Efeitos da ativação do PPAR gama no reparo ósseo e na osseointegração de implantes dentários / Descriptive analysis of the effects of PPAR-gamma activation on bone repair and osseointegration of dental implants

Os receptores ativados por proliferadores de peroxissoma de isoforma gama (PPARgama) são fatores de transcrição que se encontram no entrelaçamento de várias vias metabólicas e determinam a gênese da obesidade e doenças associadas. Estudos recentes têm relatado o potencial dos medicamentos agonistas PPARs, usados no tratamento de doenças cardiovasculares e diabetes tipo 2, de afetar a função das células ósseas e o risco de fratura. O objetivo deste estudo foi avaliar os efeitos da ativação do PPAR-gama no processo de reparo ósseo e osseointegração de implantes dentários. Foram utilizados 42 ratos Wistar alimentados com ração sólida padrão para roedores e água "ad Libitum". A administração do agonista PPAR-gama(durante 4 semanas) foi realizada incorporada à dieta perfazendo dois grupos experimentais: Grupo Controle (SC) e Grupo PPAR-gama (SC-gama). Os animais, em seguida, foram submetidos a procedimento cirúrgico para instalação de implantes dentários e confecção de defeitos ósseos nas tíbias direita e esquerda, respectivamente. Após períodos de 7, 15 e 45 dias os animais foram eutanasiados e as tíbias removidas seguiram para processamento e posterior análise histológica descritiva e histomorfometria. Em relação aos defeitos, no aspecto histológico descritivo, em todos os períodos analisados, há atraso no reparo ósseo do grupo SC-gama em relação ao SC. A histomorfometria apresenta diferença comparando os grupos teste e controle nos parâmetros ossoneoformado (ON) em 7 dias (P=0,0374) e 15 dias (P=0,0134) e osso maduro (OM) em 15 dias (P=0,0009). Em 45 dias, os valores tanto de OM quanto de ON não apresentam significância. Já as tíbias onde o implante foi instalado, nas áreas de roscas os dois grupos apresentam-se muito semelhantes tanto aos eventos celulares quanto à maturação óssea exceto no período de 15 dias onde o grupo teste apresentou atraso no reparo peri-implantar. Conclui-se que, em relação ao reparo ósseo o processo de diferenciação e remodelação é lento no grupo tratado; e em relação ao reparo peri-implantar o comportamento biológico demonstra atraso do grupo tratado apenas no período intermediário(AU)

The peroxisome proliferator-activated receptor-gamma isoform (PPAR­gamma) are transcription factors found in the interlacing of several metabolic pathways that determine the genesis of obesity and associated diseases. Recent studies have reported the potential of PPAR agonist drugs, used to treat cardiovascular disease and type 2 diabetes, to affect bone cell function and fracture risk. This study aimed to evaluate the effects of PPAR-gamma activation on the process of bone repair and osseointegration of dental implants. Thirty-six Wistar rats received standard rodent solid chow and "ad Libitum" water. The administration of the PPAR-gamma agonist (during four weeks) was performed incorporated into the diet, making two experimental groups: Control Group (SC) and PPAR gamma Group (SC-gama). The animals were then submitted to a surgical procedure to install dental implants and make bone defects in the right and left tibias, respectively. After periods of 7, 15, and 45 days the animals were euthanized, the tibiae were removed for histological protocols and subsequent descriptive histological analysis and histomorphometry. Concerning the defects, the descriptive histological aspect revealed a slight delay in bone repair in the SC-gamma group in comparison with the SC for all parameters. Conversely, the histomorphometry showed difference between the groups regarding neoformed bone (NB) in 7 days (P = 0.0374) and 15 days (P = 0.0134) and mature bone (MB) in 15 days (P = 0.0009). At 45 days, there were no differences between the groups regarding MB and NB. As for tibiae, where the implant was placed, the two groups were similar to both cellular events and bone maturation in the areas of threads, except at 15 days where the test group showed delay in peri-implant repair. In conclusion, regarding the bone defect, the process of differentiation and remodeling is slow in the treated group. Regarding the implant, a descriptive histological analysis showed biological behavior delay in the treated group only in the intermediate period(AU)

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class ofmedication that mainly lowers theblood triglyceride levels. Theyreduce the LDL andincrease the levels of HDL C, in the blood.Clofibrate,the first member to bediscovered in 1962, and introduced in USA in 1967, is withdrawnin 2002, due to unexplained hepatomegaly,hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular diseaseand diabeticretinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial andangiography trials, like LOCAT(LopidCoronary Angiography Trial) and BECLAIT(Bezafibrate Coronary Atherosclerosis Intervention Trial)demonstrated thebeneficial effects of gemfibrozil and fenofibrate.Their mechanism of action remained obscure for three decades,ie till 1990s, when theirmode of actionwas found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involvingthevariousenzymes like LCAT (Lecithin-cholesterol acyl transferase)andCYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochromeP450 7A1 (CYP7A1)) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP,OATP (Na+-dependent taurocholate transporter/ organic anion transporters) . These are the.) andnuclear factors like LXR, PPAR alfa etc. (liver orphan receptorα , and peroxisome proliferative nuclear factor) , in relation to the mechanismsof action of fibrates are discussed . Areas of current interests in literature are briefed.

Conjugated linoleic acid improves glucose and lipid metabolism in diabetic mice / 南方医科大学学报

OBJECTIVE@#To analyze the effect of conjugated linoleic acid (CLA) on glucose and lipid metabolism in obese diabetic (db/db) mice.@*METHODS@#db/db mice were randomized for treatment with saline or CLA mixture administered intragastrically. The changes in body weight, dietary intake, water intake, oral glucose tolerance, triglyceride and total cholesterol were recorded after the treatments. HE staining and oil red O staining were used to assess liver pathologies and fatty acid content. The expression levels of PPARα, PPARγ, CD36, CHREBP and SREBP-1c were detected using real-time PCR and Western blotting. HepG2 cells were treated with CLA and linoleic acid and the expressions of PPARα, ACC, P-ACC, and CD36 were detected; the level of acetyl-CoA in the cell supernatant was detected using ELISA.@*RESULTS@#CLA treatment obviously reduced the dietary and water intake of db/db mice, effectively reduced the body weight and decreased serum triglyceride and cholesterol levels ( < 0.05). CLA significantly reduced fasting blood glucose, increased glucose tolerance, reduced the accumulation of lipid droplets in the liver and improved lipid metabolism in db/db mice. The mice showed significantly increased expression of PPARα ( < 0.05) and lowered CD36 expression ( < 0.001) in the liver after CLA treatment. Cellular experiments showed that CLA significantly up-regulated PPARα ( < 0.001) and P-ACC and decreased the expression of CD36 ( < 0.01). ELISA showed that acetyl-CoA was significantly up-regulated in the cells after CLA treatment ( < 0.01).@*CONCLUSIONS@#The mixture of two conjugated linoleic acid isomers can reduce fasting blood glucose, increase glucose tolerance and improve glycolipid metabolism in db/db mice by enhancing the expression of PPARα, increasing P-ACC and inhibiting CD36 expression.

Role of 20-HETE in amelioration of renal impairment by bezafibrate in mice with diabetic nephropathy / 中国药理学通报

Aim To investigate the protective effect of bezafibrate on renal injury and the changcs of 20- HETE in mice with diabetic nephropathy. Methods A diabctic model was established by long-term high-energy feeding combined with streptozotocin. The structural and functional changes of kidney were evaluated by renal pathological examination and blood urea nitrogen (BUN), serum creatinine ( Scr) , urinary albumin levels. The expressions of PPAIls and CYP4A protein were detected by Western blot. The level of 20-HETE was measured by ELISA kit. Results After four weeks with high-energy feeding, streptozotocin (40 mg • kg-1 • d"1 i. p) administration had been performed for five days. Then after seven days,fasting blood glucose (FBG) of mice exceeded 11.1 nimol • L"1, which suggested the establishment of the diabetic model. After four weeks of diabetic onset, the levels of BUN,Scr,urinary albumin increased significantly (P er and thickened basement membrane were observed in diabetic mice. Meanwhile,the expressions of PPARs and CYP4A protein in the kidney and the content of 20-HETE in serum decreased in model group (P <0. 01). With bezafibrate supplementation (75 mg • kg"' • d"1) for four weeks, both the structure and function of kidney were improved in diabetic mice,with the up-regulation of PPARs and CYP4A protein expressions and the increase of 20-HETE level (P <0. 01 ). Conclusions Bezafibrate can ameliorate renal injury in diabetic mice, which may be related to activating CYP4A-20-HETE.

The roles of PPARs and PPARγ coactivator-1 alpha in mitochondrial cardiomyopathy / 中华地方病学杂志

In mitochondria,peroxisome proliferator activated receptor (PPARs) and PPARγ coactivator-1 alpha (PGC-1α) work together to regulate the energy metabolism.Mitochondrial cardiomyopathy is a disease characterized by myocardial damage and abnormal energy metabolic that results from abnormalities in mitochondria quantity,structure and function in cardiac myocytes.However,there is inadequate knowledge on the pathogenesis of mitochondrial cardiomyopathy.In this paper,we summarize the roles played by PPARs and PGC-1α in mitochondrial cardiomyopathy.We expect this paper will provide some new clues for further studies of mitochondrial cardiomyopathy.

PPARs signaling pathway is involved in diabetic hepatopathy in mice / 中国病理生理杂志

AIM:To investigate the role of peroxisome proliferator-activated receptors(PPARs)-inflammation signaling pathways in diabetic hepatopathy.METHODS:Diabetic mouse model was established by feeding the mice with a high-energy diet for 4 weeks combined with intraperitoneal injection of streptozotocin(STZ;40 mg· kg-1· d-1for 5 d). The hepatopathy model was confirmed by histopathological observation and the indexes of liver function, such as alanine aminotransferase(ALT),aspartate aminotransferase(AST)and alkaline phosphatase(ALP),after another 4 weeks.Mo-reover,fasting blood glucose(FBG), and serum levels of total cholesterol(TC), triglyceride(TG)and insulin were measured,and the HOMA insulin resistance index(HOMA-IR)was calculated.The mRNA and protein expression levels of PPARs and inflammation-related factors were measured by qPCR and Western blot, respectively.RESULTS: After treatment with STZ for 7 d,the FBG of mice exceeded 11.1 mmol/L,suggesting that the diabetic model was established. After 4 weeks,the structural deformation of the hepatocytes(including hepatocytes containing abundant fat vacuoles, and inflammatory cell infiltration),and the increases in the serum levels of insulin,HOMA-IR,TC,TG,ALT,AST and ALP were observed(P<0.01), indicating the occurrence and progression of hepatopathy in diabetic mice.Meanwhile, com-pared with the control group,the mRNA and protein expression of PPARα,PPARβand PPARγdecreased,but the expres-sion of nuclear factor-κB(NF-κB),cyclooxygenase 2(COX-2)and inducible nitric oxide synthase(iNOS)significantly increased in the diabetic hepatopathy mice(P <0.01).CONCLUSION: Down-regulation of PPARα, PPARβand PPARγand activation of NF-κB-COX-2/iNOS signaling pathways may be involved in the diabetic hepatopathy in mice in-duced by long-term high-energy diet feeding combined with intraperitoneal injection of STZ.

Research progress on natural agonists of PPARs / 中草药

Peroxisome proliferators-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily, including three subtypes (α, β, and γ). PPARs are responsible for a variety of metabolic processes in the cell, and the occurrence of metabolic syndrome and other diseases may be related to the abnormal regulation, which has become a hot research target in the medical and biological fields. At present, the synthesis of PPARs agonists in the market is accompanied with a series of side effects, therefore, the search for safe and effective PPARs agonists from natural products has become the main trend of current research.

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

Metabolic nuclear receptors and metabolic syndrome / 基础医学与临床

Metabolic nuclear receptors consist of a group of nuclear hormone receptor transcription factors including peroxisome proliferator-activated receptors(PPARs),liver X-activated receptors(LXRs) and farnesoid X-activated receptors(FXRs).They have been identified and drawn enormous attention due to key roles in regulating adipogenesis,lipid metabolism,energy metabolism,insulin sensitivity,inflammation,blood pressure,cell growth and differentiation.Growing evidences support a causative relationship between these three metabolic nuclear receptors and the metabolic syndrome,which is characterized by insulin resistance,glucose intolerance or type II diabetes,obesity,dyslipidemia,hypertension,and microalbuminuria.These receptors have also been implicated in pathogenesis of atherosclerosis.Here we review the literature pertaining to the action and physiological role of metabolic nuclear receptors with particular emphasis on their pathogenic roles in the metabolic syndrome.

Study on the expression of PPARs and NF?B in endothciial cells of hyperlipidemic rats / 重庆医科大学学报

Objective: To investigate the expression of PPAR?, PPAR? and NF?B in the aortic endothelial cells of the normal and hyperlipidemic rats and the change of IL-6 with the treatment of fibrates in vivo.Methods:The hyperlipidemic rat was established by feeding the high cholesterol food.The expressions of PPAR?,PPAR?,NF?B and IL-6 in endothelial cells located in the aorta were presented by immunohistochemistry.The alteration among the PPAR?,PPAR? and IL-6 in the hyperlipidemic rat with the treatment of gemfibrate and bezafibrate was observed.Results:There was a weak expression of PPAR?,PPAR?,NF?B and IL-6 in the normal rat aorta endothelial cells,which were all enhanced in the hyperlipidemic rat.NF?B was drastically presented.After the treatment of gemfibrate and bezafibrate the expression of PPAR? increased,while that of IL-6 decreased relatively,but NF?B expression was not directly influenced.Conclusion:The expressions of PPARs and NF?B increased in hyperlipidemic rats.Fibrates may relieve the secretion of inflammation factors in vivo to some degree through the activation of PPARs.

Study on the expressions of NF?B,IL-6 and PPARs with treatment of different oxidized Iipoproteins / 重庆医科大学学报

Objective:To investigate the expressions of NF?B and IL-6 in vascular endothelial cells with treatment of different oxidized lipoproteins; the different expressions of PPAR?, PPAR? and NF?B when incubated with oxidized lipoproteins.Methods:HUVECs were isolated from fresh umbilical cords obtained at normal deliveries.THP-1 cell line was commercially purchased. The lipoproteins were obtained by density-gradient ultracentrifugation and were oxidized through incubation with 15?mol/L CuSO 4. The different response extent of transcription factors and cytokine factors among four different oxidized lipoproteins were observed through immunohistochcmistry,FACS,and ELISA.The would-be unbalanced expressions of three transcription factors PPAR?,PPAR? and NF?B were confirmed by immunohistochemistry and FACS.Results:There were some differences among the four kinds of oxidized lipoproteins to activate the transcription factor and inflammatory factors in the EC and THP.oxLp(a) had the strongest effect.The proinflammation transcription factor NF?B has been far more vigorously activated than PPARs when encountered with oxidized lipoproteins. Their expressions were all enhanced with time.Conclusion:The different patterns of lipoproteins vary in activating the nuclear transcription factors and the inflammation factors. Unbalanced activation between PPARs and NF?B exists with the incubation of oxidized lipoproteins in vascular endothelial cells.

Advance of glitazones on hypoglycemic effect / 中国药理学通报

Chemically Glitazones belong to Thi-azolidinediones. Glitazones enhance the sensitivity of target tissues to insulin and reduce insulin resistance. They, celled insulin sensitizers, are a new class of oral hypoglycemics. These agents can't reduce the blood glucose values either in normal animal or I type diabetic animal, but do have good effects on spontaneous diabetic animal and artificial insulin resistance animal. The research on insulin resistance needs euglycemic clamp for determination and the main index of assessing euglycemicclamp is glucose infusion rate in stable state. So far, the hypoglycemic mechanism of glitazones has been believed to be associated with PPARs(Peroxi-some Proliferator-Activated Receptors ). Gli-taziones act on PPAR Y, play an indirect part in insulin signal transduction and enhance the action of insulin. However, the precise mechanism still remains unknown.

PPARs:Target for lipid metabolism disorder and insulin resistance therapy / 中国药理学通报

The peroxisome prolifrator-activated receptors(PPARs)? and ? constitute a subfamily of nuclear receptors. PPAR? has been shown to be activat ed by the hypolipidemic drugs of the fibrate class; While the antidiabetic TZD a re synthetic ligands for PPAR?. Upon binding and activation by their ligands, t hey regulate the transcription of numerous genes involving lipid metabolism and insulin resistance. The research indicated that PPAR? also plays a key role in lipid metabolism. PPARs therefore constitute interesting targets for the develop ment of single and dual agonists useful in the treatment of obesity and type 2 d iabetes.

Peroxisome prolifreator-activated receptors and neurodegenerative diseases / 中国药理学通报

Peroxisome prolifreator-activated receptors (PPARs) are ligand-activated nuclear transcription factors, members of nuclear hormone receptor superfamily. PPARs play critical roles in growth, proliferation and apoptosis of variety of cells. Recently, PPAR ligands have been reported to ameliorate neuronal damage in neurodegenerative diseases including Alzheim- ers disease, Parkinsons disease,cerebral ischemia and multiple sclerosis. PPAR agonists may have potential values in treatment of neurodegenerative diseases. In this paper, we reviewed recent findings on PPARs′ neuroprotective actions and their underlying mechanisms.