of Langerhans (1981) Diabetologia, 21, pp. 407-475Boschero, A.C., Szpak-Glasman, M., Carneiro, E.M., Bordin, S., Paul, I., Rojas, E., Atwater, I., Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors (1995) Am J Physiol, 268, pp. E336-E342Anderson, A., Isolated mouse pancreatic islets in culture: Effect of serum and different culture media on the insulin production of the islets (1978) Diabetologia, 14, pp. 397-404Green, L.C., Wanger, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S., Tannenbaum, S.R., Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids (1982) Anal Biochem, 126, pp. 131-138Malaisse, W.J., Sener, A., Mahy, M., The stimulus-secretion coupling of glucose-induced insulin release. Sorbitol metabolism in isolated islets (1974) Eur J Biochem, 47, pp. 365-370Sokal, R.R., Rohlf, F.J., Assumptions of analysis of variance (1995) Biometry: The Principles and Practice of Statistics in Biological Research, pp. 392-450. , (R.R. Sokal and F.J. Rohlf, eds.), W.H. Freeman and Company, New York, NY, USACorbett, J.A., Lancaster J.R., Jr., Sweetland, M.A., McDaniel, M.L., Interleukin-1β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans (1991) J Biol Chem, 266, pp. 21351-21354Young, J.K., Dixit, P.K., Lack of diabetogenic effect of alloxan in protein-calorie malnourished rats (1979) J Nutr, 110, pp. 703-709Panten, U., Zielmann, S., Joost, H.G., Lanzen, S., Branched chain amino and keto acids (1984) Branched Chain Amino and Keto Acids in Health and Disease, pp. 134-146. , S. Adibi and P. Schander eds.), S. Karger, BaselMarletta, M.A., Yoon, P.S., Iyengar, R., Leaf, C.D., Wishnok, J.S., Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate (1988) Biochemistry, 27, pp. 8706-8711Schimidt, H.H.H.W., Warner, T.D., Ischii, K., Sheng, H., Murad, F., Insulin secretion from pancreatic β-cells caused by L-arginine-derived nitric oxide (1991) Science, 255, pp. 721-723Eizirik, D.L., Cagliero, E., Björtheklund, A., Welsh, N., Interleukin-1β induces the expression of an isoform of nitric oxide synthase in insulin producing cells which is similar to that observed in actived macrophages (1992) FEBS Lett, 308, pp. 249-252Carneiro, E.M., Mello, M.A.R., Gobatto, C.A., Boschero, A.C., Low protein diet impairs glucose-induced insulin secretion from and 45Ca uptake by pancreatic islets (1995) J Nutr Biochem, 6, pp. 314-318Latorraca, M.Q., Carneiro, E.M., Mello, M.A.R., Boschero, A.C., Reduced insulin secretion in response to nutrients in islets from malnourished young rats is associated with a diminuished calcium uptake (1999) J Nutr Biochem, 10, pp. 37-43Shimabukuro, M., Koyama, K., Lee, Y., Unger, R.H., Leptin-or troglitazone-induced lipopenia protects islets from interleukin 1 beta cytotoxicity (1997) J Clin Invest, 100, pp. 1750-1754Shimabukuro, M., Zhou, Y.-T., Lee, Y., Unger, R.H., Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats (1998) J Biol Chem, 273, pp. 3547-3550Shimabukuro, M., Zhou, Y.-T., Levi, M., Unger, R.H., Fatty acid-induced β cell apoptosis: A link between obesity and diabetes (1998) Proc Natl Acad Sci USA, 95, pp. 2498-250

Effect of atorvastatin on wound healing in rats

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOSkin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-α when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways.Skin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1?, IL-6, and tumor necrosis factor (TNF)-?. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-? when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways172159168CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOAdami, M., Prudente, A.A.S., Mendes, D.A., Horinouchi, C.D., Cabrini, D.A., Otuki, M.F., Simvastatin ointment, a new treatment for skin inflammatory conditions (2012) Journal of Dermatological Science, 66, pp. 127-135Araújo, F.A., Rocha, M.A., Mendes, J.B., Andrade, S.P., Atorvastatin inhibits inflammatory angiogenesis in mice through down regulation of VEGF, TNF-alpha and TGF-beta1 (2010) Biomedicine & Pharmacotherapy, 64, pp. 29-34Asai, J., Takenaka, H., Hirakawa, S., Sakabe, J., Hagura, A., Kishimoto, S., Katoh, N., Topical simvastatin accelerates wound 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Blockade of IRS1 in isolated rat pancreatic islets improves glucose-induced insulin secretion

Several neural, hormonal and biochemical inputs actively participate in the balance of insulin secretion induced by blood glucose fluctuations. The exact role of insulin as an autocrine and paracrine participant in the control of its own secretion remains to be determined, mostly due to insufficient knowledge about the molecular phenomena that govern insulin signaling in pancreatic islets. In the present experiments we demonstrate that higher insulin receptor and insulin receptor substrates-1 and -2 (IRS1 and IRS2) concentrations are predominantly encountered in cells of the periphery of rat pancreatic islets, as compared to centrally located cells, and that partial blockade of IRS1 protein expression by antisense oligonucleotide treatment leads to improved insulin secretion induced by glucose overload, which is accompanied by lower steady-state glucagon secretion and blunted glucose-induced glucagon fall. These data reinforce the inhibitory role of insulin upon its own secretion in isolated, undisrupted pancreatic islets. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved531343744

Short-term Calorie Restriction Improves Glucose Homeostasis In Old Rats: Involvement Of Ampk

The occurrence of metabolic disorders, such as diabetes, obesity, atherosclerosis, and hypertension, increases with age. Inappropriate food intake, when combined with genetic and hormonal factors, can trigger the occurrence of these diseases in aged organisms. This study investigated whether short-term calorie restriction (CR; 40% of the intake of control animals (CTL) for 21 days) benefits 1-year-old (CR1yr) and 2-year-old (CR2yr) Wistar rats, with regard to insulin secretion and action. Plasma insulin and the insulin secreted by isolated islets were measured with radioimmunoassay, and the insulin sensitivity of peripheral tissues was assessed with the intraperitoneal glucose tolerance test (IPGTT), intraperitoneal insulin tolerance test, and hepatic and muscle adenosine monophosphate-activated protein kinase (AMPK) phosphorylation measurements. Body weight, epididymal fat pad, epididymal fat pad/body weight index, plasma glucose, and insulin were lower in the CR1yr than in the control (CTL1yr) rats. Serum cholesterol, triglycerides, and protein, as well as hepatic and muscle glycogen content, were similar between the CR and CTL groups. The IPGTT was higher in CR2yr and CTL2yr rats than in CR1yr and CTL1yr rats, and insulin sensitivity was higher in CR1yr and CR2yr rats than in their respective CTLs. This was associated with an increase in hepatic and muscle AMPK phosphorylation. No differences in glucose-induced insulin secretion in the isolated islets were observed between CRs and their respective CTL rats. In conclusion, short-term calorie restriction provoked more severe alterations in CR1yr than CR2yr rats. 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