KAROLLINE SANTANA DA SILVA
Projetos de Pesquisa
Unidades Organizacionais
LIM/10 - Laboratório de Lípides, Hospital das Clínicas, Faculdade de Medicina
4 resultados
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- Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products(2017) FABRE, Nelly T.; THIEME, Karina; SILVA, Karolline S.; CATANOZI, Sergio; CAVALEIRO, Ana Mercedes; PINTO JR., Danilo A. C.; OKAMOTO, Maristela M.; MORAIS, Mychel Raony P. T.; FALQUETTO, Barbara; ZORN, Telma M.; MACHADO, Ubiratan E.; PASSARELLI, Marisa; CORREA-GIANNELLA, Maria LuciaBecause of the paucity of information regarding metabolic effects of advanced glycation end products (AGEs) on liver, we evaluated effects of AGEs chronic administration in (1) insulin sensitivity; (2) hepatic expression of genes involved in AGEs, glucose and fat metabolism, oxidative stress and inflammation and; (3) hepatic morphology and glycogen content. Rats received intraperitoneally albumin modified (AIbAGE) or not by advanced glycation for 12 weeks. AIbAGE induced whole-body insulin resistance concomitantly with increased hepatic insulin sensitivity, evidenced by activation of AKT, inactivation of GSK3, increased hepatic glycogen content, and decreased expression of gluconeogenesis genes. Additionally there was reduction in hepatic fat content, in expression of lipogenic, pro-inflamatory and pro oxidative genes and increase in reactive oxygen species and in nuclear expression of NRF2, a transcription factor essential to cytoprotective response. Although considered toxic, AGEs become protective when administered chronically, stimulating AKT signaling, which is involved in cellular defense and insulin sensitivity.
- N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats(2017) SILVA, Karolline S. da; PINTO, Paula R.; FABRE, Nelly T.; GOMES, Diego J.; THIEME, Karina; OKUDA, Ligia S.; IBORRA, Rodrigo T.; FREITAS, Vanessa G.; SHIMIZU, Maria H. M.; TEODORO, Walcy R.; MARIE, Suely K. N.; WOODS, Tom; BRIMBLE, Margaret A.; PICKFORD, Russell; RYE, Kerry-Anne; OKAMOTO, Maristela; CATANOZI, Sergio; CORREA-GIANNELA, Maria L.; MACHADO, Ubiratan F.; PASSARELLI, MarisaBackground: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and prevents insulin resistance. Therefore, it may be a useful tool in the prevention of AGE action on insulin resistance and long-term complications of DM.
- Advanced glycation end products-induced insulin resistance involves repression of skeletal muscle GLUT4 expression(2018) PINTO-JUNIOR, Danilo C.; SILVA, Karolline S.; MICHALANI, Maria L.; YONAMINE, Caio Y.; ESTEVES, Joao V.; FABRE, Nelly T.; THIEME, Karina; CATANOZI, Sergio; OKAMOTO, Maristela M.; SERAPHIM, Patricia M.; CORREA-GIANNELLA, Maria L.; PASSARELLI, Marisa; MACHADO, Ubiratan F.Little is known about advanced glycation end products (AGEs) participation in glucose homeostasis, a process in which skeletal muscle glucose transporter GLUT4 (Scl2 alpha 4 gene) plays a key role. This study investigated (1) the in vivo and in vitro effects of AGEs on Slc2 alpha 4/GLUT4 expression in skeletal muscle of healthy rats, and (2) the potential involvement of endoplasmic reticulum and inflammatory stress in the observed regulations. For in vivo analysis, rats were treated with advanced glycated rat albumin (AGE-albumin) for 12 weeks; for in vitro analysis, soleus muscles from normal rats were incubated with bovine AGE-albumin for 2.5 to 7.5 hours. In vivo, AGE-albumin induced whole-body insulin resistance; decreased (similar to 30%) Slc2 alpha 4 mRNA and GLUT4 protein content; and increased (similar to 30%) the nuclear content of nuclear factor NF-kappa-B p50 subunit (NFKB1), and cellular content of 78 kDa glucose-regulated protein (GRP78). In vitro, incubation with AGE-albumin decreased (similar to 50%) the Slc2 alpha 4/GLUT4 content; and increased cellular content of GRP78/94, phosphorylated-IKK-alpha/beta, nuclear content of NFKB1 and RELA, and the nuclear protein binding into Slc2 alpha 4 promoter NFKB-binding site. The data reveal that AGEs impair glucose homeostasis in non-diabetic states of increased AGEs concentration; an effect that involves activation of endoplasmic reticulum-and inflammatory-stress and repression of Slc2 alpha 4/GLUT4 expression.
- N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats(2016) THIEME, Karina; SILVA, Karolline S. Da; FABRE, Nelly T.; CATANOZI, Sergio; MONTEIRO, Maria Beatriz; SANTOS-BEZERRA, Daniele Pereira; COSTA-PESSOA, Juliana Martins; OLIVEIRA-SOUZA, Maria; MACHADO, Ubiratan F.; PASSARELLI, Marisa; CORREA-GIANNELLA, Maria LuciaAim: To assess the renal effects of chronic exposure to advanced glycation end-products (AGEs) in the absence of diabetes and the potential impact of concomitant treatment with the antioxidant N-acetyl cysteine (NAC). Methods: Wistar rats received intraperitoneally 20 mg/kg/day of albumin modified (AIbAGE) or not (AIbC) by advanced glycation for 12 weeks and oral NAC (600mg/L; AIbAGE+NAC and AlbC+NAC, respectively). Biochemical, urinary and renal morphological analyses; carboxymethyl-lysine (CML, an AGE), CD68 (macrophage infiltration), and 4-hydroxynonenal (4-HNE, marker of oxidative stress) immunostaining; intrarenal mRNA expression of genes belonging to pathways related to AGEs (Ager, Ddost, Nfkb1), renin-angiotensin system (Agt, Ren, Ace), fibrosis (Tgfb1, Col4a1), oxidative stress (Nox4, Txnip), and apoptosis (Box, Bcl2); and reactive oxidative species (ROS) content were performed. Results: AIbAGE significantly increased urine protein-to-creatinine ratio; glomerular area; renal CML content and macrophage infiltration; expression of Ager, Nfkb1, Agt, Ren, Tgfb1, Col4a1, Txnip, Bax/Bcl2 ratio; and 4-HNE and ROS contents. Some of these effects were attenuated by NAC concomitant treatment. Conclusion: Because AGEs are highly consumed in modern diets and implicated in the progression of different kidney diseases, NAC could be a therapeutic intervention to decrease renal damage, considering that long-term restriction of dietary AGEs is difficult to achieve in practice. (C) 2016 The Author(s) Published by S. Karger AG, Basel