PPARγ、UCP2与非乙醇性脂肪性肝病

研究显示过氧化物酶体增殖物激活受体γ和解耦联蛋白2参与了非乙醇性脂肪性肝病的发病。过氧化物酶体增殖物激活受体γ和胰岛素抵抗及脂肪细胞因子间有密切联系。解耦联蛋白2也可调节胰岛素分泌、限制活性氧产生、调节ATP合成等。阐明过氧化物酶体增殖物激活受体γ、解耦联蛋白2与非乙醇性脂肪性肝病之间的联系有助于进一步防治非乙醇性脂肪性肝病。     

Sorghum extract exerts an anti-diabetic effect by improving insulin sensitivity via PPAR-�� in mice fed a high-fat diet

This study investigated the hypothesis that a sorghum extract exerts anti-diabetic effects through a mechanism that improves insulin sensitivity via peroxisome proliferator-activated receptor gamma (PPAR-γ) from adipose tissue. Seven C57BL/6 mice were fed an AIN-93M diet with fat consisting of 10% of total energy intake (LF) for 14 weeks, and 21 mice were fed a high-fat AIN diet with 60% of calories derived from fat (HF). From week 8, the HF diet-fed mice were orally administered either saline (HF group), 0.5% (0.5% SE group), or 1% sorghum extract (1% SE group) for 6 weeks (n = 7/group). Perirenal fat content was significantly lower in the 0.5% SE and 1% SE groups than that in the HF mice. Levels of total and low-density lipoprotein cholesterol, triglycerides, glucose, and the area under the curve for glucose were significantly lower in mice administered 0.5% SE and 1% SE than those in HF mice. Serum insulin level was significantly lower in mice administered 1% SE than that in HF mice or those given 0.5% SE. PPAR-γ expression was significantly higher, whereas the expression of tumor necrosis factor-α was significantly lower in mice given 1% SE compared to those in the HF mice. Adiponectin expression was also significantly higher in mice given 0.5% SE and 1% SE than that in the HF mice. These results suggest that the hypoglycemic effect of SE may be related with the regulation of PPAR-γ-mediated metabolism in this mouse model.     

Novel Pituitary Ligands: Peroxisome Proliferator Activating Receptor-γ

Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We have recently demonstrated abundant expression of nuclear hormone receptor PPAR-gamma in human pituitary tumors of different subtypes. PPAR-gamma activators (thiazolidinediones) induced G0-G1 cell-cycle arrest and apoptosis in human, and murine corticotroph, somatolactotroph, and gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine corticotroph, somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20, PRL- and GH-secreting GH3, and LH-secreting LbetaT2, and alpha-T3 cells, was markedly suppressed in rosiglitazone treated mice, and plasma ACTH, and serum corticosterone, GH, PRL and LH levels were attenuated in all treated animals. PPAR-gamma is an important novel molecular target in pituitary adenoma cells and as PPAR-gamma ligands inhibit tumor cell growth and ACTH, GH, PRL and LH secretion in vitro and in vivo, thiazolidinediones are proposed as a novel oral medical management for pituitary tumors.     

Adipokines in the HIV/HAART-associated lipodystrophy syndrome

The use of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus has dramatically altered both the landscape of this disease and the prognosis for those affected. With more patients now receiving HAART, adverse effects such as lipodystrophy and metabolic syndrome have emerged. In HIV/HAART-associated lipodystrophy syndrome (HALS), patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Recent studies have contributed to the elucidation of the pathophysiological abnormalities seen in this syndrome and have provided guidance for the study and use of potential treatments for these patients, but widely accepted guidelines have not yet been established. Two adipokines, leptin and adiponectin, are decreased in patients with HALS and lipoatrophy or lipodystrophy. Further, recent proof-of-concept clinical trials have proven the efficacy of leptin replacement and medications that increase circulating adiponectin levels in improving the metabolic profile of HALS patients. This review article highlights recent evidence on leptin replacement and compares leptin’s efficacy to that of other treatments, including metformin and thiazolidinediones, on metabolic abnormalities such as impaired insulin-glucose homeostasis associated with lipodystrophy in patients receiving HAART. It is hoped that forthcoming large phase III clinical trials will allow the addition of leptin to our therapeutic armamentarium for use in patients suffering from this disease state.     

Expressions of GSK-3beta, Beta-catenin and PPAR-gamma in medulloblastoma

Objective  To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application. Methods  Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues. Results  The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal (P<0.05). Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation. Conclusion  Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.      

Solid Tumor Differentiation Therapy – Is It Possible?

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiationbased therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.     

The PPAR-γ agonist rosiglitazone facilitates Akt rephosphorylation and inhibits apoptosis in cardiomyocytes during hypoxia/reoxygenation

Background and Aim: Results on the cardiovascular effects of PPAR‐γ agonists are conflicting. On one hand, it was suggested that the PPAR‐γ agonist rosiglitazone may increase the risk of cardiovascular events. On the other hand, PPAR‐γ agonists reduce myocardial infarct size and improve myocardial function during ischemia/reperfusion in animal studies in vivo. However, the mechanism of this effect is unclear, and it is open if PPAR‐γ agonists have a direct effect on cardiac myocyte survival in ischemia/reperfusion. The aim of this study was to determine the effect of the PPAR‐γ agonist rosiglitazone on hypoxia/reoxygenation‐induced apoptosis of isolated cardiomyocytes. Methods: Isolated rat cardiac myocytes were pretreated with rosiglitazone or vehicle for 30 min before they were subjected to hypoxia for 4 h followed by different times of reoxygenation (5 min to 12 h). Apoptosis was determined by in situ hybridization for DNA fragmentation (TUNEL) as well as detection of cytoplasmic accumulation of histone‐associated DNA fragments by enzyme‐linked immunosorbent assay (ELISA). Activation of apoptosis regulating intracellular signalling pathways was studied by immunoblotting using phosphospecific antibodies. Results: Rosiglitazone significantly reduced apoptosis of isolated cardiomyocytes subjected to hypoxia/reoxygenation, independently determined with two methods. After 4 h of hypoxia and 12 h of reoxygenation, 34 ± 3.6% of the vehicle treated cardiac myocytes stained positive for DNA fragmentation in the TUNEL staining. Rosiglitazone treatment reduced this effect by 23% (p < 0.01). Even more pronounced, cytoplasmic accumulation of histone‐associated DNA fragments detected by ELISA was reduced by 35% (p < 0.05) in the presence of rosiglitazone. This inhibition of hypoxia/reoxygenation‐induced apoptosis was associated with an increased reoxygenation‐induced rephosphorylation of the protein kinase Akt, a crucial mediator of cardiomyocyte survival in ischemia/reperfusion of the heart. This effect was reversed by GW‐9662, an irreversible PPAR‐γ antagonist. However, rosiglitazone did not alter phosphorylation of the MAP kinases ERK1/2 and c‐Jun N‐terminal kinase (JNK). Conclusion: It can be concluded that cardiac myocytes are direct targets of PPAR‐γ agonists promoting its survival in ischemia/reperfusion, at least in part by facilitating Akt rephosphorylation. This effect may be of clinical relevance inhibiting the reperfusion‐induced injury in patients suffering from myocardial infarction or undergoing cardiac surgery.     

过氧化物酶体增殖物激活受体-γ在兔动脉粥样硬化模型中的表达及阿托伐他汀的干预作用

目的探讨过氧化物酶体增殖物激活受体-γ(PPAR-γ)在兔动脉粥样硬化模型中的表达,以及阿托伐他汀的干预作用。方法2005年1月至2006年12月,在吉林大学中日联谊医院心内科将24只雄性日本大耳白兔随机分为高脂饮食组(A组)、高脂饮食 阿托伐他汀组(B组)和正常饮食组(C组)3组,每组8只。各组分别在喂养16周末处死,免疫组化法检测PPAR-γ,全自动生化分析仪检测血脂的表达水平。结果PPAR-γ的表达分别为A组(11·23±1·21)%,B组(11·05±1·02)%,C组(7·68±1·04)%,A、B2组比较差异无显著性意义(P>0·05),A、B2组与C组相比差异均有显著性意义(均P<0·01)。总胆固醇(TC)在A、B、C3组的表达分别为(23·51±10·58)mmol/L,(14·27±3·51)mmol/L,(1·36±0·33)mmol/L,各组间比较差异有显著性意义;低密度脂蛋白(LDL)在A、B、C3组的表达分别为(21·39±10·00)mmol/L,(14·23±4·01)mmol/L,(0·72±0·35)mmol/L,各组间比较差异亦有显著性意义;甘油三酯(TG)在3组间比较差异无显著性意义(P>0·05)。结论在兔动脉粥样硬化模型中PPAR-γ表达增高;阿托伐他汀可促进PPAR-γ的表达。     

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

In Alzheimer's disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13- to 15-month-old AD mice using [¹¹C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks' treatment, 5-week wash-out period). [¹¹C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [¹¹C]-(R)-PK11195 μPET could not demonstrate genotype- or treatment-dependent differences in the 13- to 14-month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.