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BACKGROUND/AIMS: Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in ß cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to ß cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic ß cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions. METHODS: We incubated the pancreatic ß cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O2 consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting). RESULTS: MitoQ increased insulin secretion and prevented the enhancement of ROS production and O2 consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions. CONCLUSION: Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic ß cell function.
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Antioxidantes/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/análogos & derivados , Animais , Linhagem Celular Tumoral , Glucose/metabolismo , Hiperglicemia/patologia , Células Secretoras de Insulina/patologia , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Ubiquinona/farmacologiaRESUMO
BACKGROUND: The relationship between caloric restriction-mediated weight loss and the generation of ROS and its effects on atherosclerotic markers in obesity is not fully understood. Therefore, we set out to investigate whether dietary weight loss intervention improves markers of oxidative stress in leukocytes and subclinical parameters of atherosclerosis. SUBJECTS AND METHODS: This was an interventional study of 59 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical parameters, inflammatory markers-hsCRP, TNFα and NFκB -, oxidative stress parameters-total superoxide, glutathione, catalase activity and protein carbonyl groups-, soluble cellular adhesion molecules-sICAM, sP-selectin, sPSGL-1 -, myeloperoxidase (MPO), leukocyte-endothelium cell interactions-rolling flux, velocity and adhesion-and LDL subfractions, before and after the dietary intervention. RESULTS: After losing weight, an improvement was observed in the patients' anthropometric, blood pressure and metabolic parameters, and was associated with reduced inflammatory response (hsCRP, TNFα and NFκB). Oxidative stress parameters improved, since superoxide production and protein carbonyl content were reduced and antioxidant systems were enhanced. In addition, a significant reduction of subclinical markers of atherosclerosis-small and dense LDL particles, MPO, sP-selectin and leukocyte adhesion-and an increase in soluble PSGL-1 were reported. CONCLUSIONS: Our findings reveal that the improvement of subclinical atherosclerotic markers after dietary weight loss intervention is associated with a reduction of oxidative stress in leukocytes and inflammatory pathways, suggesting that these are the underlying mechanisms responsible for the reduced risk of cardiovascular disease in obese subjects after losing weight.
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Aterosclerose , Restrição Calórica , Obesidade , Estresse Oxidativo/fisiologia , Adulto , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Feminino , Humanos , Leucócitos/química , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/dietoterapia , Redução de PesoRESUMO
BACKGROUND/AIMS: There is a lack of reliable biological markers for the early diagnosis of diabetic nephropathy (DN) during type 2 diabetes. In this pilot study we aim to assess whether miR-31 levels are modulated by the presence of DN and whether the expression of this miRNA is related to leukocyte-endothelial interactions and inflammation. METHODS: Thirty-one T2D patients were enrolled in this pilot study; 18 with no diabetic complications and 13 with diabetic nephropathy. 24 non-diabetic subjects and 13 T2D patients with retinopathy (absent of other complications) were included to test the specificity of miR-31. Following anthropometric and biochemical evaluation, serum miR-31 levels were assessed by Real Time-PCR. Leukocyte-endothelial interactions were evaluated by a parallel flow chamber in vitro model. Serum TNFα, IL-6 and ICAM-1 levels were determined by XMAP-technology in a flow cytometry-based Luminex 200 instrument. RESULTS: Serum miR-31 levels were similar between control and T2D subjects. However, T2D patients with DN displayed reduced levels of miR-31 with respect to patients without complications. This decrease in miR-31 was more pronounced in patients with macroalbuminuria than in those with microalbuminuria and was specific for DN, since patients with retinopathy displayed unaltered miR-31 levels. The presence of DN involved a lower leukocyte rolling velocity and an increased rolling flux and adhesion. miR-31 levels were positively correlated with leukocyte rolling velocity and negatively associated to leukocyte adhesion, TNFα, IL-6 and ICAM-1 levels. CONCLUSION: Serum miR-31 may be a biomarker for DN in T2D patients. The regulation of this miRNA seems to be related to the recruitment of leukocytes to vascular walls induced by pro-inflammatory and adhesion molecules.
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Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , MicroRNAs/sangue , Idoso , Albuminúria/etiologia , Biomarcadores/sangue , Adesão Celular , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Regulação para Baixo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Humanos , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: To evaluate the relationship between leukocyte-endothelial cell interactions and oxidative stress parameters in non-diabetic patients with different grades of obesity. MATERIAL AND METHODS: For this cross-sectional study, 225 subjects were recruited from January 1, 2014 to December 31, 2016 and divided into groups according to BMI (<30 kg/m2 , 30-40 kg/m2 and >40 kg/m²). We determined clinical parameters, systemic inflammatory markers, soluble cellular adhesion molecules, leukocyte-endothelium cell interactions-rolling flux, velocity and adhesion-, oxidative stress parameters-total ROS, total superoxide, glutathione-and mitochondrial membrane potential in leukocytes. RESULTS: We verified that HOMA-IR and hsCRP increased progressively as obesity developed, whereas A1c, IL6 and TNFα were augmented in the BMI > 40 kg/m² group. The cellular adhesion molecule sP-selectin was increased in patients with obesity, while sICAM, total ROS, total superoxide and mitochondrial membrane potential were selectively higher in the BMI > 40 kg/m² group. Obesity induced a progressive decrease in rolling velocity and an enhancement of rolling flux and leukocyte adhesion. CONCLUSION: Our findings reveal that endothelial dysfunction markers are altered in human obesity and are associated with proinflammatory cytokines and increased oxidative stress parameters.
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Células Endoteliais/fisiologia , Leucócitos/fisiologia , Obesidade/fisiopatologia , Estresse Oxidativo/fisiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Estudos Transversais , Citocinas/metabolismo , Feminino , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Potencial da Membrana Mitocondrial/fisiologia , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Adulto JovemRESUMO
Hypertension is a complex disorder ensuing necessarily from alterations in the pressure-natriuresis relationship, the main determinant of long-term control of blood pressure. This mechanism sets natriuresis to the level of blood pressure, so that increasing pressure translates into higher osmotically driven diuresis to reduce volemia and control blood pressure. External factors affecting the renal handling of sodium regulate the pressure-natriuresis relationship so that more or less natriuresis is attained for each level of blood pressure. Hypertension can thus only develop following primary alterations in the pressure to natriuresis balance, or by abnormal activity of the regulation network. On the other hand, increased sympathetic tone is a very frequent finding in most forms of hypertension, long regarded as a key element in the pathophysiological scenario. In this article, we critically analyze the interplay of the renal component of the sympathetic nervous system and the pressure-natriuresis mechanism in the development of hypertension. A special focus is placed on discussing recent findings supporting a role of baroreceptors as a component, along with the afference of reno-renal reflex, of the input to the nucleus tractus solitarius, the central structure governing the long-term regulation of renal sympathetic efferent tone.
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Hipertensão , Natriurese , Humanos , Pressão Sanguínea , Natriurese/fisiologia , Rim , Sódio , Sistema Nervoso Simpático/fisiologiaRESUMO
Bread crust constitutes an important by-product of the bakery industry, and its utilization for the isolation of melanoidins to be used as a functional ingredient can enhance its added value and contribute to health. The aim of this study was to evaluate the bioaccessibility, bioactivity, and genoprotective effect of melanoidins derived from bread crust. Bioaccessibility was assessed in gastric, intestinal digestion, and colonic fermentation fractions. The results revealed a relationship between bioaccessible melanoidins and their type (common or soft bread). No cytotoxicity effects were observed for bioaccessible fractions, as assessed by MTT and RTA methods, and they did not affect the distribution of E-cadherin in Caco-2 cells, confirming their ability to maintain membrane integrity. Furthermore, our study demonstrated that the gastrointestinal and colonic fermentation fractions successfully transported across the intestinal barrier, without affecting cell permeability, and showed antioxidant activity on the basolateral side of the cell monolayer. Remarkably, both fractions displayed a significant genoprotective effect in Caco-2 cells. Our findings provide crucial insights into the relationship between the melanoidins and their bioactivity and genoprotective effect. These results demonstrated the potential of bioaccessible melanoidins as valuable bioactive compounds for the development of functional foods, without showing toxic effects on gastrointestinal cells.
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Melanoidins isolated from bakery by-products are proposed as new sustainable ingredients for bakery products. The colour, odour profile, texture, water activity, and antioxidant capacity of two bakery food models, fat and fat-free, enriched with 2% and 4% soft bread and common bread melanoidins, were analysed. The colour of the bakery food models with melanoidins was darker than that of the respective control; the fat-free models with melanoidins showed higher values of hardness than the control, while no significant effect was observed in the fat models; the water activity did not change compared to the control; the odour profile was significantly modified with different effects depending on the type of melanoidin quantity added and the food model (fat or fat-free); and the antioxidant capacity increased proportionally to the quantity of melanoidin added. In general, melanoidins from soft bread exhibited a higher effect than the melanoidins from common bread. The melanoidins isolated from both fat and fat-free bakery food models did not show cytotoxicity nor did they modify the levels of reactive oxygen species in Caco-2 cells. Therefore, the results seem to indicate the favourable potential of bread melanoidins as new sustainable ingredients for bakery products.
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Antioxidantes , Pão , Humanos , Antioxidantes/farmacologia , Pão/análise , Células CACO-2 , PolímerosRESUMO
This work gives novel information about the antimicrobial effect and volatiles of melanoidins isolated from Maria biscuit, common and soft bread. Melanoidins were isolated from scraped and sieved crusts (1 mm), after gluten digestion, 10 kDa ultrafiltration, and diafiltration. Finally, they were freeze-dried. Headspace solid-phase dynamic extraction coupled with a gas chromatograph with a mass spectrometer was used to determine the volatile profiles. The antimicrobial effect was evaluated against isolated strains of the most relevant food spoilage and pathogen microorganisms, together with some molds and yeasts. Melanoidins from common bread exhibited the most extensive antimicrobial activities and showed the most composite volatile profile. No undesirable compounds, such as furfural and 5-hydroxy-methyl-furfural, were found in any of the melanoidins studied. The obtained data pointed out that bakery melanoidins can exert effective food technological properties as natural antimicrobials that can improve shelf-life and security of foodstuffs, together with a possible contribution to food aroma.
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Anti-Infecciosos , Compostos Orgânicos Voláteis , Anti-Infecciosos/farmacologia , Pão/análise , Odorantes , PolímerosRESUMO
Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Melanoidins contribute to organoleptic properties of processed foods and exert benefits in health. The aim of this study was to isolate and characterize melanoidins from baked products (common bread, soft bread and biscuits), evaluate their cytotoxicity and determine their suitability as functional additives. Extraction yield, spectrophotometric characteristics, colorimetric properties, antioxidant capacity, and cytotoxicity of melanoidins were assessed. Among the studied products, soft bread had the highest extraction throughput. Melanoidins from biscuit showed the highest antioxidant capacity, closely followed by those of soft bread. Melanoidins did not exert cytotoxic effects on Caco-2 and HUVEC cells (viability was >80%). Nevertheless, incubation of HUVEC cells with melanoidins from common bread and biscuit slightly decreased viability, whereas gastrointestinal digestion of such melanoidins softened the decrease in cell viability. This study point to soft bread as a safe and efficient source of melanoidins, that could be potentially used in the future as functional ingredient.
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Antioxidantes/farmacologia , Pão , Polímeros/farmacologia , Antioxidantes/química , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Digestão , Células Endoteliais da Veia Umbilical Humana , Humanos , Polímeros/isolamento & purificação , Polímeros/farmacocinéticaRESUMO
Sodium-glucose co-transporter 2 inhibitors (iSGLT2) have been linked to a considerable reduction in cardiovascular risk in patients with type 2 diabetes (T2D), but the precise molecular mechanisms are still elusive. We aimed to evaluate the effects of the iSGLT2 empagliflozin on systemic inflammation and its potential antioxidant properties. This is an observational, prospective follow-up study of a cohort of fifteen patients with T2D who received 10 mg/day of empagliflozin according to standard clinical care. Measures at baseline, 12 and 24 weeks were taken. Metabolic and anthropometric parameters were evaluated. Production of mitochondrial superoxide, glutathione content, and glutathione s-reductase and catalase mRNA levels were measured in leukocytes. Serum levels of myeloperoxidase, hs-CRP and IL-10 were determined. In addition to decreased body weight and reduced glucose and HbA1c levels, we observed a reduction in superoxide production in leukocytes of diabetic patients and increased glutathione content, prominently after 24 weeks of empagliflozin treatment. Leukocyte expression of glutathione s-reductase and catalase, and serum levels of IL-10 were enhanced at 24 weeks of empagliflozin treatment. Concomitantly, reduced hs-CRP and myeloperoxidase levels were seen. This study provides evidence of the antioxidant and anti-inflammatory properties of empagliflozin treatment in humans, which may contribute to its beneficial cardiovascular effects.
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Since mitochondrial dysfunction is associated with NOD-like receptor family protein 3 (NLRP3) activation in type 2 diabetes (T2D), which can eventually lead to an impaired immune response, we set out to determine if glycemic control modulates the effects of T2D on the NLRP3 inflammasome. We have studied leukocytes from 61 diabetic patients [25 with glycated hemoglobin (HbA1c) ≤7% and 36 with HbA1c ≥8%] and 40 healthy controls. Total and mitochondrial reactive oxygen species (ROS) production was enhanced in T2D patients, and mitochondrial ROS was more pronounced in those with poor glycemic control. Levels of gene and protein expression of NLRP3 were decreased in both diabetic groups and more so in those with HbA1c ≥8%. In addition, there was a decrease in gene expression and serum concentrations of interleukin (IL)-1ß, IL-12, and caspase-1 in line with inhibition of the NLRP3 inflammasome. Our data also suggest negative correlations between HbA1c levels and NLRP3 protein expression, serum levels of IL-12 and IL-1ß, and caspase-1 messenger RNA expression. Our findings lead us to raise the hypothesis of an association between poor glycemic control in T2D and an impairment of the NLRP3 inflammasome, suggesting that glycemic control plays an important role in the immune response of diabetic subjects.
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Glicemia , Diabetes Mellitus Tipo 2/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Biomarcadores , Pesos e Medidas Corporais , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Since type 2 diabetes (T2D) is associated with oxidative stress and metformin has been shown to exert a protective role against the said stress, we wondered whether metformin treatment might also modulate endoplasmic reticulum (ER) stress and autophagy in leukocytes of T2D patients. We studied 53 T2D patients (37 of whom had been treated with metformin 1700 mg for at least 1 year) and 30 healthy volunteers. Leukocytes from both groups of T2D patients exhibited increased protein levels of 78-kDa glucose-regulated protein (GRP78) with respect to controls, whereas activating transcription factor 6 (ATF6) was enhanced specifically in nonmetformin-treated T2D, and (s-xbp1) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α) increased only in the metformin-treated group. The autophagy markers beclin1 (becn1), autophagy-related 7 (atg7), and microtubule-associated protein 1A/1B-light chain 3II/I (LC3 II/I) increased in nonmetformin-treated T2D, and metformin treatment reduced mitochondrial superoxide and increased glutathione (GSH) levels. Our observations raise the question of whether metformin treatment could reduce oxidative stress and act as an ER stress modulator in T2D patients by promoting an adaptive unfolded protein response (s-xbp1 and p-eIF2α) in their leukocytes; this was in contrast with nonmetformin-treated patients whose response could be driven by the ATF6-dependent pro-apoptotic pathway. Further, our findings lead to us to form the hypothesis of an autophagy-dependent clearance of misfolded proteins in nonmetformin-treated T2D patients that could be repressed by metformin treatment.-Antioxid. Redox Signal. 28, 1562-1569.
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Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Metformina/farmacologia , Administração Oral , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacosRESUMO
The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>C) displayed statistically significant higher levels of fasting glucose and HbA1c than those of the other haplogroups, suggesting a poorer glycaemic control. Furthermore, diabetic patients with the JT haplogroup showed a worse kidney function than those with other haplogroups, evident by higher levels of serum creatinine, lower estimated glomerular filtration rate (eGFR), and slightly higher (although not statistically significant) urinary albumin-to-creatinine ratio. Our results suggest that JT haplogroup (in particular, change at position 4216 of the mtDNA) is associated with poorer glycaemic control in T2D, which can trigger the development of diabetic nephropathy.
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There is growing focus on mitochondrial impairment and cardiovascular diseases (CVD) in type 2 diabetes (T2D), and the development of novel therapeutic strategies in this context. It is unknown whether mitochondrial-targeting antioxidants such as SS-31 protect sufficiently against oxidative damage in diabetes. We aimed to evaluate if SS-31 modulates SIRT1 levels and ameliorates leukocyte-endothelium interactions, oxidative stress and inflammation in T2D patients. Anthropometric and metabolic parameters were studied in 51 T2D patients and 57 controls. Production of mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, glutathione content, leukocyte-endothelium interactions, NFκB-p65, TNFα and SIRT1 levels was measured in leukocytes treated or not with SS-31. We observed increased mitochondrial ROS production that was restored by SS-31 treatment. SS-31 also increased mitochondrial membrane potential, glutathione content, SIRT1 levels and leukocyte rolling velocity and reduced rolling flux and adhesion in T2D patients. NFκB-p65 and TNFα, which were enhanced in diabetic patients, were also reduced by SS-31 treatment. Our results reveal that SS-31 exerts beneficial effects on the leukocytes of T2D patients by reducing oxidative stress, leukocyte-endothelium interactions, NFκB and TNFα and by increasing SIRT1 levels. These actions support its use as a potential agent against CVD risk.
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Antioxidantes/farmacologia , Diabetes Mellitus Tipo 2/patologia , Leucócitos/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Idoso , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/prevenção & controle , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelA/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Mitochondria play a key role in maintaining cellular metabolic homeostasis. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis. Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS) and low levels of ATP. Mitochondrial fusion is modulated by different proteins, including mitofusin-1 (MFN1), mitofusin-2 (MFN2) and optic atrophy (OPA-1), while fission is controlled by mitochondrial fission 1 (FIS1), dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF). PARKIN and (PTEN)-induced putative kinase 1 (PINK1) participate in the process of mitophagy, for which mitochondrial fission is necessary. In this review, we discuss the molecular pathways of mitochondrial dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone. Furthermore, we discuss the pathophysiological implications of impaired mitochondrial dynamics, especially in type 2 diabetes.
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Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia/genética , Trifosfato de Adenosina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial/genética , Dinâmica Mitocondrial/fisiologia , Proteínas Mitocondriais/genética , Mitofagia/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Since metformin can exert beneficial vascular effects, we aimed at studying its effect on reactive oxygen species (ROS) production, antioxidant enzyme expression, levels of adhesion molecules, and leukocyte-endothelium interactions in the leukocytes from type 2 diabetic (T2D) patients. The study was carried out in 72 T2D patients (41 of whom were treated with metformin for at least 12 months at a dose of 1700 mg per day), and in 40 sex- and age-matched control subjects. Leukocytes from T2D patients exhibited enhanced levels of mitochondrial ROS and decreased mRNA levels of glutathione peroxidase 1 (gpx1) and sirtuin 3 (sirt3) with respect to controls, whereas metformin was shown to revert these effects. No changes were observed on total ROS production and the expression levels of superoxide dismutase 1 and catalase. Furthermore, increases in leukocyte-endothelial interactions and intercellular adhesion molecule-1 and P-selectin levels were found in T2D and were also restored in metformin-treated patients. Our findings raise the question of whether metformin could modulate the appearance of atherosclerosis in T2D patients and reduce vascular events by decreasing leukocyte oxidative stress through an increase in gpx1 and sirt3 expression, and undermining adhesion molecule levels and leukocyte-endothelium interactions. Antioxid. Redox Signal. 27, 1439-1445.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Leucócitos/efeitos dos fármacos , Metformina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Idoso , Catalase , Adesão Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Feminino , Glutationa Peroxidase/genética , Humanos , Hipoglicemiantes/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos/metabolismo , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Selectina-P/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/genética , Superóxido Dismutase-1/genética , Glutationa Peroxidase GPX1RESUMO
INTRODUCTION: Low testosterone levels in men are associated with type 2 diabetes and cardiovascular risk. However, the role of testosterone in mitochondrial function and leukocyte-endothelium interactions is unknown. Our aim was to evaluate the relationship between testosterone levels, metabolic parameters, oxidative stress, mitochondrial function, inflammation and leukocyte-endothelium interactions in type 2 diabetic patients. MATERIALS AND METHODS: The study was performed in 280 male type 2 diabetic patients and 50 control subjects. Anthropometric and metabolic parameters, testosterone levels, reactive oxygen species (ROS) production, mitochondrial membrane potential, TNFα, adhesion molecules and leukocyte-endothelium cell interactions were evaluated. RESULTS: Testosterone levels were lower in diabetic patients. Total and mitochondrial ROS were increased and mitochondrial membrane potential, SOD and GSR expression levels were reduced in diabetic patients. TNFα, ICAM-1 and VCAM-1 levels, leukocyte rolling flux and adhesion were all enhanced in diabetic patients, while rolling velocity was reduced. Testosterone levels correlated negatively with glucose, HOMA-IR, HbA1c, triglycerides, nonHDL-c, ApoB, hs-CRP and AIP, and positively with HDL-c and ApoA1. The multivariable regression model showed that HDL-c, HOMA-IR and age were independently associated with testosterone. Furthermore, testosterone levels correlated positively with membrane potential and rolling velocity and negatively with ROS production, VCAM-1, rolling flux and adhesion. CONCLUSIONS: Our data highlight that low testosterone levels in diabetic men are related to impaired metabolic profile and mitochondrial function and enhanced inflammation and leukocyte-endothelium cell interaction, which leaves said patients at risk of cardiovascular events.
Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leucócitos/fisiologia , Mitocôndrias/metabolismo , Testosterona/metabolismo , Adulto , Aterosclerose/complicações , Aterosclerose/diagnóstico , Biomarcadores/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Risco , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
BACKGROUND: Cholesterol-lowering therapy has been related with several beneficial effects; however, its influence on oxidative stress and endothelial function is not fully elucidated. AIMS: To investigate the effect of simvastatin and ezetimibe on mitochondrial function and leukocyte-endothelium interactions in polymorphonuclear cells of hyperlipidemic patients. METHODS: Thirty-nine hyperlipidemic patients were randomly assigned to one of two groups: one received simvastatin (40 mg/day) and the other received ezetimibe (10 mg/day) for 4 weeks, after which both groups were administered combined therapy for an additional 4-week period. Lipid profile, mitochondrial parameters (oxygen consumption, reactive oxygen species (ROS) and membrane potential), glutathione levels, superoxide dismutase activity, catalase activity and leukocyte/endothelial cell interactions and adhesion molecules -VCAM-1, ICAM-1, E-selectin, were evaluated. RESULTS: An improvement in lipid profile was observed after administration of simvastatin or ezetimibe alone (LDLc: -40.2 vs -19.6%, respectively), though this effect was stronger with the former (p < 0.001), and a further reduction was registered when the two were combined (LDLc: -50.7% vs -56.8%, respectively). In addition to this, simvastatin, ezetimibe and simvastatin + ezetimibe significantly increased oxygen consumption, membrane potential and glutathione content, and decreased levels of ROS, thereby improving mitochondrial function. Furthermore, simvastatin + ezetimibe increased catalase activity. In addition, simvastatin and simvastatin/ezetimibe improved leukocyte/endothelium interactions by decreasing leukocyte rolling and adhesion and increasing leukocyte rolling velocity. Finally, simvastatin, ezetimibe and simvastatin + ezetimibe reduced levels of the adhesion molecule ICAM-1, and ezetimibe + simvastatin significantly decreased levels of E-selectin. CONCLUSION: Co-administration of simvastatin and ezetimibe has an additive cholesterol-lowering effect and beneficial consequences for mitochondrial function and leukocyte/endothelium interactions in leukocytes of hypercholesterolemic patients.
Assuntos
Anticolesterolemiantes/uso terapêutico , Adesão Celular/efeitos dos fármacos , Colesterol/sangue , Células Endoteliais/efeitos dos fármacos , Combinação Ezetimiba e Simvastatina/uso terapêutico , Ezetimiba/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sinvastatina/uso terapêutico , Idoso , Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/metabolismo , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Leucócitos/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espanha , Fatores de Tempo , Resultado do TratamentoRESUMO
It is generally accepted that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are related to insulin resistance and type 2 diabetes. Mitochondria use substrates from lipid and glucose metabolism in order to generate ATP, and when mitochondrial O2 consumption is decreased due to an altered metabolism there is an increase in reactive oxygen species (ROS) that can impair different types of molecules and cells, especially in ß- cells during type 2 diabetes. Furthermore, the maintenance of ER function in insulin-secreting ß-cells is crucial, and when ER homeostasis is disrupted, the ER develops an unfolded protein response (UPR) in order to maintain the homeostasis of this organelle. However, when homeostasis fails in mitochondria and ER, these organelles can initiate death signalling pathways. New research has suggested that hyperlipidemia and hyperliglucaemia, known as key factors of type 2 diabetes (T2D), disrupt mitochondrial activity and ER homeostasis, thus triggering a disruption of energy metabolism, unresolvable UPR activation and ß-cell death. This review explains the mechanisms of mitochondrial function and ER stress related to the pathological effects of type 2 diabetes in different tissues.