Modulation of paracellular permeability and intercellular junctions in cultured epithelia

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Disarray Of Glomerular And Tubular Cell Adhesion Molecules In The Course Of Experimental Bothrops Moojeni Envenomation

In this study, we show that administration of Bothrops moojeni venom in rats induces a general disturbance in the distribution and content of the tight junctional protein ZO-1, the cell-matrix receptor beta 1 integrin, the cytoskeletal proteins, vinculin and F-actin, and of the extracellular matrix component laminin in renal corpuscles and cortical nephron tubules. These findings suggest that cell-cell and cell-matrix adhesion proteins may be molecular targets in the B. moojeni-induced kidney injury. © 2013 Published by Elsevier Ltd.784146Assakura, M.T., Reichl, A.P., Asperti, M.C.A., Mandelbaum, F.R., Isolation of the major proteolytic enzyme from the venom of the snake Bothrops moojeni (caissaca) (1985) Toxicon, 23, pp. 691-706Barbosa, P.S., Havt, A., Facó, P.E., Sousa, T., Bezerra, I.S., Fonteles, M.C., Toyama, M.H., Monteiro, H.S., Renal toxicity of Bothrops moojeni snake venom and its main myotoxins (2002) Toxicon, 40, pp. 1427-1435Berfield, A.K., Spicer, D., Abrass, C.K., Insulin-like growth factor i (IGF-I) induces unique effects in the cytoskeleton of cultured rat glomerular mesangial cells (1997) J. Histochem. Cytochem., 45, pp. 583-593Boer-Lima, P.A., Gontijo, J.A.R., Cruz-Höfling, M.A., Bothrops moojeni snake venom-induced renal glomeruli changes in rat (2002) Am. J. Trop. Med. Hyg., 67, pp. 217-222Boer-Lima, P.A., Gontijo, J.A.R., Cruz-Höfling, M.A., Histologic and functional renal alterations caused by Bothrops moojeni snake venom in rats (1999) Am. J. Trop. Med. Hyg., 61, pp. 698-706Burdmann, E.A., Woronik, V., Prado, E.B.A., Abdulkader, R.C., Saldanha, L.B., Barreto, O.C.O., Marcondes, M., Snakebite-induced acute renal failure: An experimental model (1993) Am. J. Trop. Med. Hyg., 48, pp. 82-88Calgarotto, A.K., Damico, D.C., Ponce-Soto, L.A., Baldasso, P.A., Da Silva, S.L., Souza, G.H., Eberlin, M.N., Marangoni, S., Biological and biochemical characterization of new basic phospholipase A(2) BmTX-I isolated form Bothrops moojeni snake venom (2008) Toxicon, 51, pp. 1509-1519Cattell, V., Focal mesangial proliferative glomerulonephritis in the rat caused by Habu snake venom: The role of platelets (1979) Br. J. Exp. Pathol., 60, pp. 201-207Collares-Buzato, C.B., Jepson, M.A., McEwan, G.T.A., Simmons, N.L., Hirst, B.H., Increased tyrosine phosphorylation causes redistribution of adherens junction and tight junction protein and perturbs paracellular barrier function in MDCK epithelia (1998) Eur. J. Cell Biol., 76, pp. 85-92Collares-Buzato, C.B., De Paula Le Sueur, L., Cruz-Höfling, M.A., Impairment of the cell-to-matrix adhesion and cytotoxicity induced by Bothrops moojeni snake venom in cultured renal tubular epithelia (2002) Toxicol. Appl. Pharmacol., 181, pp. 124-132Cruz-Höfling, M.A., Paronetto, C.C., Cogo, J.C., Rodrigues-Simioni, L., D'Abreu, A.C., Histopathological changes in avian kidney caused by Bothrops insularis (jararaca ilhoa) venom and a phospholipase A2-containing fraction (2001) Histol. Histopathol., 16, pp. 185-195Damico, D.C., Nascimento, J.M., Lomonte, B., Ponce-Soto, L.A., Joazeiro, P.P., Novello, J.C., Marangoni, S., Collares-Buzato, C.B., Cytoxicity of Lachesis muta muta snake (bushmaster) venom and its purified basic phospholipase A2 (LmTX-I) in cultured cells (2007) Toxicon, 49, pp. 678-692Demler, C., Bühler, B., Menin, L., Stöcklin, R., Wilmer, M., Ernst, B., Perchuc, A.M., Platelet-active substances in the venom of Bothrops moojeni snake-a novel evaluation method using whole blood aggregometry (2010) Platelets, 21, pp. 20-28Hartner, A., Schöcklmann, H., Pröls, F., Müller, U., Sterzel, R.B., Alpha8 integrin in glomerular mesangial cells and in experimental glomerulonephritis (1999) Kidney Int., 56, pp. 1468-1480Hillis, G.S., Roy-Chaudhury, P., Duthie, L.A., Stewart, K.N., Brown, P.A.J., Simpson, J.G., Macleod, A.M., Expression of β1-integrins in IgA nephropathy (1997) Nephrol. Dial Transplant., 12, pp. 1137-1142Kagami, S., Kondo, S., Beta 1-Integrins and glomerular injury (2004) J. Med. Invest., 51, pp. 1-13Kurihara, H., Anderson, J.M., Farquhar, M.G., Diversity among tight junctions in rat kidney: Glomerular slit diaphragm and endothelial junctions express only one isoform of the tight junction protein ZO-1 (1992) Proc. Natl. Acad. Sci. U. S. A., 89, pp. 7075-7079Krautkramer, E., Grouls, S., Stein, N., Reiser, J., Zeier, M., Pathogenic old world Hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts (2011) J. Virol., 85, pp. 9811-9823Linardi, A., Rocha Silva E, T.A., Miyabara, E.H., Franco-Penteado, C.F., Cardoso, K.C., Boer, P.A., Moriscot, A.S., Hyslop, S., Histological and functional renal alterations caused by Bothrops alternatus snake venom: Expression and activity of Na+/K+-ATPase (2011) Biochim. Biophys. Acta, 1810, pp. 895-906Macconi, D., Ghilardi, M., Bonassi, M.E., Mohamed, E.I., Abbate, M., Colombi, F., Remuzzi, G., Remuzzi, A., Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of Zonula Occludens-1 in MWF rats (2000) J. Am. Soc. Nephrol., 11, pp. 477-489Miao, J., Fan, Q., Cui, Q., Zhang, H., Chen, L., Wang, S., Guan, N., Ding, J., Newly identified cytoskeletal components are associated with dynamic changes of podocyte foot processes (2009) Nephrol. Dial Transplant., 24, pp. 3297-3305Molina, A., Ubeda, M., Escribese, M.M., Garcia-Bermejo, L., Sancho, D., Lema, G.P., Lianõ, F., Mampaso, F., Renal ischemia/reperfusion injury: Functional tissue preservation by anti-activated beta1 integrin therapy (2005) J. Am. Soc. Nephrol., 16, pp. 374-382Nascimento, J.M., Franchi, Jr.G.C., Nowill, A.E., Collares-Buzato, C.B., Hyslop, S., Cytoskeletal rearrangement and cell death induced by Bothrops alternatus snake venom in cultured Madin-Darby canine kidney cells (2007) Biochem. Cell Biol., 85, pp. 591-605Peixoto, E.B., Collares-Buzato, C.B., Modulation of the epithelial barrier by dexamethasone and prolactin in cultured Madin-Darby canine kidney (MDCK) cells (2006) Cell Biol. Int., 30, pp. 101-113Queiroz, G.P., Pessoa, L.A., Portaro, F.C., Furtado, M.D.F., Tambourgi, D.V., Interspecific variation in venom composition and toxicity of Brazilian snakes from Bothrops genus (2008) Toxicon, 52, pp. 842-851Rincón-Choles, H., Vasylyeva, T.L., Pergola, P.E., Bhandari, B., Bhandari, K., Zhang, J.-H., Wang, W., Abboud, H.E., ZO-1 expression and phosphorylation in diabetic nephropathy (2006) Diabetes, 55, pp. 894-900Schnabel, E., Anderson, J.M., Farquhar, M.G., The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium (1990) J. Cell Biol., 111, pp. 1255-1263Serrano, S.M., Sampaio, C.A., Mandelbaum, F.R., Basic proteinases from Bothrops moojeni (caissaca) venom-II. Isolation of the metalloproteinase MPB. Comparison of the proteolytic activity on natural substrates by MPB, MSP 1 and MSP 2 (1993) Toxicon, 31, pp. 483-492Sgrignolli, L.R., Mendes, G.E.F., Carlos, C.P., Burdmann, E.A., Acute kidney injury caused by Bothrops snake venom (2011) Nephron Clin. Pract., 119, pp. 131-c13

Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats

<div><p>Atropine (AT) and dipyrone (Dp) induce a delay of gastric emptying (GE) of liquids in rats by inhibiting muscarinic receptors and activating β2-adrenergic receptors, respectively. The objective of the present study was to determine the effects of pretreatment with AT and Dp, given alone or in combination, on the effect of hypoglycemia in the liquid GE in rats. Male Wistar adult rats (280-310 g) were pretreated intravenously with AT, Dp, AT plus Dp or their vehicle and then treated 30 min later with iv insulin or its vehicle (n=8-10 animals/group). Thirty min after treatment, GE was evaluated by determining, in awake rats, the percent gastric retention (%GR) of a saline meal labeled with phenol red administered by gavage. The results indicated that insulin induced hypoglycemia in a dose-dependent manner resulting in a significant reduction in %GR of liquid only at the highest dose tested (1 U/kg). Pretreatment with AT significantly increased %GR in the rats treated with 1 U/kg insulin. Surprisingly, after pretreatment with AT, the group treated with the lowest dose of insulin (0.25 U/kg) displayed significantly lower %GR compared to its control (vehicle-treated group), which was not seen in the non-pretreated animals. Pretreatment with Dp alone at the dose of 40 mg/kg induced an increase in %GR in both vehicle and 0.25 U/kg-treated rats. A higher dose of Dp alone (80 mg/kg) significantly reduced the effect of a marked hypoglycemia induced by 1 U/kg of insulin on GE while in combination with AT the effect was completely abolished. The results with AT suggest that moderate hypoglycemia may render the inhibitory mechanisms of GE ineffective while Dp alone and in combination with AT significantly overcame the effect of hypoglycemia on GE.</p></div

Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier function in vitro

Evidence suggests that administration of a high-fat diet (HFD) results in changes in the intestinal lumen environment. Gut dysbiosis associated with intestinal barrier disruption may be involved in type 2 diabetes mellitus (T2DM) development through increased intestinal permeability, which would trigger an inflammatory response leading to peripheral insulin resistance state and ultimately T2DM. In this study, we investigated the effect of the intestinal luminal content isolated from control or HFD-fed prediabetic mice upon the tight junction (TJ)-mediated epithelial barrier in Caco-2 and MDCK epithelial cell lines. Exposure to small intestine luminal content (SI) isolated from HFD-fed prediabetic mice induced a more significant decrease in transepithelial electrical resistance (TEER), associated with higher paracellular flux in Caco-2 and MDCK cells after 6 h and 4 h respectively, as compared to the SI obtained from control mice. Such changes were accompanied by a significant decrease in TJ content of claudins, occludin, and ZO-1, indicative of disruption of the TJ barrier. Meanwhile, large intestine luminal content from control (Ctrl-LI) and prediabetic (HFD-LI) animals did not change TEER significantly, however, paracellular flux was significantly increased after 24 h, accompanied by a decrease in ZO-1 (after HFD-LI exposure) in Caco-2 and significant changes in the junctional distribution of claudins-1, -2, occludin and ZO-1 proteins in MDCK, particularly after HFD-LI exposure. Luminal components of intestinal content, altered by HFD exposure, induce impairment of the TJ structure and function in vitro, corroborating the idea of a role of the intestinal paracellular barrier in the obesity-related T2DM pathogenesis2161021CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP304991/2015-52013/15676-0; 2018/02118-2The authors thank Dr. Valéria H. A. C. Quitete, Dr. Eduardo Galembeck and Dr. Alexandre L. R. de Oliveira for allowing the access to their laboratory facilities. CBC-B (CNPq# 304991/2015-5) is a recipient of Research Fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil). RBO and LCP were recipients of Ph.D. and MSc. fellowships from CNPq (Brazil), respectively. This work was funded by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP # 2013/15676-0 and 2018/02118-2, Brazil

Co-culture Of Two Mdck Strains With Distinct Junctional Protein Expression: A Model For Intercellular Junction Rearrangement And Cell Sorting

Distinct epithelial MDCK cell strains displaying extremes in transepithelial electrical resistance (paracellular permeability) have been established in co-culture and the subsequent cellular behaviour and formation of junctional complexes investigated. After high-density seeding, MDCK strain I and II cells in co-culture are initially randomly distributed but subsequently sort themselves out in a time-dependent manner to form separate homotypic aggregates. The final pattern of cell arrangement of homotypic aggregates depends on the relative seeding proportion of each cell type. Immunostaining of established marker proteins for junctional complexes has revealed that MDCK I and II cells differ in the degree of expression of the zonula-adherens-associated protein, E-cadherin, their cytoskeletal architecture and the junctional distribution of a desmosomal protein, and by showing subtle differences in tight junction staining for the zona-occludens-associated proteins, ZO-1 and occludin. The distinct pattern of junctional protein expression is maintained when the two MDCK strains are co-cultured; however, morphologically atypical intercellular junctions between heterotypic cells at the boundary of homotypic cell aggregates have been observed. It has been suggested that cell sorting, a phenomenon yet to be completely understood, is involved in important morphogenetic processes. We propose that co-culture of strains of the well-characterised MDCK cell line may be a novel but well-defined cell system for studying epithelial cell rearrangement and sorting in intact epithelial sheets.2912267276Aberle, H., Scwartz, H., Kemler, R., Cadherin-catenin complexes: Protein interactions and their implications for cadherin function (1996) J Cell Biochem, 61, pp. 514-523Armstrong, P.B., A fine structural study of adhesive cell junctions in heterotypic cell aggregates (1970) J Cell Biol, 47, pp. 197-210Armstrong, P.B., Cell sorting out: The self-assembly of tissues in vitro (1989) Crit Rev Biochem Mol Biol, 24, pp. 119-149Balda, M.S., Whitney, J.A., Flores, C., Gonzales, S., Cereijido, M., Matter, K., Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction protein (1996) J Cell Biol, 134, pp. 1031-1049Barker, G., Simmons, N.L., Identification of two strains of cultured canine renal epithelial cells (MDCK cells) which display entirely different physiological properties (1981) Q J Exp Physiol, 66, pp. 61-72Citi, S., The molecular organization of tight junctions (1993) J Cell Biol, 121, pp. 485-489Claude, P., Morphological factors influencing transepithelial permeability: A model for the resistance of the zonula occludens (1978) J Membr Biol, 39, pp. 219-232Collares-Buzato, C.B., Jepson, M.A., McEwan, G.T.A., Simmons, N.L., Hirst, B.H., Junctional uvomorulin/E-cadherin and phosphotyrosine-modified protein content are correlated with paracellular permeability in Madin-Darby canine kidney (MDCK) epithelia (1994) Histochemistry, 101, pp. 185-194Collares-Buzato, C.B., McEwan, G.T.A., Jepson, M.A., Simmons, N.L., Hirst, B.H., Paracellular permeability and junctional protein distribution depend on basolateral extracellular Ca2+ in cultured epithelia (1994) Biochim Biophys Acta, 1222, pp. 147-158Edelman, G.M., Cell adhesion and the molecular processes of morphogenesis (1985) Annu Rev Biochem, 54, pp. 135-169Farquhar, M.G., Palade, G.E., Junctional complexes in various epithelia (1963) J Cell Biol, 17, pp. 375-412Friedlander, D.R., Mege, R.M., Cunningham, B.A., Edelman, G.M., Cell sorting-out is modulated by both the specificity and amount of different cell adhesion molecules (CAMs) expressed on cell surfaces (1989) Proc Natl Acad Sci USA, 86, pp. 7043-7047Fristom, D.K., Septate junctions in imaginai disks of Drosophila: A model for the redistribution of septa during rearrangement (1982) J Cell Biol, 94, pp. 77-87Furuse, M., Itoh, M., Hirase, T., Nagafuchi, A., Yonemura, S., Tsukita, S., Tsukita, S., Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions (1994) J Cell Biol, 127, pp. 1617-1626Garrod, D.R., Desmosomes and hemidesmosomes (1993) Curr Opin Cell Biol, 5, pp. 30-40Geiger, B., Ayalon, O., Cadherins (1992) Annu Rev Cell Biol, 8, pp. 307-332Goodenough, D.A., Goliger, J.A., Paul, D.L., Connexins, connexons, and intercellular communication (1996) Annu Rev Biochem, 65, pp. 475-502Graner, F., Can surface adhesion drive cell-arrangement? Part I: Biological cell-sorting (1993) J Theor Biol, 164, pp. 455-476Gumbiner, B.M., Breaking through the tight junction barrier (1994) J Cell Biol, 123, pp. 1631-1633Gumbiner, B.M., Cell adhesion: The molecular basis of tissue architecture and morphogenesis (1996) Cell, 84, pp. 345-357Hirai, Y., Nose, A., Kobayashi, S., Takeichi, M., Expression and role of E- and P-cadherin adhesion molecules in embryonic histogenesis. I. Lung epithelial morphogenesis (1989) Development, 105, pp. 263-270Hirano, S., Nose, A., Hatta, K., Kawakami, A., Takeichi, M., Calcium-dependent cell-cell adhesion molecules (cadherins): Subclass specificities and possible involvement of actin bundles (1987) J Cell Biol, 105, pp. 2501-2510Ide, H., Wada, N., Uchiyama, K., Sorting out of cells from different parts and stages of the chick limb bud (1994) Dev Biol, 162, pp. 71-76Moscona, A., The development in vitro of chimeric aggregates of dissociated embryonic chick and mouse cells (1957) Proc Natl Acad Sci USA, 43, pp. 184-194Nicol, A., Garrod, D.R., The sorting out of embryonic cells in monolayer, the differential adhesion hypothesis and the nonspecificity of cell adhesion (1979) J Cell Sci, 38, pp. 249-266Nose, A., Takeichi, M., A novel cadherin cell adhesion molecule: Its expression patterns associated with implantation and organogenesis of mouse embryos (1986) J Cell Biol, 103, pp. 2649-2658Nose, A., Nagafuchi, A., Takeichi, M., Expressed recombinant cadherins mediate cell sorting in model systems (1988) Cell, 54, pp. 993-1001Overton, J., Formation of junctions and cell sorting in aggregates of chick and mouse cells (1977) Dev Biol, 55, pp. 103-116Richardson, J.C.W., Scalera, V., Simmons, N.L., Identification of two strains of MDCK cells which resemble separate nephron tubule segments (1981) Biochim Biophys Acta, 673, pp. 26-36Steinberg, M.S., Reconstruction of tissues by dissociated cells (1963) Science, 141, pp. 401-408Steinberg, M.S., Takeichi, M., Experimental specification of cell sorting, tissue spreading, and specific spatial patterning by quantitative differences in cadherin expression (1994) Proc Natl Acad Sci USA, 91, pp. 206-209Steinberg, M.S., Wiseman, L.L., Do morphogenetic tissue rearrangements require active cell movements? the reversible inhibition of cell sorting and tissue spreading by cytochalasin B (1972) J Cell Biol, 55, pp. 606-615Stevenson, B.R., Siliciano, J.D., Mooseker, M.S., Goodenough, D.A., Identification of ZO-1: A high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia (1986) J Cell Biol, 103, pp. 755-766Stevenson, B.R., Anderson, J.M., Goodenough, D.A., Mooseker, M., Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance (1988) J Cell Biol, 107, pp. 2401-2408Takeichi, M., Cadherin cell adhesion receptors as a morphogenetic regulator (1991) Science, 251, pp. 1451-1455Takeichi, M., Atsumi, T., Yoshida, C., Uno, K., Okada, T.S., Selective adhesion of embryonal carcinoma cells and differentiated cells by Ca2+-dependent sites (1981) Dev Biol, 87, pp. 340-350Trinkaus, J.P., Lentz, J.P., Direct observation of type-specific segregation in mixed cell aggregates (1964) Dev Biol, 9, pp. 115-136Van Itallie, C.M., Anderson, J.M., Occludin confers adhesiveness when expressed in fibroblasts (1997) J Cell Sci, 110, pp. 1113-112

Venom Apparatus Of The Brazilian Tarantula Vitalius Dubius Mello-leitão 1923 (theraphosidae).

Tarantula venoms are a cocktail of proteins and peptides that have been increasingly studied in recent years. In contrast, less attention has been given to analyzing the structure of the paired cephalic glands that produce the venom. We have used light, electron, and confocal microscopy to study the organization and structure of the venom gland of the Brazilian tarantula Vitalius dubius. The chelicerae are hairy chitinous structures, each with a single curved hollow fang that opens via an orifice on the anterior surface. Internally, each chelicera contains striated muscle fiber bundles that control fang extension and retraction, and a cylindrical conical venom gland surrounded by a thick well-developed layer of obliquely arranged muscle fibers. Light microscopy of longitudinal and transverse sections showed that the gland secretory epithelium consists of a sponge-like network of slender epithelial cell processes with numerous bridges and interconnections that form lacunae containing secretion. This secretory epithelium is supported by a basement membrane containing elastic fibers. The entire epithelial structure of the venom-secreting cells is reinforced by a dense network of F-actin intermediate filaments, as shown by staining with phalloidin. Neural elements (axons and acetylcholinesterase activity) are also associated with the venom gland. Transmission electron microscopy of the epithelium revealed an ultrastructure typical of secretory cells, including abundant rough and smooth endoplasmic reticulum, an extensive Golgi apparatus, and numerous mitochondria.335361762

Impaired Compensatory Beta-cell Function And Growth In Response To High-fat Diet In Ldl Receptor Knockout Mice

In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr-/- mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr-/- mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr-/- mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr-/- mice showed no significant changes in beta-cell mass, but lower islet-duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr-/- mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion. © 2014 International Journal of Experimental Pathology.954296308Abderrahmani, A., Niederhauser, G., Favre, D., Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells (2007) Diabetologia, 50, pp. 1304-1314Ahrén, J., Ahrén, B., Wierup, N., Increased β-cell volume in mice fed a high-fat diet: a dynamic study over 12 months (2010) Islets, 2, pp. 353-356Allagnat, F., Alonso, F., Martin, D., Abderrahmani, A., Waeber, G., Haefliger, J.A., ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells (2008) J. Biol. 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Brazilian berry extract (Myrciaria jaboticaba): a promising therapy to minimize prostatic inflammation and oxidative stress

Brazilian berry is a fruit popularly known as “Jaboticaba,” rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. Methods: PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3+, cyclooxygenase 2 [COX-2], toll-like receptor 4 [TLR4], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and IL-1β) and oxidative-stress (catalase, superoxide dismutase 2 [SOD2], glutathione reductase [GSR], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. Results: Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, GSR, catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, TNF-α, and pSTAT-3) and CD3+ T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and TLR4 levels in aging mice; and SOD2, IL-6, and IL-1β levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. Conclusions: PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.8011859871CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP141766/2015‐8 ; 301108/2016‐1 ; 403328/2016‐0Sem informação2015/25714‐1 ; 2015/50333‐1 ; 2018/11069‐

Expression Of A Thioredoxin Peroxidase In Insulin-producing Cells

The presence of thioredoxin peroxidase (TPx), also known as thiol specific antioxidant (TSA), was investigated in neonatal and adult rat islets, and in the β-cell line HIT-T15. Western blotting of extracts from neonatal and adult pancreatic islets and from the tumoral cell line HIT-T15 revealed the presence of a 25 kDa protein that comigrated with purified yeast TPx. Endocrine pancreatic TPx accounted for approximately 0.01% of the total protein content. Treatment with H 2O 2 for 3 h increased the expression of TPx in HIT-T15 cells. The distribution of TPx throughout the islet cells was confirmed by immunocytochemistry. Since pancreatic β-cells possess a weak antioxidant enzyme defense system, especially with regard to hydrogen peroxidase-decomposing enzymes, the presence of a TPx analog in islets suggests that this enzyme may play a role in protecting pancreatic cells against reactive oxygen species.286 II3S253S28Malaisse, W.J., Malaisse-Lagae, F., Sener, A., Determinants of the selective toxicity of alloxan to the pancreatic β-cell (1982) Proc Natl Acad Sci USA, 79, pp. 927-930Tiedge, M., Lortz, S., Drinkgem, J., Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin producing cells (1997) Diabetes, 46, pp. 1733-1742Eizirik, D.L., Flodstrom, M., Karlsen, A.E., The harmony of the spheres: Inducible nitric oxide synthase and related genes in pancreatic beta cells (1996) Diabetologia, 39, pp. 875-890Kim, K., Kim, I.H., Lee, K.Y., The isolation and purification of a specific "protector" protein which inhibits enzyme inactivation by a thiol/Fe(III)/O 2 mixed function oxidation system (1988) J Biol Chem, 263, pp. 4704-4710Kim, M., Kim, K., Rhee, S.G., Induction of an antioxidant protein of Saccharomyces cerevisiae by O 2, Fe 3-, or 2-mecaptoethanol (1989) Proc Natl Acad Sci USA, 86, pp. 6018-6022Netto, L.E.S., Chae, H.Z., Kang, S.W., Removal of hydrogen peroxide by thiol-specific antioxidant enzyme (TSA) is involved with its antioxidant properties (1996) J Biol Chem, 271, pp. 15315-15321Zhang, P., Liu, B., Kang, S.W., Thioredoxin peroxidase is a novel inhibitor of apoptosis with a mechanism distinct from that of Bcl-2 (1997) J Biol Chem, 272, pp. 30615-30618Hotta, M., Tashiro, F., Ikegami, H., Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes (1998) J Expl Med, 188, pp. 1445-1451Chae, H.Z., Uhm, T.B., Rhee, S.G., Dimerization of thiol-specific antioxidant and the essential role of cysteine 47 (1994) Proc Natl Acad Sci USA, 91, pp. 7022-7026Chen, H., Carlson, E.C., Pellet, L., Overexpression of metallothionein in pancreatic beta-cells reduces streptozotocin-induced DNA damage and diabetes (2001) Diabetes, 50, pp. 2040-204

Low-protein Diets Reduce Pkaα Expression In Islets From Pregnant Rats

We investigated the effect of protein restriction on insulin secretion and the expression of protein kinase (PK)Aα and PKCα in islets from control and pregnant rats. Adult control nonpregnant (CN) and control pregnant (CP) rats were fed a normal-protein diet (17%), whereas low-protein nonpregnant (LPN) and low-protein pregnant (LPP) rats were fed a low-protein diet (6%) for 15 d. In the presence of 2.8 and 8.3 mmol glucose/L, insulin secretion by islets of CP rats was higher than that by islets of CN rats. Compared with the CN groups, insulin secretion by islets of LPN rats was lower with 8.3 but not with 2.8 mmol glucose/L. The insulin secretion by islets of LPP rats was higher than by LPN rats at both glucose concentrations. IBMX (1 mmol/L), a phosphodiesterase inhibitor, increased insulin secretion by islets from pregnant rats, and this effect was greater in islets of CP rats than in LPP rats. Forskolin (0.01-100 μmol/L), a stimulator of adenylyl cyclase, increased insulin secretion only in islets of CN and CP rats, with a higher 50% effective concentration in islets of CP rats compared with CN rats. The insulin secretion induced by phorbol 12-myristate 13-acetate (a stimulator of PKC) was higher in islets of LPN and LPP rats than in the respective controls, especially at 8.3 mmol glucose/L. PKAα, but not PKCα, expression was lower in islets of rats fed low protein than in the controls, regardless of the physiological status of the rats. All endocrine cells of the islets, including β-cells, expressed the PKAα isoform. The cytoplasmic distribution of this enzyme in β-cells was not modified by pregnancy and/or protein restriction. In conclusion, our results indicate that the response of islets from rats fed low protein during pregnancy is similar to that of control rats, at least for physiologic glucose concentration. 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