RESUMO
Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age-dependent impairment of glucose tolerance and glucose-stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80-positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP-1 and TNF-α), part of the senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 ß-cells to MGO confirms its casual role on ß-cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Lactoilglutationa Liase/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Intolerância à Glucose/genética , Lactoilglutationa Liase/genética , Óxido de Magnésio , Camundongos , Aldeído Pirúvico/metabolismoRESUMO
PREP1 is a homeodomain transcription factor that impairs metabolism and is involved in age-related aortic thickening. In this study, we evaluated the role of PREP1 on endothelial function. Mouse Aortic Endothelial Cells (MAECs) transiently transfected with a Prep1 cDNA showed a 1.5- and 1.6-fold increase in eNOSThr495 and PKCα phosphorylation, respectively. Proinflammatory cytokines Tnf-α and Il-6 increased by 3.5 and 2.3-fold, respectively, in the presence of Prep1, while the antioxidant genes Sod2 and Atf4 were significantly reduced. Bisindolylmaleimide reverted the effects induced by PREP1, suggesting PKCα to be a mediator of PREP1 action. Interestingly, resveratrol, a phenolic micronutrient compound, reduced the PREP1 levels, eNOSThr495, PKCα phosphorylation, and proinflammatory cytokines and increased Sod2 and Atf4 mRNA levels. The experiments performed on the aorta of 18-month-old Prep1 hypomorphic heterozygous mice (Prep1i/+) expressing low levels of this protein showed a 54 and 60% decrease in PKCα and eNOSThr495 phosphorylation and a 45% reduction in Tnf-α levels, with no change in Il-6, compared to same-age WT mice. However, a significant decrease in Sod2 and Atf4 was observed in Prep1i/+ old mice, indicating the lack of age-induced antioxidant response. These results suggest that Prep1 deficiency partially improved the endothelial function in aged mice and suggested PREP1 as a novel target of resveratrol.
Assuntos
Células Endoteliais , Proteínas de Homeodomínio , Camundongos , Animais , Resveratrol/farmacologia , Proteínas de Homeodomínio/genética , Células Endoteliais/metabolismo , Proteína Quinase C-alfa , Fator de Necrose Tumoral alfa/genética , Antioxidantes/farmacologia , Interleucina-6/genética , Citocinas , Aorta/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismoRESUMO
Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.
Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Animais , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Epigênese Genética , Humanos , Medição de RiscoRESUMO
Evidence has been provided linking microRNAs (miRNAs) and diabetic complications, by the regulation of molecular pathways, including insulin-signaling, involved in the pathophysiology of vascular dysfunction. Methylglyoxal (MGO) accumulates in diabetes and is associated with cardiovascular complications. This study aims to analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin responsiveness in mouse aortic endothelial cells (MAECs). miRNA modulation was performed by transfection of specific miRNA mimics and inhibitors in MAECs, treated or not with MGO. miRNA-target protein levels were evaluated by Western blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulation by miR-214 was tested by luciferase assays and by the use of a target protector specific for miR-214 on PHLPP2-3'UTR. This study reveals a 4-fold increase of PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be dependent by miR-214. Finally, the inhibition of miR-214 impairs the insulin-dependent Akt activation, while its overexpression rescues the insulin effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 downregulation as a contributing factor to MGO-induced endothelial insulin-resistance.
Assuntos
Endotélio Vascular/metabolismo , Fosfoproteínas Fosfatases/genética , Animais , Aorta/citologia , Aorta/metabolismo , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Insulina/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aldeído Pirúvico/toxicidade , Transdução de SinaisRESUMO
Methylglyoxal (MGO) is a reactive dicarbonyl produced as by-product of glycolysis, and its formation is heightened in hyperglycaemia. MGO plasma levels are two-fold to five-fold increased in diabetics and its accumulation promotes the progression of vascular complications. Impairment of endothelium-derived nitric oxide represents a common feature of endothelial dysfunction in diabetics. We previously demonstrated that MGO induces endothelial insulin resistance. Increasing evidence shows that high glucose and MGO modify vascular expression of several microRNAs (miRNAs), suggesting their potential role in the impairment of endothelial insulin sensitivity. The aim of the study is to investigate whether miRNAs may be involved in MGO-induced endothelial insulin resistance in endothelial cells. MGO reduces the expression of miR-190a both in mouse aortic endothelial cells (MAECs) and in aortae from mice knocked-down for glyoxalase-1. miR-190a inhibition impairs insulin sensitivity, whereas its overexpression prevents the MGO-induced insulin resistance in MAECs. miR-190a levels are not affected by the inhibition of ERK1/2 phosphorylation. Conversely, ERK1/2 activation is sustained by miR-190a inhibitor and the MGO-induced ERK1/2 hyper-activation is reduced by miR-190a mimic transfection. Similarly, protein levels of the upstream KRAS are increased by both MGO and miR-190a inhibitor, and these levels are reduced by miR-190a mimic transfection. Interestingly, silencing of KRAS is able to rescue the MGO-impaired activation of IRS1/Akt/eNOS pathway in response to insulin. In conclusion, miR-190a down-regulation plays a role in MGO-induced endothelial insulin resistance by increasing KRAS. This study highlights miR-190a as new candidate for the identification of strategies aiming at ameliorating vascular function in diabetes.
Assuntos
Regulação para Baixo , Células Endoteliais/metabolismo , Resistência à Insulina , Insulina/metabolismo , MicroRNAs/genética , Aldeído Pirúvico/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus/metabolismo , Glicólise , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
The highly reactive dicarbonyl methylglyoxal (MGO) is mainly formed as byproduct of glycolysis. Therefore, high blood glucose levels determine increased MGO accumulation. Nonetheless, MGO levels are also increased as consequence of the ineffective action of its main detoxification pathway, the glyoxalase system, of which glyoxalase 1 (Glo1) is the rate-limiting enzyme. Indeed, a physiological decrease of Glo1 transcription and activity occurs not only in chronic hyperglycaemia but also with ageing, during which MGO accumulation occurs. MGO and its advanced glycated end products (AGEs) are associated with age-related diseases including diabetes, vascular dysfunction and neurodegeneration. Endothelial dysfunction is the first step in the initiation, progression and clinical outcome of vascular complications, such as retinopathy, nephropathy, impaired wound healing and macroangiopathy. Because of these considerations, studies have been centered on understanding the molecular basis of endothelial dysfunction in diabetes, unveiling a central role of MGO-Glo1 imbalance in the onset of vascular complications. This review focuses on the current understanding of MGO accumulation and Glo1 activity in diabetes, and their contribution on the impairment of endothelial function leading to diabetes-associated vascular damage.
Assuntos
Lactoilglutationa Liase/metabolismo , Doenças Vasculares/enzimologia , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Resistência à Insulina , Modelos Biológicos , Aldeído Pirúvico/metabolismoRESUMO
AIMS/HYPOTHESIS: Insulin exerts a direct action on vascular cells, thereby affecting the outcome and progression of diabetic vascular complications. However, the mechanism through which insulin signalling is impaired in the endothelium of diabetic individuals remains unclear. In this work, we have evaluated the role of the AGE precursor methylglyoxal (MGO) in generating endothelial insulin resistance both in cells and in animal models. METHODS: Time course experiments were performed on mouse aortic endothelial cells (MAECs) incubated with 500 µmol/l MGO. The glyoxalase-1 inhibitor S-p-bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to increase the endogenous levels of MGO. For the in vivo study, an MGO solution was administrated i.p. to C57BL/6 mice for 7 weeks. RESULTS: MGO prevented the insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs. Similar results were obtained in MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued insulin-dependent Akt activation and NO generation, indicating that MGO inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin sensitivity and induced endothelial insulin resistance. CONCLUSIONS/INTERPRETATION: MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes.
Assuntos
Células Endoteliais/efeitos dos fármacos , Resistência à Insulina/fisiologia , Insulina/metabolismo , Aldeído Pirúvico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Células Endoteliais/metabolismo , Glutationa/análogos & derivados , Glutationa/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The transcription factor HOXA5, from the HOX gene family, has long been studied due to its critical role in physiological activities in normal cells, such as organ development and body patterning, and pathological activities in cancer cells. Nonetheless, recent evidence supports the hypothesis of a role for HOXA5 in metabolic diseases, particularly in obesity and type 2 diabetes (T2D). In line with the current opinion that adipocyte and adipose tissue (AT) dysfunction belong to the group of primary defects in obesity, linking this condition to an increased risk of insulin resistance (IR) and T2D, the HOXA5 gene has been shown to regulate adipocyte function and AT remodeling both in humans and mice. Epigenetics adds complexity to HOXA5 gene regulation in metabolic diseases. Indeed, epigenetic mechanisms, specifically DNA methylation, influence the dynamic HOXA5 expression profile. In human AT, the DNA methylation profile at the HOXA5 gene is associated with hypertrophic obesity and an increased risk of developing T2D. Thus, an inappropriate HOXA5 gene expression may be a mechanism causing or maintaining an impaired AT function in obesity and potentially linking obesity to its associated disorders. In this review, we integrate the current evidence about the involvement of HOXA5 in regulating AT function, as well as its association with the pathogenesis of obesity and T2D. We also summarize the current knowledge on the role of DNA methylation in controlling HOXA5 expression. Moreover, considering the susceptibility of epigenetic changes to reversal through targeted interventions, we discuss the potential therapeutic value of targeting HOXA5 DNA methylation changes in the treatment of metabolic diseases.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Humanos , Animais , Camundongos , Fatores de Transcrição/genética , Genes Homeobox , Diabetes Mellitus Tipo 2/genética , Tecido Adiposo , Doenças Metabólicas/genética , Obesidade/genética , Proteínas de Homeodomínio/genéticaRESUMO
Adipose-derived stem cells (ADSCs) play a crucial role in angiogenesis and repair of damaged tissues. However, in pathological conditions including diabetes, ADSC function is compromised. This work aims at evaluating the effect of Methylglyoxal (MGO), a product of chronic hyperglycemia, on mouse ADSCs' (mADSCs) pro-angiogenic function and the molecular mediators involved. The mADSCs were isolated from C57bl6 mice. MGO-adducts and p-p38 MAPK protein levels were evaluated by Western Blot. Human retinal endothelial cell (hREC) migration was analyzed by transwell assays. Gene expression was measured by qRT-PCR, and SA-ßGal activity by cytofluorimetry. Soluble factor release was evaluated by multiplex assay. MGO treatment does not impair mADSC viability and induces MGO-adduct accumulation. hREC migration is reduced in response to both MGO-treated mADSCs and conditioned media from MGO-treated mADSCs, compared to untreated cells. This is associated with an increase of SA-ßGal activity, SASP factor release and p53 and p21 expression, together with a VEGF- and PDGF-reduced release from MGO-treated mADSCs and a reduced p38-MAPK activation in hRECs. The MGO-induced impairment of mADSC function is reverted by senolytics. In conclusion, MGO impairs mADSCs' pro-angiogenic function through the induction of a senescent phenotype, associated with the reduced secretion of growth factors crucial for hREC migration.
Assuntos
Diabetes Mellitus , Aldeído Pirúvico , Humanos , Camundongos , Animais , Aldeído Pirúvico/farmacologia , Aldeído Pirúvico/metabolismo , Óxido de Magnésio , Camundongos Endogâmicos C57BL , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células-Tronco/metabolismoRESUMO
BACKGROUND: First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR. RESULTS: Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression. CONCLUSIONS: Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
Assuntos
Diabetes Mellitus Tipo 2 , Histonas , Humanos , Histonas/genética , Diabetes Mellitus Tipo 2/genética , Peróxido de Hidrogênio , Metilação de DNA , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Proteínas Mitocondriais/genéticaRESUMO
For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these conditions are accompanied by major abnormalities in fuel metabolism, evidence indicates that altered immune cell functions also play an important role in shaping of obesity and T2D phenotypes. Interestingly, these events have been shown to be determined by epigenetic mechanisms. Consistently, recent epigenome-wide association studies have demonstrated that immune cells from obese and T2D individuals feature specific epigenetic profiles when compared to those from healthy subjects. In this work, we have reviewed recent literature reporting epigenetic changes affecting the immune cell phenotype and function in obesity and T2D. We will further discuss therapeutic strategies targeting epigenetic marks for treating obesity and T2D-associated inflammation.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Epigenômica , Humanos , Inflamação/genética , Obesidade/complicações , Obesidade/genéticaRESUMO
One of the hallmarks of cancer cells is their metabolic reprogramming, which includes the preference for the use of anaerobic glycolysis to produce energy, even in presence of normal oxygen levels. This phenomenon, known as "Warburg effect", leads to the increased production of reactive intermediates. Among these Methylglyoxal (MGO), a reactive dicarbonyl known as the major precursor of the advanced glycated end products (AGEs), is attracting great attention. It has been well established that endogenous MGO levels are increased in several types of cancer, however the MGO contribution in tumor progression is still debated. Although an anti-cancer role was initially attributed to MGO due to its cytotoxicity, emerging evidence has highlighted its pro-tumorigenic role in several types of cancer. These apparently conflicting results are explained by the hormetic potential of MGO, in which lower doses of MGO are able to establish an adaptive response in cancer cells while higher doses cause cellular apoptosis. Therefore, the extent of MGO accumulation and the tumor context are crucial to establish MGO contribution to cancer progression. Several therapeutic approaches have been proposed and are currently under investigation to inhibit the pro-tumorigenic action of MGO. In this review, we provide an overview of the early and latest evidence regarding the role of MGO in cancer, in order to define its contribution in tumor progression, and the therapeutic strategies aimed to counteract the tumor growth.
RESUMO
Non-alcoholic-fatty liver disease (NAFLD) is spreading worldwide. Specific drugs for NAFLD are not yet available, even if some plant extracts show beneficial properties. We evaluated the effects of a combination, composed by Berberis Aristata, Elaeis Guineensis and Coffea Canephora, on the development of obesity, hepatic steatosis, insulin-resistance and on the modulation of hepatic microRNAs (miRNA) levels and microbiota composition in a mouse model of liver damage. C57BL/6 mice were fed with standard diet (SD, n = 8), high fat diet (HFD, n = 8) or HFD plus plant extracts (HFD+E, n = 8) for 24 weeks. Liver expression of miR-122 and miR-34a was evaluated by quantitativePCR. Microbiome analysis was performed on cecal content by 16S rRNA sequencing. HFD+E-mice showed lower body weight (p < 0.01), amelioration of insulin-sensitivity (p = 0.021), total cholesterol (p = 0.014), low-density-lipoprotein-cholesterol (p < 0.001), alanine-aminotransferase (p = 0.038) and hepatic steatosis compared to HFD-mice. While a decrease of hepatic miR-122 and increase of miR-34a were observed in HFD-mice compared to SD-mice, both these miRNAs had similar levels to SD-mice in HFD+E-mice. Moreover, a different microbial composition was found between SD- and HFD-mice, with a partial rescue of dysbiosis in HFD+E-mice. This combination of plant extracts had a beneficial effect on HFD-induced NAFLD by the modulation of miR-122, miR-34a and gut microbiome.
Assuntos
Disbiose/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Arecaceae/química , Berberina/administração & dosagem , Berberis/química , Coffea/química , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Disbiose/imunologia , Disbiose/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Resistência à Insulina/imunologia , Fígado/patologia , Masculino , Camundongos , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Extratos Vegetais/química , Tocotrienóis/administração & dosagemRESUMO
Citrus aurantium L. dry extracts (CAde) improve adipogenesis in vitro. These effects are dependent from an early modulation of CCAAT/enhancer-binding protein beta (C/Ebpß) expression and cyclic Adenosine Monophosphate (cAMP) response element-binding protein (CREB) activation. C/Ebpß and Creb are also targets of miR-155. This study investigated whether CAde regulates miR-155 expression in the early stages of adipogenesis and whether it ameliorates adipocyte differentiation of cells exposed to tumor necrosis factor-alpha (TNFα). Adipogenic stimuli (AS) were performed in 3T3-L1 pre-adipocytes treated with CAde, TNFα, or both. Gene and miRNA expression were determined by quantitative real-time PCR. Adipogenesis was evaluated by Oil-Red O staining. CAde treatment enhanced AS effects during the early adipogenesis phases by further down-regulating miR-155 expression and increasing both C/Ebpß and Creb mRNA and protein levels. At variance, TNFα inhibited 3T3-L1 adipogenesis and abolished AS effects on miR-155, C/Ebpß, and Creb expression. However, in cells exposed to TNFα, CAde improved adipocyte differentiation and restored the AS effects on miRNA and gene expression at early time points. In conclusion, this study identified miR-155 down-regulation as part of the mechanism through which CAde enhances adipogenesis of pre-adipocytes in vitro. Furthermore, it provides evidence of CAde efficacy against TNFα negative effects on adipogenesis.
Assuntos
Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Citrus/química , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/efeitos adversos , Células 3T3 , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration.
Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Envelhecimento Saudável/metabolismo , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Aldeído Pirúvico/metabolismo , Envelhecimento/patologia , Animais , Células Cultivadas , Senescência Celular , Humanos , Camundongos , RatosRESUMO
Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated. In this study we have clarified for the first time the molecular mechanism involved in the impairment of angiogenesis induced by MGO accumulation. Angiogenesis was evaluated in mouse aortic endothelial cells isolated from Glo1-knockdown mice (Glo1KD MAECs) and their wild-type littermates (WT MAECs). Reduction in Glo1 expression led to an accumulation of MGO and MGO-modified proteins and impaired angiogenesis of Glo1KD MAECs. Both mRNA and protein levels of the anti-angiogenic HoxA5 gene were increased in Glo1KD MAECs and its silencing improved both their migration and invasion. Nuclear NF-ĸB-p65 was increased 2.5-fold in the Glo1KD as compared to WT MAECs. Interestingly, NF-ĸB-p65 binding to HoxA5 promoter was also 2-fold higher in Glo1KD MAECs and positively regulated HoxA5 expression in MAECs. Consistent with these data, both the exposure to a chemical inhibitor of Glo1 "SpBrBzGSHCp2" (GI) and to exogenous MGO led to the impairment of migration and the increase of HoxA5 mRNA and NF-ĸB-p65 protein levels in microvascular mouse coronary endothelial cells (MCECs). This study demonstrates, for the first time, that MGO accumulation increases the antiangiogenic factor HoxA5 via NF-ĸB-p65, thereby impairing the angiogenic ability of endothelial cells.
Assuntos
Indutores da Angiogênese/metabolismo , Aorta/metabolismo , Células Endoteliais/metabolismo , Proteínas de Homeodomínio/metabolismo , Lactoilglutationa Liase/metabolismo , Fosfoproteínas/metabolismo , Aldeído Pirúvico/metabolismo , Aldeído Pirúvico/farmacologia , Animais , Aorta/efeitos dos fármacos , Movimento Celular , Diabetes Mellitus/metabolismo , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Lactoilglutationa Liase/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , NF-kappa B/metabolismo , Fosfoproteínas/genética , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Fatores de TranscriçãoRESUMO
Post-conflict affiliation is a mechanism favored by natural selection to manage conflicts in animal groups thus avoiding group disruption. Triadic affiliation towards the victim can reduce the likelihood of redirection (benefits to third-parties) and protect and provide comfort to the victim by reducing its post-conflict anxiety (benefits to victims). Here, we test specific hypotheses on the potential functions of triadic affiliation in Theropithecus gelada, a primate species living in complex multi-level societies. Our results show that higher-ranking geladas provided more spontaneous triadic affiliation than lower-ranking subjects and that these contacts significantly reduced the likelihood of further aggression on the victim. Spontaneous triadic affiliation significantly reduced the victim's anxiety (measured by scratching), although it was not biased towards kin or friends. In conclusion, triadic affiliation in geladas seems to be a strategy available to high-ranking subjects to reduce the social tension generated by a conflict. Although this interpretation is the most parsimonious one, it cannot be totally excluded that third parties could also be affected by the negative emotional state of the victim thus increasing a third party's motivation to provide comfort. Therefore, the debate on the linkage between third-party affiliation and emotional contagion in monkeys remains to be resolved.
Assuntos
Comportamento Animal , Conflito Psicológico , Comportamento Social , Theropithecus/psicologia , Agressão/psicologia , Animais , Ansiedade/psicologia , Feminino , Relações Interpessoais , MasculinoRESUMO
Glucose serves as a primary, and for some tissues the unique, fuel source in order to generate and maintain the biological functions. Hyperglycemia is a hallmark of type 2 diabetes and is the direct consequence of perturbations in the glucose homeostasis. Insulin resistance, referred to as a reduced response of target tissues to the hormone, contributes to the development of hyperglycemia. The molecular mechanisms responsible for the altered glucose homeostasis are numerous and not completely understood. MicroRNAs (miRNAs) are now recognized as regulators of the lipid and glucose metabolism and are involved in the onset of metabolic diseases. Indeed, these small non-coding RNA molecules operate in the RNA silencing and posttranscriptional regulation of gene expression and may modulate the levels of kinases and enzymes in the glucose metabolism. Therefore, a better characterization of the function of miRNAs and a deeper understanding of their role in disease may represent a fundamental step toward innovative treatments addressing the causes, not only the symptoms, of hyperglycemia, using approaches aimed at restoring either miRNAs or their specific targets. In this review, we outline the current understanding regarding the impact of miRNAs in the glucose metabolism and highlight the need for further research focused on altered key kinases and enzymes in metabolic diseases.
RESUMO
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been proposed as a therapeutic option for patients with Systemic Lupus Erythematosus (SLE) refractory to standard therapy. This therapeutic approach has been applied to other severe autoimmune diseases refractory to standard therapy with promising results. AIM: To systematically review the literature and analyze the available evidence on HSCT therapy in patients with SLE and antiphospholipid syndrome (APS), with a focus on therapy efficacy and occurrence of adverse events. METHODS: A detailed literature search, applied to Ovid MEDLINE, In-Process and Other Non-Indexed Citation and Ovid Medline 1986 to 2014, has been developed a priori to identify articles that reported findings from clinical and laboratory studies that investigated the effect of HCT in patients with SLE. RESULTS: Twenty-five studies met all inclusion criteria, including a total of 279 SLE patients; of those, 54 patients also fulfilled the classification criteria of APS. The majority of the studies reported an improvement after HSCT in terms of diseases activity control (assessed with SLEDAI, or time-free from diseases) or overall survival. However, one study reported no net benefit of HSCT when compared to immunosuppression alone. One retrospective study reported an overall survival at 5years of 81% in 28 SLE patients. Of note, 5 cases (9.3%) of aPL negativization were reported after HSCT in the APS patients. When combining these studies and analyzing these patients with APS, 32 out of 44 (73%) were able to discontinue anticoagulation after HSCT. Our findings also demonstrate a total of 86 infections in the pool of patients (30.8%), 3 of which resulted in the death of the patient (1.3%). We observed an annual incidence of infection of 11.9% with a mean follow up of 36.2months. CONCLUSION: Preliminary results of HSCT as a therapeutic option for SLE appear promising. Further studies are warranted in order to assess the safety of the procedure for both the occurrence of secondary autoimmune disease and the rate of infection. However, the rate of adverse effects confines this option to very selected cases of SLE patients resistant or refractory to standard approaches.
Assuntos
Síndrome Antifosfolipídica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Lúpus Eritematoso Sistêmico/terapia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
Antiphospholipid syndrome (APS) is a prothrombotic disease characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (apL). Management of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thrombo-prophylaxis is recommended in patients with systemic lupus erythromatosus (SLE) and obstetric APS. Obstetric APS care is based on high-risk management and treatment with aspirin and heparin. Possible future therapies include statins, hydroxychloroquine, rituximab, and new anticoagulant drugs. Current research is focused on targeting components of the complement system, interfering with aPL-mediated cell activation and using tailored peptides to block the pathogenic subpopulation of aPL.