Preliminary study of PPARA regulate the ferroptosis of hepatocellular carcinoma to prevent disease deterioration / 中华预防医学杂志

To explore whether PPARA is involved in the process of ferroptosis in hepatoma cells, peroxisome proliferator activated receptor (PPARA) was comprehensively analyzed in hepatocellular carcinoma (HCC) through public database and experimental data, including the expression, the functions and the potential roles of tumor progression. The research design is experimental research,data analysis based on bioinformatics and cell experiment. From January 2022 to August 2022, relevant cell experiments were conducted in the Basic Medical Laboratory of the General Hospital of the Southern Theatre of the Chinese People's Liberation Army. The expression and the correlation with clinicopathologic features of PPARA in HCC were analyzed by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To study the protein expression of PPARA in HCC and normal tissues through the Human Protein Atlas (HPA). The protein-protein interaction (PPI) network between PPARA and the core factor of ferroptosis was constructed based on Search Tool for the Retrival of Interacting Genes/Protein (STRING) database, then, the correlation between PPARA and the core gene Glutamate-cysteine Ligase Catalytic Subunit (GCLC) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Assessed the expression of PPARA in HCC cell lines SK-HEP-1, SMMC-7721, MHCC-97H, BEL-7402 and normal liver cell L02 by Western Blot (WB) and the changes of PPARA expression after 48h treatment with ferroptosis inducer Erastin were observed. Single factor analysis of variance was used to compare the expression of PPARA between groups in GEPIA database. The expression of PPARA in GSE25097 and GSE112790 data was compared by rank sum test. Survival analysis was performed using time series test method. The difference of PPARA expression between clinical and pathological features was compared using the Kruskal-Wallis test. The correlation between the expression of GCLC and PPARA was compared by the method of Spearman correlation. The expression of PPARA in cell lines was compared by paired T test. The results showed that the RNA and protein expression of PPARA in HCC was lower than that in normal tissues (P<0.05). PPARA alterations were correlated with patient clinicopathological features and prognosis (P<0.05). The PPI constructed by STRING database suggests that PPARA interact with the key factors of ferroptosis, such as NFE2 like bZIP transcription factor 2 (NFE2L2), Heme Oxygenase 1 (HMOX1), Tumor Protein P53 (TP53), GCLC, Dipeptidyl Peptidase 4 (DPP4), Citrate Synthase (CS), Arachidonate 15-Lipoxygenase (ALOX15) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4). Furthermore, the PPARA was significantly associated with GCLC validated via GEPIA database(R=0.6, P<0.05). The expression of PPARA increased after treatment with ferroptosis inducer Erastin for 48 h by WB. In conclusion, the expression of PPARA is lower in HCC with a poor prognosis. PPARA interacts with GCLC in regulating ferroptosis in HCC.

Bone Marrow Adipocytes Promote the Survival of Multiple Myeloma Cells and Up-Regulate Their Chemoresistance / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of adipocytes in the bone marrow microenvironment of patients with multiple myeloma (MM) on the pathogenesis of MM.@*METHODS@#Bone marrow adipocytes (BMA) in bone marrow smears of health donors (HD) and newly diagnosed MM (ND-MM) patients were evaluated with oil red O staining. The mesenchymal stem cells (MSC) from HD and ND-MM patients were isolated, and in vitro co-culture assay was used to explore the effects of MM cells on the adipogenic differentiation of MSC and the role of BMA in the survival and drug resistance of MM cells. The expression of adipogenic/osteogenic differentiation-related genes PPAR-γ, DLK1, DGAT1, FABP4, FASN and ALP both in MSC and MSC-derived adipocytes was determined with real-time quantitative PCR. The Western blot was employed to detect the expression levels of IL-6, IL-10, SDF-1α, TNF-α and IGF-1 in the supernatant with or without PPAR-γ inhibitor.@*RESULTS@#The results of oil red O staining of bone marrow smears showed that BMA increased significantly in patients of ND-MM compared with the normal control group, and the BMA content was related to the disease status. The content of BMA decreased in the patients with effective chemotherapy. MM cells up-regulated the expression of MSC adipogenic differentiation-related genes PPAR-γ, DLK1, DGAT1, FABP4 and FASN, but the expression of osteogenic differentiation-related gene ALP was significantly down-regulated. This means that the direct consequence of the interaction between MM cells and MSC in the bone marrow microenvironment is to promote the differentiation of MSC into adipocytes at the expense of osteoblasts, and the cytokines detected in supernatant changed. PPAR-γ inhibitor G3335 could partially reverse the release of cytokines by BMA. Those results confirmed that BMA regulated the release of cytokines via PPAR-γ signal, and PPAR-γ inhibitor G3335 could distort PPAR-γ mediated BMA maturation and cytokines release. The increased BMA and related cytokines effectively promoted the proliferation, migration and drug resistance of MM cells.@*CONCLUSION@#The BMA and its associated cytokines are the promoting factors in the survival, proliferation and migration of MM cells. BMA can protect MM cells from drug-induced apoptosis and plays an important role in MM treatment failure and disease progression.

Neither polyphenol-rich red wine nor fenofibrate affects the onset of type-1 diabetes mellitus in the BB rat / 한국실험동물학회지

Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when β-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted β-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances.

Sex-specific regulation of immune responses by PPARs

The prevalence of autoimmune, infectious and metabolic diseases is different for men and women owing to the respective ability of their immune systems to respond to self and foreign antigens. Although several factors, including hormones and the X-chromosome, have been suggested to contribute to such sex-specific immune responses, the underlying factors remain poorly defined. Recent studies using peroxisome proliferator-activated receptor (PPAR) ligands and knockout mice have identified sex-dimorphic expression of PPARs, and have shown that the inhibitory functions of PPAR in T cells are substantially affected by the sex hormones. In this review, we consider the sex-specific differences in PPARs and summarize the diverse PPAR-mediated, sex-specific properties of effector T-cell responses, such as T-cell activation, survival and differentiation, as well as their involvement in T-cell-related autoimmune diseases, including colitis, graft-versus-host disease and experimental autoimmune encephalomyelitis. Understanding PPAR-mediated sex differences in immune responses will provide more precise insights into the roles of PPARs in effector T cells.

Efecto del ciprofibrato sobre el metabolismo del colesterol HDL y la capacidad antioxidante plasmática en el ratón / Effect of ciprofibrate on HDL cholesterol metabolism and plasma anti-oxidant capacity in mice

Antecedentes: Las dislipidemias, ya sea un aumento en los niveles de colesterol LDL y/o una disminución en las cifras de colesterol HDL, son muy relevantes para el desarrollo de la enfermedad cardiovascular ateroesclerótica, siendo el colesterol HDL bajo la dislipidemia más frecuente en la población chilena. Con respecto al colesterol HDL bajo y los tri -glicéridos elevados, los fibratos, agonistas del receptor nuclear PPAR-a que modula la transcripción de genes involucrados en el metabolismo de lípidos, representan una importante alternativa de manejo farmacológico de las dislipidemias. Sin embargo, estudios clínicos recientes no han sido concluyentes con respecto a su beneficio real sobre el control de la ateroesclerosis cuando se usan combinados con estatinas. Objetivo: Evaluar el impacto de la administración de fibratos sobre el metabolismo del colesterol HDL y la función antioxidante del plasma usando el ratón como modelo experimental. Metodología: Los ratones de la cepa C57BL/6 fueron tratados con ciprofibrato al 0,2% en dieta control durante 7 días. Luego del tratamiento, se analizaron los niveles de colesterol plasmático y triglicéridos, la expresión hepática de proteínas claves involucradas en el metabolismo de colesterol HDL, el contenido de colesterol hepático, la secreción de colesterol biliar y el daño oxidativo y la función antioxidante plasmática. Resultados: El tratamiento con ciprofibrato disminuyó significativamente los niveles de triglicéridos plasmáticos y la expresión hepática del receptor de HDL SR-BI, efecto que se correlacionó con un aumento en el tamaño de las partículas de HDL, pero no en los niveles de colesterol HDL. Además, el ciprofibrato disminuyó los niveles proteicos de los transportadores de colesterol ABCG1 y ABCG8, aunque no modificó ABCA1, en conjunto con una reducción del contenido hepático de colesterol y un aumento en la secreción de colesterol hacia la bilis. Finalmente, el uso de este hipolipemiante mejoró la función antioxidante del plasma, aunque se detectó un aumento en el daño nitrosativo de las proteínas plasmáticas. Conclusión: Este estudio ha permitido obtener nueva información sobre el efecto metabólico y funcional de la administración de fibratos en ratones, lo cual podría ayudar comprender los resultados de estudios clínicos recientes que han usado esta clase de hipolipemiantes en humanos.

Background: Increased serum levels of LDL cholesterol and/or decreased values of HDL cholesterol are very relevant for atherosclerotic cardiovascular disease. Low HDL cholesterol is the most prevalent dyslipidemia in the Chilean population. Regarding reduced HDL cholesterol and high triglyceride levels, fibrates, nuclear receptor PPAR-a agonists that modulate transcription of genes involved in lipid metabolism, represent an important alternative for pharmacological management of dyslipidemia. However, recent clinical studies have been inconclusive with respect to their real benefit on atherosclerosis when used in combination with statins. Aim: To evaluate the impact of fibrate administration on HDL cholesterol metabolism and antioxidant plasma functionality using the mouse as experimental model. Methodology: Using wild-type C57BL/6 mice, ciprofibrate was administered at 0.2% in chow diet for 7 days. After treatment, plasma cholesterol and triglycerides levels, hepatic expression of key proteins involved in HDL cholesterol metabolism, liver cholesterol content, biliary cholesterol secretion, and plasma oxidative damage and antioxidant function were analyzed. Results: Ciprofibrate treatment significantly decreased plasma triglycerides levels and hepatic HDL receptor SR-BI expression. This latter finding was associated with increased HDL particle size, without changes in HDL cholesterol levels. Furthermore, ci-profibrate decreased hepatic expression of cholesterol transporters ABCG1 and ABCG8, but not ABCA1, which correlated with reduced liver cholesterol content and increased biliary cholesterol secretion. Fina-lly, fibrate therapy improved plasma antioxidant func-tion, even though increased nitrosative plasma protein damage was detected. Conclusion: This study has provided new information on metabolic and functional effects derived from fibrate use in mice and it may help to better understand recent clinical findings using this lipid-lowering drug class in humans.

Effect of Fibroblast Growth Factor-2 and Retinoic Acid on Lineage Commitment of Bone Marrow Mesenchymal Stem Cells

In this study, we examined the effect of a combination of fibroblast growth factor-2 (FGF-2) and retinoic acid (RA) on osteoblast and adipocyte lineage commitment and differentiation of human bone marrow mesenchymal stem cells (BMSCs). Pretreatment of human BMSCs with FGF-2 or RA for 5 days followed by osteoblast differentiation induction showed high calcium deposition compared to control. A combination of FGF-2 and RA further induced calcium deposition compared to FGF-2 or RA alone. The enhanced mineral deposition was accompanied with the increased expression of osteoblast differentiation markers, alkaline phosphatase and osteocalcin. On the other hand, FGF-2 pretreatment followed by adipocyte differentiation induction also showed increased formation of lipid droplets in human BMSCs, whereas RA pretreatment suppressed formation of lipid droplets. However, a combination of FGF-2 and RA increased formation of lipid droplets and expression of adipocyte marker genes, including adiponectin, ADIPOQ, FABP4, peroxisome proliferator-activated receptor γ (PPARγ), and C/EBPα. During pretreatment of BMSCs with FGF-2, RA or in combination, the cells expressed similar levels of MSC surface markers such as CD29, CD44, CD90, and CD105, indicating that they maintain stem cell potential. To determine how RA cooperates with FGF-2 in osteoblast and adipocyte lineage commitment, the expression of RA receptors and intracellular lipid-binding proteins was examined. A combination of FGF-2 and RA strongly induced the expression of RA receptor α, β, γ, PPAR β/δ, CRABP-II, and FABP5. Collectively, these results demonstrate that combined pretreatment of human BMSCs with FGF-2 and RA enhances the commitment into osteoblast and adipocyte lineages through modulation of the expression of RA-related genes.

Research progress on active ingredients of traditional Chinese medicines improved insulin resistance based on PPARs targets / 中国中药杂志

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcriptional factors closely related to glucose and lipid metabolism, insulin sensitivity. Activation of PPARs targets treated type 2 diabetes, obesity, hypertension and other metabolic diseases by insulin resistance. Recently, a variety of active ingredients of traditional Chinese medicines (TCMs) have been proved to activate PPARs targets for improving insulin resistance, which has attracted widespread attention at home and abroad. In this paper, we reviewed the pathological mechanisms between insulin resistance and PPARs, and summarized the active ingredients of TCMs improved insulin resistance based on PPARs targets. This paper may provide some theoretical guidance for the development of new drugs and TCMs.

Effects of fenofibrate on hepatocyte apoptosis in nonalcoholic fatty liver / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To use a rat model of nonalcoholic liver disease (NAFLD) to observe effects of the peroxisome proliferator-activated receptor-a (PPAR-a) agonist fenofibrate on hepatic steatosis in nonalcoholic fatty liver and to investigate the underlying mechanism.</p><p><b>METHODS</b>Sixty-six Sprague-Dawley rats were given adaptive feeding for 1 week and then randomly allocated into the following three groups: unmodeled control (group C,n =18), untreated NAFLD model (group M, n =24), and fenofibrate-treated NAFLD model (group F, n =24).Group C rats were given a normal diet, while group M and group F rats were given a high-fat diet. After model establishment, the group F rats were treated with fenofibrate (10 mg/kg/d, intraperitoneal) and the group C and group M rats were given sham-treatment with cosolvent (5 mL/kg/d, intraperitoneal). At the end of treatment weeks 4, 6 and 8, one-third of rats in each group were euthanized.Liver tissues were assessed by hematoxylin-eosin (HE) staining to determine level of steatosis and inflammaion activity, and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling to measure changes in hepatocyte apoptosis index. Changes in expression levels of the PPAR-a receptor and apoptosis factors (bcl-2, bax and caspase-3) were assessed by reverse transcription-PCR and immunohistochemistry.</p><p><b>RESULTS</b>The NAFLD modeled rats showed appropriate induction of hepatic steatosis, hepatic inflammation, and hepatocyte apoptosis. Compared to the group M rats, the group F rats showed lower expression of PPAR-and bcl-2 and higher expression of bax and caspase-3 at both the mRNA and protein level.</p><p><b>CONCLUSION</b>Fenofibrate can ameliorate hepatic steatosis in an experimental rat model of NAFLD, and the mechanism may be associated with inhibition of hepatocyte apoptosis.</p>

Association and interaction between 10 SNP of peroxisome proliferator-activated receptor and non-HDL-C / 中华预防医学杂志

<p><b>OBJECTIVE</b>To examine the main effect of 10 Peroxisome proliferators-activated receptor (PPAR) SNP in contribution to non-HDL-C and study whether there is an interaction in the 10 SNPs.</p><p><b>METHODS</b>Participants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort-population-survey, which was initiated from April 1999 to June 2004, and 5-year follow-up data from total 4 582 subjects were obtained between March 2006 and October 2007. A total of 4 083 participants received follow-up examination. After excluding subjects who had experienced stroke or exhibited cardiovascular disease, type 2 diabetes or a BMI <18.5 kg/m(2), a total of 820 unrelated individual subjects were selected from 3 731 subjects on October of 2009. Blood samples which were collected at the baseline were subjected to PPARα, PPARδ and PPARγ 10 SNPs genotype analysis. Logistic regression model was used to examine the association between 10 SNPs in the PPARs and non-HDL-C. Interactions within the 10 SNP were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR).</p><p><b>RESULTS</b>A total of 820 participants (mean age was 50.05±9.41) were included in the study and 270 were males and 550 were females. Single-locus analysis showed that after adjusting gender, age, smoking, alcohol consumption, physical activity, high-fat diet and low-fiber diet factors, rs1800206-V and rs3856806-T were significantly associated with higher non-HDL-C levels. V allele (LV + VV genotype) carriers of rs1800206 have a average non-HDL-C levels on (3.15 ± 0.89)mg/L (F = 15.01, P = 0.002); T allele (CT+TT genotype) carriers of rs3856806 have a average non-HDL-C levels on (3.03±1.01) mg/L (F = 9.87, P = 0.005). GMDR model analysis showed that after adjusting the same factors, two-locus model, five-locus model, six-locus model and seven-order interaction models were all statistically significant (P<0.05), and the seven-locus model (rs1800206, rs3856806, rs135539, rs4253778, rs2016520, rs1805192, rs709158) was the best model (P = 0.001), the cross-validation consistency was 10/10 and testing accuracy was 0.656.</p><p><b>CONCLUSION</b>Rs1800206 and rs3856806 were significantly associated with non-HDL-C. And there was an gene-gene interaction among rs1800206, rs3856806, rs1800206, rs135539, rs4253778, rs2016520, rs1805192, rs3856806 and rs709158 which could influence the non-HDL-C levels.</p>

Effect of apigenin on protein expressions of PPARs in liver tissues of rats with nonalcoholic steatohepatitis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the effect of apigenin on the protein expression levels of peroxisome proliferator-activated receptors (PPARs) in liver tissues of rats with nonalcoholic steatohepatitis (NASH).</p><p><b>METHODS</b>The NASH rat model was established by feeding of a high-fat diet. Unmodeled rats served as the normal controls. The modeled rats were divided into a model control group, Essentiale treatment grouP(300 mg/kg/day),and three apigenin treatment groups for low-dose (15 mg/kg/day), moderate-dose (30 mg/kg/day) and high-dose (60 mg/kg/day). After 13 weeks of treatment,changes in insulin sensitivity from pre-treatment baseline were assessed by measuring the alanine aminotransferase (ALT), aspartate aminotransferase (AST),total cholesterol (TC),triglycerides (TG),low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C),fasting blood glucose (FBG) and fasting insulin (FINS).The liver index and HOMA-IR were also calculated.Protein and gene expression of PPARα and PPARgamma in liver tissue were assessed by immunohistochemistry and RT-PCR.Statistical analysis was performed by the LSD test and Games-Howell test.</p><p><b>RESULTS</b>The apigenin-treated groups showed a significantly greater change in insulin sensitivity than the untreated model group,with the most significant change occurring in the high-dose grouP(P less than 0.05).Compared with the untreated model group,the apigenin-treated groups showed lower levels of ALT (95.4+/-7.3),AST (183.7+/-14.3),TC (1.61+/-0.25),TG (1.23+/-0.21),LDL-C (1.86+/-0.14),FBG (5.29+/-1.45) and FINS (0.76+/-0.86),but a higher level of HDL-C (1.04+/-0.17); again,the high-dose group showed the greatest change (all P less than 0.05).Compared to the untreated model group,the apigenin-treated groups showed significantly lower liver index (3.75+/-0.25 vs.2.90+/-0.17) and HOMA-IR (1.34+/-0.06 vs.0.18+/-0.04),with the high-dose group showing the greatest change (both P less than 0.05). Compared to the untreated model group,the apigenin-treated groups showed higher levels of protein and mRNA of PPARα (18.27+/-4.05 and 0.63+/-0.02,respectively) and PPARgamma(8.48+/-5.05 and 0.39+/-0.02),with the high-dose group showing the greatest change (all P < 0.05).</p><p><b>CONCLUSION</b>Apigenin can improve glucose tolerance,lipid metabolism and insulin resistance while decreasing blood levels of TC,TG,LDL-C,FBG,FINS and HOMA-IR,and increasing HDL-C in NASH,as shown in a high-fat diet induced rat model, and may have therapeutic potential.</p>

Design, synthesis and antidiabetic activity of novel tetrahydrocarboline PPAR regulators / 药学学报

A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.

Peroxisome Proliferator-Activated Receptor (PPAR) alpha/gamma Agonist / 대한내과학회지

Peroxisome proliferator-activated receptor (PPAR) agonists improve glucose control and insulin sensitivity, reduce concentrations of atherogenic lipoproteins, and decrease circulating levels of inflammatory mediators. PPAR activation is considered an important pharmacologic target for patients with type 2 diabetes. However, the PPAR agonists in clinical use have undesirable side effects, including weight gain, heart failure, and bone fractures. PPAR alpha/gamma dual agonists each target one or more of the key cardiometabolic risk factors of diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation; thus, combining their benefits to provide glucose control and ameliorate cardiovascular risks has emerged as an attractive treatment option. Aleglitazar, which was designed to balance the activation of PPAR alpha/gamma, proved efficacious in improving glycemic control and lipid homeostasis and is anticipated to minimize PPAR-related side effects. Whether the effects of aleglitazar on cardiometabolic risk factors translate into improved cardiovascular outcomes, particularly in high-risk patients, is currently being evaluated by AleCardio, a large, long-term, time-, and event-driven outcome study of type 2 diabetics with recent acute coronary syndrome.

Anti-Inflammatory and PPAR Transactivational Effects of Oleanane-Type Triterpenoid Saponins from the Roots of Pulsatilla koreana

In this study, 23 oleanane-type triterpenoid saponins were isolated from a methanol extract of the roots of Pulsatilla koreana. The NF-kappaB inhibitory activity of the isolated compounds was measured in TNFalpha-treated HepG2 cells using a luciferase reporter system. Compounds 19-23 inhibited TNFalpha-stimulated NF-kappaB activation in a dose-dependent manner, with IC50 values ranging from 0.75-8.30 microM. Compounds 19 and 20 also inhibited the TNFalpha-induced expression of iNOS and ICAM-1 mRNA. Moreover, effect of the isolated compounds on PPARs transcriptional activity was assessed. Compounds 7-11 and 19-23 activated PPARs the transcriptional activity significantly in a dose-dependent manner, with EC50 values ranging from 0.9-10.8 microM. These results suggest the presence of potent anti-inflammatory components in P. koreana, and will facilitate the development of novel anti-inflammatory agents.

Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts

Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 +/- 8.9 years; body mass index, 24.6 +/- 3.2 kg/m2). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 x 10(-6)), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 x 10(-7), Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS.

Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis / Os receptores ativados pelo proliferador de peroxissoma (PPAR): uma perspectiva promissora na conducao da psoriase e artrite psoriasica

Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis.

A psoríase é uma doença poligênica, inflamatória, progressiva e recorrente, caracterizada por um ciclo evolutivo acelerado dos queratinócitos, associado à ativação imune desordenada e a alterações sistêmicas correlacionadas, sendo a artrite psoriásica o comprometimento articular inflamatório crônico que pode ocorrer em pacientes com a doença cutânea. Na inflamação autoimune, uma rede interativa entre células e citocinas suporta o início e a perpetuação da doença. A fisiopatologia da psoríase e da artrite psoriásica compreende uma disfunção das células do sistema imune e da rede de citocinas, levando à inflamação de pele, enteses e articulações. Estudos recentes têm demonstrado um papel importante da inflamação sistêmica no desenvolvimento da aterosclerose. Corroborando esses achados, pacientes portadores de psoríase grave apresentam marcada incidência de artrite psoriásica, doença cardiovascular, hipertensão arterial sistêmica, dislipidemia, obesidade e diabetes mellitus, evidenciando um risco aumentado para infarto agudo do miocárdio e sugerindo que a doença não se restringe à pele. Os receptores nucleares são fatores de transcrição ligante-dependente cuja ativação afeta genes controladores de processos vitais. Entre eles, destacam-se os receptores ativados pelo proliferador de peroxissoma, responsáveis por estabelecer a relação entre os lipídios, doenças metabólicas e imunidade inata. Na pele, os receptores ativados pelo proliferador de peroxissoma têm ação importante na homeostase dos ceratinócitos, exibindo uma função pró-diferenciação, antiproliferativa e imunomoduladora, sugerindo um papel relevante ...

Efeito do agonista PPAR LYSO-7 sobre a instalação e cicatrização de úlceras gástricas induzidas em camundongos / Effect of PPAR agonist LYSO-7 on installation and healing of gastric ulcers induced in mice

A úlcera gástrica é uma doença crônica, de alta prevalência, e a eficácia dos tratamentos farmacológicos disponíveis é limitada pela alta incidência de efeitos adversos. Neste trabalho é mostrado o mecanismo de ação terapêutica e os efeitos toxicológicos da molécula indol-tiazolidínica LYSO-7 em diferentes modelos experimentais de úlcera gástrica. Camundongos Swiss machos foram tratados com veículo, LYSO-7 (5, 25 ou 50 mg/kg, v.o.) ou bezafibrato (25 ou 50 mg/kg, v.o.) 1 hora antes da administração oral de Et/HCl (60%/0,03 M) ou indometacina (100 mg/kg). Em outro conjunto de ensaios, animais foram pré-tratados com GW9962, um antagonista PPARγ (2 mg/kg, i.p.); anticorpo anti-granulócito (50 µL, i.p.), ou L-NAME (70 mg/kg, i.p) 1 hora antes dos tratamentos com veículo ou LYSO-7. Uma hora após administração da solução de Et/HCl, os neutrófilos foram quantificados no sangue e medula óssea, a rede microcirculatória gástrica foi estudada em in situ, utilizando a técnica de microscopia intravital; o tecido gástrico foi utilizado para quantificar a percentagem de área lesada, atividade da MPO, a expressão gênica e proteica de PPARγ, expressão proteica de iNOS e eNOS, e a atividade das enzimas catalase, SOD, GPx, GR e GST. Uma hora após a administração de indometacina, o tecido gástrico foi removido para avaliar a eficácia do tratamento e a secreção de mediadores inflamatórios. Ensaio de úlcera crônica, induzida por ácido acético, foi realizado em camundongos Balb/c WT ou ANXA1-/-, aplicando-se 20µL de ácido acético na camada subserosa do estômago e 24 horas após a indução, os animais foram tratados, uma vez ao dia, durante sete dias com LYSO-7 (50 mg/kg), bezafibrato (50 mg/kg) ou veículo. Foram realizados ensaios com macrófagos recrutados para o peritônio pela ação do tioglicolato de sódio (3%, i.p.) e com neutrófilos recrutados pela ação do glicogênio de ostra (1%, i.p.). Ensaios de toxicologia aguda, crônica e mutagenicidade também foram realizados. Os resultados obtidos mostram que o tratamento com LYSO-7 reduz a área lesada, o influxo de neutrófilos e a estase da rede microcirculatória provocada pela administração de Et/HCl. Os efeitos protetores foram revertidos em animais pré-tratados com GW9962, indicando a participação do PPARγ no efeito. O influxo de neutrófilos é determinante para a lesão, uma vez que a depleção destas células reduziu a ulceração gástrica, e indica que o bloqueio da mobilização de neutrófilos da medula óssea para o sangue e destes para o tecido lesado pela LYSO-7 pode ser um mecanismo de ação gastroprotetora desta molécula. A reversão da estase vascular na microcirculação, mas não o influxo de neutrófilos, é mediado pelo NO, pois o pré-tratamento com L-NAME aboliu os efeitos da LYSO-7 no restabelecimento do fluxo sanguíneo da microcirculação. Este efeito pode ser dependente da maior e menor expressão proteica de eNOS e iNOS, respectivamente. A LYSO-7 foi capaz de alterar favoravelmente a atividade das enzimas antioxidantes no tecido gástrico. Ainda, a LYSO-7 diminuiu a área lesada e reduziu a concentração de TNFα e aumentou a de IL-10 no tecido gástrico lesado pela indometacina. Na resolução do processo inflamatório, o tratamento com LYSO-7 diminuiu a percentagem de área lesada, aumentou a apoptose de neutrófilos e a eferocitose de neutrófilos por macrófagos peritoneais, inibiu a secreção de TNFα e aumentou a secreção de IL-10, TFG-1ß e VEGF para o sobrenadante de macrófagos em fagocitose. A resolução de lesão gástrica, bem como a indução da fagocitose pela LYSO-7 foi reduzida em animais ANXA1-/-. As investigações destes últimos dados mostraram a relação da ANXA1 e PPARγ, já que a expressão do receptor é reduzida em macrófagos obtidos de animais depletados de ANXA1. Os estudos toxicológicos mostraram que a LYSO-7 apresenta baixa toxicidade aguda e crônica in vivo, além de não ocasionar mutagenicidade em eritrócitos da medula óssea. Os dados obtidos mostram que a molécula LYSO-7 atua como agonista PPARγ na modulação da úlcera gástrica e modula a migração de neutrófilos e o fluxo sanguíneo na microcirculação. A transativação e transrepressão de eNOS e iNOS, respectivamente, o bloqueio da migração de neutrófilos para a lesão e a inibição da atividade de enzimas oxidativa, ativação de enzimas antioxidantes no epitélio gástrico e a inibição da secreção de mediadores inflamatórios parecem ser os mecanismos de ação da LYSO-7 na citoproteção gástrica. Adicionalmente, a LYSO-7 atua na resolução do processo inflamatório promovendo downregulation na secreção de mediadores inflamatórios, aumento na apoptose de neutrófilos e eferocitose de neutrófilos apoptóticos

Gastric ulcer is a chronic disease that presents high prevalence, and effectiveness of pharmacological treatments available is limited by several adverse effects. In this study is shown the mechanism of action and toxicological effects of the molecule indole-thiazolidine LYSO-7 in different models of gastric ulcer. Male Swiss mice were treated with vehicle LYSO-7 (5, 25, or 50 mg/kg, p.o.) or bezafibrate (25 or 50 mg/kg, p.o.) 1 hour before the oral administration of Et/HCl (60%/0.03 M) or indomethacin (100 mg/kg). In another set of assays, animals were pre-treated with GW9962, a PPARγ antagonist (2 mg/kg, i.p.), anti-granulocyte antibody (50 µL, i.p.) or L-NAME (70 mg/kg, i.p.) 1 hour before the treatment with vehicle or LYSO-7. One hour after administration of the Et/HCl solution, neutrophils were quantified in the blood and bone marrow, the gastric microcirculatory network was studied in situ by intravital microscopy, in the gastric tissue were quantified the percentage of injured area, MPO activity, PPARγ gene and protein expression, iNOS and eNOS protein expression, and catalase, SOD, GPx, GR and GST activity. One hour after indomethacin administration, gastric tissue was removed to verify the efficacy of LYSO-7 on inflammatory mediator secretion. Chronic ulcer assay induced by acetic acid was carried out in Balb/c WT or ANXA1-/-, applying 20µL of acetic acid in the subserosal layer of the stomach and 24 hours after induction, animals were treated during seven days, once a day, with LYSO-7 (50 mg/kg), bezafibrate (50 mg/kg) or vehicle. Assays were performed with macrophages recruited to the peritoneum by sodium thioglycollate (3%, i.p.) and neutrophils by oyster glycogen (1%, i.p.). Acute and chronic toxicological and mutagenicity assays were also conducted. The results obtained show that LYSO-7 treatment decrease the injured area, neutrophil influx and microcirculatory stasis evoked by Et/HCl administration. Protective effects were reversed in animals pretreated with GW9962, indicating the involvement of PPARγ. Neutrophil influx is a determinant of the gastric lesion, once the depletion of these cells decreased the gastric damage, indicating that in the neutrophil mobilization blockade from the bone marrow to blood and to injured tissue may be a gastroprotective mechanism of LYSO-7. The vascular stasis reversion in the microcirculation is mediated by NO, but not the neutrophil influx, since the pretreatment with L-NAME abolished the effects of LYSO-7 on blood flow. This effect was dependent on increase and decrease of eNOS and iNOS protein expression, respectively. LYSO-7 positively altered the activity of antioxidant enzymes in the gastric tissue. Furthermore, LYSO-7 reduced the injured area and the concentration of TNFα and increased IL-10 in the gastric tissue in the indomethacin-induced ulcer model. In the resolution of inflammation, LYSO-7 treatment decreased the percentage of the injured area, increased the neutrophils apoptosis and the efferocytosis of apoptotic neutrophils by peritoneal macrophages, inhibited the TNFα release and increased the secretion of IL-10, IL-1ß and VEGF in the supernatant of phagocytosis assay. The resolution of gastric lesions, as well as, the induction of phagocytosis by LYSO-7 was reduced in animals ANXA1-/-. This data shown the relation of PPARγ and ANXA1, as PPARγ expression is reduced in macrophages obtained from ANXA1-/- animals. Toxicological studies showed that LYSO-7 has low acute and chronic toxicity in vivo, and did not cause mutagenicity in bone marrow erythrocytes. The data obtained show that LYSO-7 acts as PPARγ in the modulation of gastric ulcer and modulate neutrophil migration and blood flow in the microcirculation. The transactivation and transrepression of eNOS and iNOS, respectively, blocking the neutrophil influx into the injury, antioxidant enzymes activation in the gastric epithelium and inhibition of inflammatory mediators release seem to be the mechanisms action of LYSO-7 in gastric cytoprotection. Additionally, LYSO-7 operates in the resolution of inflammation promoting downregulation in the secretion of inflammatory mediators and increases the neutrophil apoptosis and efferocytosis of apoptotic neutrophils

Nitro-fatty acids: novel anti-inflammatory lipid mediators

Nitro-fatty acids are formed and detected in human plasma, cell membranes, and tissue, modulating metabolic as well as inflammatory signaling pathways. Here we discuss the mechanisms of nitro-fatty acid formation as well as their key chemical and biochemical properties. The electrophilic properties of nitro-fatty acids to activate anti-inflammatory signaling pathways are discussed in detail. A critical issue is the influence of nitroarachidonic acid on prostaglandin endoperoxide H synthases, redirecting arachidonic acid metabolism and signaling. We also analyze in vivo data supporting nitro-fatty acids as promising pharmacological tools to prevent inflammatory diseases.

Propriedades antiaterogênicas de novas tiazolidino-2, 4-dionas / Antiatherogenic properties of new thiazolidin-2, 4-diones

Tiazolidinadionas (TZDs) são agentes sensibilizadores de insulina que agem por ligação ao receptor gama ativado por proliferador de peroxissomos (PPARγ). Elas têm apresentado efeitos cardioprotetores em humanos e propriedades anti-aterogênicas em modelos animais. Estudos in vitro têm sugerido que esses efeitos anti-aterogênicos da ativação de PPARγ ocorrem por inibição da expressão de genes pro-inflamatórios e por aumentar o efluxo de colesterol via ativação dos receptores LXR-ABCA1. Entretanto, vários efeitos colaterais são associados ao tratamento com as TZDs, tornando necessária a pesquisa por novos compostos desta classe. Neste estudo, 14 novas tiazolidina-2,4- dionas, que são TZDs modificadas por bioisosterismo, foram avaliadas quanto à expressão de fatores aterogênicos e inflamatórios em linhagens de macrófagos J774 e RAW 264.7 e em camundongos com deleção genética para o receptor de LDL (LDLr-/-). Após a avaliação da citotoxicidade em macrófagos, foram eleitas cinco TZDs, denominadas de GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7. Três destas TZDs (GQ- 145, GQ-177 e LYSO-7) aumentaram significativamente a expressão de RNAm dos fatores de transcrição PPARγ1, PPARγ2 e do receptor CD36, assim como também aumentaram a expressão gênica de ABCA1 em 2.9, 3.5 e 6.7 vezes, respectivamente. Em adição, estas TZDs diminuíram a expressão gênica de iNOS, COX2, VCAM e IL-6 associado a redução na produção de nitritos, mas apenas a LYSO-7 reduziu significativamente a expressão desses genes quando comparada à rosiglitazona (RSG), além de diminuir a expressão da proteína-1 quimiotática para monócitos (MCP-1). No estudo experimental, os camundongos LDLr-/- machos foram alimentados com dieta hipercolesterolêmica por 16 semanas e quatro semanas antes da eutanásia receberam os derivados tiazolidínicos (20 mg/kg/dia) por gavagem. GQ-177 inibiu a progressão da placa aterosclerótica associada à aumento nas concentrações plasmáticas de HDL-C, com elevação na expressão de ABCA1, e redução da via inflamatória CD40-CD40L. LYSO-7 também mostrou inibição da aterogênese associada à redução das concentrações plasmáticas de colesterol total e triacilgliceróis, com diminuição na interação entre CD40-CD40L e expressão de citocinas inflamatórias. A GQ-145 não alterou os níveis plasmáticos dos lipídeos, mas aumentou a expressão de todos os genes pró-aterogênicos e pró-inflamatórios. Adicionalmente, as vias de ativação destas novas TZDs também foram estudadas por ensaio de luciferase, como gene repórter. A GQ-177 induziu ativação de PPARγ e ligação ao seu domínio, enquanto a LYSO-7 estimulou ativação de PPARα e PPARδ. Portanto, conclui-se que as novas TZDs, especialmente a GQ-177 e a LYSO-7, podem apresentar propriedades ateroprotetoras associadas ao transporte reverso de colesterol e aos efeitos antiinflamatórios, e poderiam ser uma alternativa promissora para o tratamento da aterosclerose. Porém, estudos complementares são requeridos para caracterizar as vias de sinalização intracelular, visto que as duas demonstraram ativar diferentes isotipos do fator de transcrição PPAR

Thiazolidinediones (TZDs) are insulin-sensitizing agents that act by binding to peroxisome proliferator-activated receptor-γ (PPARγ). They have been demonstrated to possess cardioprotective effects in humans and antiatherogenic properties in animal models. In vitro studies have also suggested that these antiatherogenic effects of PPARγ activation occur by inhibiting the inflammatory gene expression and by increasing cholesterol efflux via LXR-ABCA1 activation. However, several side effects are associated with TZDs treatment making necessary the search for new compounds. In this study, 14 new thiazolidine-2,4-diones, modified TZDs by bioisosterism, were tested for aterogenic and inflammtary factors in RAW 264.7 macrophages and in low-density lipoprotein receptor-deficient mice. After the citotoxicity evaluation in RAW 264.7 macrophages the TZDs named GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7 were selected for this study. Three of these TZDs (GQ-177, GQ-145 and LYSO-7) significantly increased the expression of PPARγ1, PPARγ2 and CD36 mRNA, and enhanced the expression of ABCA1 mRNA in 2.9, 3.5 and 6.7 fold, respectively. Moreover, they also significantly decreased the expression of iNOS, COX2, VCAM and IL-6 mRNA in relation to control, and these results are associated to reduction on nitrits concentration. In addition, LYSO-7 significantly reduced the expression of these genes when compared to rosiglitazone, and decreased expression of MCP1 mRNA. In the experimental study, male LDLr-/- mice were fed an atherogenic diet containing 0.5% cholesterol for 16 weeks, and 4 weeks before euthanasia they received TZDs (20mg/kg/ per day) by gavage. GQ-177 treatment inhibited progression of atherosclerotic plaque associated to increased plasma concentrations of HDL-C, with enhance of ABCA1 expression and reduction on CD40-CD40L interaction. LYSO-7 treatment also showed inhibition of the atherogenesis associated to decreased plasma concentrations of total cholesterol and TAG, with reduction on CD40-CD40L pathway and inflammatory cytokines expression.GQ-145 did not alter the lipid plasma levels and increased the expression of all pro-atherogenic and pro-inflammatory genes. Furthermore, the activation of PPARs has also been studied, by luciferase assay as reporter gene. GQ-177 induced activation of PPARγ, whereas LYSO-7 stimulated activation of PPARα and PPARß/δ. Altogether, our data suggest that the new TZDs derivatives, specially GQ- 177 and LYSO-7, may have atheroprotective properties associated with the reverse cholesterol transport and anti-inflammatory effects, and could be a promising alternative for the treatment of atherosclerosis. However, further studies are warranted in order to characterize the pathways of intracellular signaling since both have demonstrated to activate different isotypes of PPAR

Repercussões de variantes genéticas em componentes do sistema endocanabinoide e no receptor PPAR-α sobre o perfil de risco cardiometabólico, adipocitocinas e níveis plasmáticos de endocanabinoides em indivíduos com diferentes graus de adiposidade / Effects of genetic variants in components of the endocannabinoid system and the PPAR-α receptor on the cardiometabolic risk profile, adipocytokines and plasma endocannabinoid levels in subjects with varying degrees of adiposity

Analisar a associação recíproca entre fatores de risco cardiometabólico, níveis de adipocitocinas (leptina e adiponectina de alto peso molecular), endocanabinoides (anandamida [AEA] e 2-araquidonoilglicerol [2-AG]), compostos canabimiméticos (N-oleoiletanolamina [OEA] e N-palmitoiletanolamina [PEA]) e polimorfismos em genes codificadores de componentes do sistema endocanabinoide (enzima de degradação de endocanabinoides FAAH [gene FAAH] e receptor endocanabinoide CB1 [gene CNR1]) e do receptor PPAR-α[genePPARA], em indivíduos com diferentes graus de adiposidade. Duzentos indivíduos, entre 18 e 60 anos, com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, dividida em dois grupos: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC ≥30 kg/m2), com 50 homens e 50 mulheres em cada grupo. Os obesos ficaram assim distribuídos: grau 1, com IMC < 35 kg/m2(n=54), 27 homens e 27 mulheres; grau 2, com IMC < 40 kg/m2 (n=32), 16 homens e 16 mulheres e grau 3, com IMC ≥40 kg/m2(n=14), 7 homens e 7 mulheres. Todos os indivíduos foram recrutados entre funcionários, estudantes e residentes do Hospital Universitário Pedro Ernesto, bem como voluntários do quadro da Polícia Militar do Estado do Rio de Janeiro e selecionados com base em amostra de conveniência. Todos foram avaliados por parâmetros antropométricos, determinação da pressão arterial, análises laboratoriais e genotipagem, para determinar seu perfil metabólico, níveis de endocanabinoides e adipocitocinas e rastreamento dos polimorfismos FAAH385C>A, CNR13813A>G e PPARA484C>G. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas de qualquer natureza e em uso de medicação nos dez dias anteriores à entrada no estudo. A atividade inflamatória, avaliada pela proteína C reativa ultrassensível (PCRUS), acompanhou o grau de resistência insulínica...

To analyze the reciprocal association of cardiomet abolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAHgene] and endocannabinoid receptor CB1 [CNR1gene]) and the PPAR-α receptor (PPARAgene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI ≥30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2(n = 54), 27 men and 27 women; grade 2, with BMI between ≥35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI ≥40 kg/m2(n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH385C>A, CNR1 3813G>A and PPARA484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study.The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance...

Produtos naturais ativadores de PPAR e marcadores associados ao processo inflamatório na Síndrome Metabólica / The inflammatory process in the metabolic syndrome: PPAR activators of natural products and markers associated with metabolic disorders

O processo inflamatório é o elo entre a síndrome metabólica e as doenças cardiovasculares. Para verificar a presença e o grau da inflamação, vários biomarcadores têm sido propostos e investigados. Este trabalho tem como objetivo revisar as recentes pesquisas que associam alguns marcadores expressos no tecido adiposo, enfatizando, dentre eles, a adiponectina, a resistina, a leptina e o transportador de glicose GLUT-4 na síndrome metabólica, a relação da inflamação decorrente desse conjunto de desordens metabólicas sob os receptores proliferadores peroxissomais (PPARs), bem como o efeito de diferentes extratos vegetais e produtos naturais bioativos na ativação desses receptores.

The inflammatory process is the link between metabolic syndrome and cardiovascular diseases. To verify the presence and degree of inflammation, several biomarkers have been proposed and different receptors have been investigated. This study aims to review recent researches involving some markers expressed in the adipose tissue, emphasizing, among them, adiponectin, resistin, leptin and glucose transporter GLUT-4 in the metabolic syndrome, the relationship of inflammation arising from this set of metabolic disorders on the peroxisome proliferator receptors (PPARs) and the effect of different bioactive compounds in the activation of these receptors.