Dietary polyphenols and their relationship to the modulation of non-communicable chronic diseases and epigenetic mechanisms: A mini-review.

Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis.

INTRODUCTION: Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. METHODS: We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. RESULTS: Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I² = 72%) and the chi-square test (χ² = 18.32; p = 0.003). CONCLUSIONS: This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis

Abstract Introduction Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. Methods We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Results Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I2 = 72%) and the chi-square test (χ2 = 18.32; p = 0.003). Conclusion This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Self-reported dietary omega-3 polyunsaturated fatty acids are associated with adipose tissue markers and glucose metabolism in apparently healthy subjects.

BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) and resistin are associated with dysfunctional adipose tissue (AT)-related metabolic complications. The role of dietary eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids in this relationship is unknown. AIM: To investigate the association of EPA and DHA with PAI-1 and resistin, as well as the role of this association on the glucose metabolism of apparently healthy subjects. SUBJECTS AND METHODS: Thirty-six healthy individuals were included. Validated food frequency questionnaires were used to analyse dietary habits. Inflammatory and glucose metabolism markers were quantified. Subcutaneous AT samples were obtained, and adipocyte number, area, and macrophage content were assessed. RESULTS: In 36 subjects aged 56 ± 8 years and with a body mass index of 26 ± 4 kg/m2, logEPA, and logDHA showed significant association with logresistin and a marginal association with PAI-1. Adipocyte number, area, and lognumber of macrophages per adipocyte significantly correlated with PAI-1 but not with logresistin. Although logEPA and logDHA were independently associated with loginsulin, loginsulin resistance, and C-Peptide, the addition of logresistin, but not of PAI-1, into the multivariable model, abolished the associations. CONCLUSIONS: EPA and DHA could modulate glucose metabolism across AT functional states. Our data indicate that this association is independent of other metabolic risk factors.

Hemostatic state of children with type 1 diabetes.

PURPOSE: Hyperglycemia is one of the factors responsible for the molecular alterations that modify hemostasis. The aim of this study was to determine the levels of circulating molecules that have a prothrombotic impact on the child and adolescent population with type 1 diabetes mellitus. METHODS: There were 35 patients with type 1 diabetes mellitus (11.0±2.5 years of age and a median 3.7±2.0 years of the disease) with no vascular complications and 20 healthy controls with similar age, sex, and body mass index included in the study. The evaluated parameters were fibrinogen, plasminogen activator inhibitor-1 (PAI1), von Willebrand factor antigen, and standard coagulation tests (platelet count, prothrombin time, and activated partial thromboplastin time). Glycemic control was evaluated by hemoglobin A1c and fasting blood glucose tests, and the presence of retinopathy and nephropathy was ruled out. The data obtained were analyzed by IBM SPSS Statistics ver. 20.0 and expressed as mean±standard deviation. The Pearson correlation coefficient was applied to investigate correlations between variables. RESULTS: Diabetic patients showed significantly higher levels of fibrinogen (308±66 mg/dL vs. 246±18 mg/dL, P=0.0001), PAI-1 (41.6±12 ng/mL vs. 11.7±1.0 ng/mL, P=0.0001), and von Willebrand factor antigen (284%±55% vs. 121%±19%, P=0.0001). However, standard coagulation tests did not show differences between the 2 groups. PAI-1 was correlated with glycemia, hemoglobin A1c, fibrinogen, and von Willebrand factor antigen. CONCLUSION: Elevated levels of fibrinogen, PAI-1, and von Willebrand factor antigen were found in the pediatric and adolescent population with type 1 diabetes mellitus, which suggests a prothrombotic state.

The -675 4G/5G PAI-1 polymorphism confers genetic susceptibility to systemic lupus erythematosus, its clinical manifestations, and comorbidities in Mexican-Mestizo population.

Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the -675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the -675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The -675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81-3.87; p < .001) and 4G/4G (OR = 2.70; CI 1.62-4.51; p < .001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31-2.03; p < .001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84-3.84; p < .001). The 4G/5G genotype was associated with shorter disease duration (p = .039), as well as lower levels of haemoglobin (p = .001) and haematocrit (p = .009); the need for prednisone treatment (p = .001), higher BMI (p = .03), presence of type 2 DM (p = .015), clinical activity (Mex-SLEDAI = 57%; p = .047), Chronicity (SLICC-ACR = 0; p = .015) and CRP levels (p = .015) were associated with 5G/5G genotypes. In conclusion, the -675 4G/5G and 4G/4G PAI-1genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.

Immunohistochemical expression of plasminogen activator inhibitor-1 in subcutaneous versus omental adipose tissue in patients after elective abdominal surgery

Plasminogen activator inhibitor-1 (PAI-1) is a biomarker of thrombosis. Adipose and vascular tissues are among the major sources of PAI-1 production. Previous studies indicated that fat deposits mediate increased cardiovascular risk among obese individuals. We investigated the immunohistochemical (IHC) expression of PAI-1 in adipose and vascular tissues from the omentum and the subcutaneous tissue. The pathology samples were selected from 37 random patients who underwent elective abdominal surgery between 2008-2009. PAI-1 expression was semi-quantitatively scored and compared between the groups. Significant differences were noted in the IHC expression of PAI-1 between the omental and the subcutaneous adipose tissues (1.1 ± 0.8 versus 0.8 ± 0.6, respectively (p=0.05)). Adipose tissue displayed higher IHC expression of PAI-1 compared to vascular wall tissue in both omentum and subcutaneous sections (1.1 ± 0.8 versus 0.5 ± 0.9 (p=0.004), and 0.8 ± 0.6 versus 0.4 ± 0.6 (p=0.003), respectively). In conclusion, our study compared PAI-1 expression in the omentum versus the subcutaneous tissue and adipose versus vascular tissues. IHC expression of PAI-1 level was significantly higher in the omental adipose tissue compared to the subcutaneous adipose tissue. Adipose tissue displayed significantly higher PAI-1 expression than vascular tissue. The study elucidates the biological differences of adipose and vascular tissue from subcutaneous versus omental sections.

Immunohistochemical expression of plasminogen activator inhibitor-1 in subcutaneous versus omental adipose tissue in patients after elective abdominal surgery.

Plasminogen activator inhibitor-1 (PAI-1) is a biomarker of thrombosis. Adipose and vascular tissues are among the major sources of PAI-1 production. Previous studies indicated that fat deposits mediate increased cardiovascular risk among obese individuals. We investigated the immunohistochemical (IHC) expression of PAI-1 in adipose and vascular tissues from the omentum and the subcutaneous tissue. The pathology samples were selected from 37 random patients who underwent elective abdominal surgery between 2008-2009. PAI-1 expression was semi-quantitatively scored and compared between the groups. Significant differences were noted in the IHC expression of PAI-1 between the omental and the subcutaneous adipose tissues (1.1 ± 0.8 versus 0.8 ± 0.6, respectively (p=0.05)). Adipose tissue displayed higher IHC expression of PAI-1 compared to vascular wall tissue in both omentum and subcutaneous sections (1.1 ± 0.8 versus 0.5 ± 0.9 (p=0.004), and 0.8 ± 0.6 versus 0.4 ± 0.6 (p=0.003), respectively). In conclusion, our study compared PAI-1 expression in the omentum versus the subcutaneous tissue and adipose versus vascular tissues. IHC expression of PAI-1 level was significantly higher in the omental adipose tissue compared to the subcutaneous adipose tissue. Adipose tissue displayed significantly higher PAI-1 expression than vascular tissue. The study elucidates the biological differences of adipose and vascular tissue from subcutaneous versus omental sections.

PAI-1 inhibition by simvastatin as a positive adjuvant in cell therapy.

Cell therapy (CT) can be briefly described as the use of cells or cell components in the treatment of diseases. One of the main challenges in establishing new cell types for therapy is the low survival rates of homing cells. Glycoprotein plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the plasminogen activation system, and also an essential mediator of mesenchymal stem cell (MSC) post-transplant survival rate in the target tissue. It was previously observed that the survival of cells infused into the transplanted tissue increase in the presence of PAI-1 neutralizing antibodies. Simvastatin acts at several levels in the protein cascade regulating PAI-1 levels. Thus, simvastatin-induced reduction of PAI-1 levels has a therapeutic potential by modulating the main processes involved in the creation of an inhospitable environment during the process of injury (fibrosis and cell migration). In this way, simvastatin modulates process such as migration, that plays a key role in homing and engraftment of cells after cell therapy. Due to this modulatory effect, research groups proposed the use of simvastatin as an adjuvant in different cell therapy approaches. These observations allow the proposition of the potential use of simvastatin, and possibly other statins, as an adjuvant in cell therapy, due to a mechanism of action that acts in the tissue microenvironment, promoting a better efficiency of the homing and, as a consequence, an enhancement of the paracrine effects of the stem cells in the process of tissue regeneration.

Effects of a diet containing Brazilian propolis on lipopolysaccharide-induced increases in plasma plasminogen activator inhibitor-1 levels in mice.

BACKGROUND: Brazilian propolis has many biological activities including the ability to help prevent thrombotic diseases, but this particular effect has not been proven. Plasma levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, increase under inflammatory conditions such as infection, obesity and atherosclerosis and such elevated levels predispose individuals to a risk of developing thrombotic diseases. AIM: This study aimed to determine the effects of a diet containing Brazilian propolis on lipopolysaccharide (LPS)-induced increases in plasma PAI-1 levels. MATERIALS AND METHODS: Mice were fed with a diet containing 0.5% (w/w) Brazilian propolis for 8 weeks. Thereafter, the mice were subcutaneously injected with saline containing 0.015 mg/kg of LPS and sacrificed 4 h later. RESULTS: Orally administered Brazilian propolis significantly suppressed the LPS-induced increase in PAI-1 antigen and its activity in mouse plasma. CONCLUSION: This study indicated that Brazilian propolis contains natural products that can decrease thrombotic tendencies in mice.

Obesity and diabetes: the link between adipose tissue dysfunction and glucose homeostasis.

Obesity and type 2 diabetes mellitus (T2DM) epidemics, which have already spread, imply the possibility of both conditions being closely related. Thus, the goal of the present review was to draw a parallel between obesity, adipose tissue (AT) changes, and T2DM development. To this end, a search was conducted in PubMed, MEDLINE and SciELO databases, using the following key words and their combinations: obesity; diabetes; insulin resistance; diet; weight loss; adipocin; inflammation markers; and interleukins. Based on a literature review, AT dysfunction observed in obesity is characterised by adipocyte hypertrophy, macrophage infiltration, impaired insulin signalling and insulin resistance. In addition, there is release of inflammatory adipokines and an excessive amount of NEFA promoting ectopic fat deposition and lipotoxicity in muscle, liver and pancreas. Recent evidence supports the hypothesis that the conception of AT as a passive energy storage organ should be replaced by a dynamic endocrine organ, which regulates metabolism through a complex adipocyte communication with the surrounding microenvironment. The present review demonstrates how glucose homeostasis is changed by AT dysfunction. A better understanding of this relationship enables performing nutritional intervention strategies with the goal of preventing T2DM.

Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice.

The objective of this study was to investigate the impact of elevated tissue omega-3 (n-3) polyunsaturated fatty acids (PUFA) status on age-related glucose intolerance utilizing the fat-1 transgenic mouse model, which can endogenously synthesize n-3 PUFA from omega-6 (n-6) PUFA. Fat-1 and wild-type mice, maintained on the same dietary regime of a 10% corn oil diet, were tested at two different ages (2 months old and 8 months old) for various glucose homeostasis parameters and related gene expression. The older wild-type mice exhibited significantly increased levels of blood insulin, fasting blood glucose, liver triglycerides, and glucose intolerance, compared to the younger mice, indicating an age-related impairment of glucose homeostasis. In contrast, these age-related changes in glucose metabolism were largely prevented in the older fat-1 mice. Compared to the older wild-type mice, the older fat-1 mice also displayed a lower capacity for gluconeogenesis, as measured by pyruvate tolerance testing (PTT) and hepatic gene expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase). Furthermore, the older fat-1 mice showed a significant decrease in body weight, epididymal fat mass, inflammatory activity (NFκ-B and p-IκB expression), and hepatic lipogenesis (acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) expression), as well as increased peroxisomal activity (70-kDa peroxisomal membrane protein (PMP70) and acyl-CoA oxidase1 (ACOX1) expression). Altogether, the older fat-1 mice exhibit improved glucose homeostasis in comparison to the older wild-type mice. These findings support the beneficial effects of elevated tissue n-3 fatty acid status in the prevention and treatment of age-related chronic metabolic diseases.

Associação de níveis plasmáticos de PAI-1 e polimorfismo 4G/5G em pacientes com doença arterial coronariana / PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease

FUNDAMENTO: O polimorfismo 4G/5G do inibidor ativador do plasminogênio tipo 1 (PAI-1) pode influenciar a expressão do PAI-1. Níveis plasmáticos elevados de PAI-1 estão associados com Doença Arterial Coronariana (DAC). OBJETIVO: O presente estudo investigou a influência do polimorfismo 4G/5G do PAI-1 nos níveis plasmáticos de PAI-1 e sua associação com DAC avaliada por angiografia coronária. MÉTODOS: Foi avaliada amostra de sangue de 35 indivíduos com artérias coronárias angiograficamente normais, 31 indivíduos apresentando ateromatose leve/moderada, 57 indivíduos apresentando ateromatose grave e 38 indivíduos saudáveis (controles). Em pacientes e controles, o polimorfismo 4G/5G do PAI-1 foi determinado por amplificação da proteína-C reativa utilizando primers específicos de alelo. Os níveis plasmáticos de PAI-1 foram quantificados pelo ensaio ELISA (American Diagnostica). RESULTADOS: Não houve diferença entre os grupos quanto a sexo, idade e índice de massa corporal. Níveis plasmáticos de PAI-1 e frequência do genótipo 4G/4G mostravam-se significativamente maiores no grupo com ateromatose grave em comparação com os outros grupos (p < 0,001). Além disso, os pacientes com genótipo 4G/4G (r = 0,28, p < 0,001) apresentaram níveis plasmáticos de PAI-1 significativamente maiores do que aqueles com o genótipo 5G/5G (r = 0,02, p = 0,4511). Além disso, em um modelo de regressão logística múltipla, ajustado para todas as outras variáveis, o PAI-1 esteve independentemente associado com DAC > 70 por cento (p < 0,001). CONCLUSÃO: O achado mais importante deste estudo foi a associação entre o genótipo 4G/4G, elevados níveis plasmáticos de PAI-1 e estenose coronariana superior a 70 por cento em indivíduos brasileiros. Ainda não foi estabelecido se elevados níveis plasmáticos de PAI-1 são um fator decisivo para o agravamento da aterosclerose ou se são uma consequência.

BACKGROUND: Type-1 plasminogen activator inhibitor (PAI-1) 4G/5G polymorphism may influence the PAI-1 expression. High plasma levels of PAI-1 are associated with coronary artery disease (CAD). OBJECTIVE: This study investigated the influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and its association with CAD assessed by coronary angiography. METHODS: Blood sample of 35 individuals with angiographycally normal coronary arteries, 31 individuals presenting mild/moderate atheromatosis, 57 individuals presenting severe atheromatosis and 38 healthy individuals (controls) were evaluated. In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Plasma PAI-1 levels were quantified by ELISA assay (American Diagnostica). RESULTS: No difference was found between groups regarding age, gender and body mass index. Plasma PAI-1 levels and 4G/4G genotype frequency were significantly higher in the severe atheromatosis group compared to the other groups (p<0.001). Furthermore, patients with 4G/4G genotype (r=0.28, p<0.001) had significantly higher plasma PAI-1 levels than those with 5G/5G genotype (r=0.02, p=0.4511). In addition, in a multiple logistic regression model, adjusted for all the other variables, PAI-1 was observed to be independently associated with CAD > 70 percent (p<0.001). CONCLUSION: The most important finding of this study was the association between 4G/4G genotype, high plasma PAI-1 levels and coronary stenosis higher than 70 percent in Brazilian individuals. Whether high plasma PAI-1 levels are a decisive factor for atherosclerosis worsening or it is a consequence remains to be established.

The effect of thyroid hormones on the white adipose tissue gene expression of PAI-1 and its serum concentration

Metabolic syndrome is associated with an increased risk of developing cardiovascular diseases and Plasminogen activator inhibitor 1 (PAI-1) overexpression may play a significant role in this process. A positive correlation between adipose tissue gene expression of PAI-1 and its serum concentration has been reported. Furthermore, high serum levels of thyroid hormones (T3 and T4) and PAI-1 have been observed in obese children. The present study evaluates the impact of thyroid hormone treatment on white adipose tissue PAI-1 gene expression and its serum concentration. Male Wistar rats (60 days old) were treated for three weeks with T4 (50 µg/day, Hyper) or with saline (control). Additionally, 3T3-L1 adipocytes were treated for 24 h with T4 (100 nM) or T3 (100 nM). PAI-1 gene expression was determined by real-time PCR, while the serum concentration of PAI-1 was measured by ELISA using a commercial kit (Innovative Research, USA). Both the serum concentration of PAI-1 and mRNA levels were similar between groups in retroperitoneal and epididymal white adipose tissue. Using 3T3-L1 adipocytes, in vitro treatment with T4 and T3 increased the gene expression of PAI-1, suggesting non-genomic and genomic effects, respectively. These results demonstrate that thyroid hormones have different effects in vitro and in vivo on PAI-1 gene expression in adipocytes.