PPAR-γ配体抗前列腺癌作用研究现状及展望

前列腺癌是男性生殖系统常见的恶性肿瘤。激素依赖性前列腺癌的治疗主要采用内分泌治疗,而激素非依赖性前列腺癌在目前尚缺乏有效的治疗方法。近年来,有研究发现过氧化物酶体增殖物激活受体γ(PPAR-γ)与前列腺癌关系密切,PPAR-γ活化后具有抗前列腺癌作用,有望成为预防、治疗前列腺癌的新位点。本文就其配体在抗前列腺癌作用方面的研究作一综述。     

Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice

Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARalpha-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARalpha-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4(+)CD8(+) population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARalpha-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARalpha-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARalpha plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.     

UCPs和PPARγ2基因在饮食诱导大鼠肥胖抵抗中的作用

目的探讨白色脂肪组织UCPs和PPARγ2基因在高脂饮食诱导大鼠肥胖抵抗中的作用。方法36只雌性SD大鼠,按体重随机分为高脂实验组和基础对照组,分别给予高脂饲料和基础饲料13周。实验结束时,根据体重将高脂组大鼠分为饮食诱导肥胖(DIO)和饮食诱导肥胖抵抗(DIO-R)大鼠,比较各组大鼠体重、脂肪湿重、脂体比、空腹血糖(FBG)及血脂谱;RT-PCR法测定白色脂肪组织UCP2、UCP3及PPARγ2mRNA的表达水平。结果DIO-R及DIO大鼠脂体比、TC、LDL-C、TG等指标均显著高于对照组相,但DIO-R组体重、脂肪湿重、脂体比、TG显著低于DIO组(P<0.05);DIO-R大鼠UCP2和UCP3mRNA的表达水平高于DIO大鼠和对照组(P<0.01),PPARγ2mRNA的表达水平低于DIO大鼠(P<0.01),高于对照组(P<0.01)。结论高脂饮食诱导大鼠发生肥胖抵抗与白色脂肪组UCP2、UCP3高表达及PPARγ2mRNA表达下降密切相关。     

葱白制剂对5／6肾切除大鼠PPAR-γ表达的影响

目的观察葱白制剂对慢性肾衰大鼠肾组织过氧化脂质体增殖激活受体-γ（PPAR-γ）表达的影响。方法SD大鼠80只，制备5／6肾大部切除慢性肾衰大鼠模型。分为葱白制剂组、苯那普利组、模型对照组和假手术组。各组大鼠分别于第1、4、8、12周杀检，分别留取血、尿及肾组织标本，检测血清肌酐（Scr）、尿素氮（BUN），24h尿蛋白定量，肾组织免疫组化检测Ⅰ型胶原（COL—Ⅰ）、Ⅲ型胶原（COL-Ⅲ）及PPAR-γ表达，RT—PCR法检测肾组织PPAR-γ mRNA表达。结果自第8周起，葱自制剂组及苯那普利组BUN及Scr下降，较模型组明显差异（P〈0．05）；用葱自制荆及苯那普利均可明显减少尿蛋白排泄（P〈0．05）；免疫组化模型组仅在肾小球有少量PPAR-γ表达，葱白制剂组肾小球及肾小管均有PPAR-γ表达，苯那普利组仅肾小球有少量表达，而假手术组主要在肾小球表达，肾小管有少量表达；葱白制剂与苯那普利均可明显抑制Ⅰ、Ⅲ型胶原的表达。RT—PCR结果示5／6肾大部切除大鼠肾组织PPAR-γ mRNA表达下降，葱白制剂可上调其表达。结论葱白制剂可改善肾纤维化，保护肾功能。其机制可能与慢性肾衰的早期调节PPAR-γ mRNA的表达有关。     

Statins and PPARalpha agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment

Statins and fibrates (weak PPARalpha agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPARalpha agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPARalpha compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPARgamma agonist Rosiglitazone caused little or no cell death at up to 10 muM and the PPARdelta ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPARalpha agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPARalpha agonism mediates in part the toxicity response to PPARalpha compounds. Furthermore, PPARalpha agonists and statins cause myotoxicity through distinct and independent pathways.     

Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease

BACKGROUND AND AIM: There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD). METHODS AND RESULTS: Male patients with CHD and high cholesterol levels (>6.2 mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5+/-1.7% of total fatty acids to 7.5+/-2.1, p<0.001 in S and from 6.2+/-1.4 to 6.8+/-1.4, p<0.005 in F) and a decrease in linoleate (from 26.9+/-3.9 to 24.2+/-3.6, p<0.001, and from 27.8+/-3.4 to 26.1+/-4.2, p<0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p<0.05), but only in F. CONCLUSIONS: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.     

Enzymatically modified low-density lipoprotein upregulates CD36 in low-differentiated monocytic cells in a peroxisome proliferator-activated receptor-gamma-dependent way

Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been suggested to upregulate CD36. Since free oxidized polyunsaturated fatty acids are PPARgamma ligands, we studied the effects of LDL modified by the simultaneous action of sPLA2 and 15-lipoxygenase (15LO) on CD36 expression and PPARgamma activation in monocytic cells. Exposure of MM6 cells, which do not express CD36 or other scavenger receptors, to such enzymatically modified LDL (enzLDL) resulted in upregulation of CD36 surface protein and mRNA expression. Similar effects were observed with free 13-hydroperoxyoctadecadienoic acid but not its esterified counterpart. Less pronounced effects were observed with LDL modified by 15LO alone. Upregulation of CD36 was inversely correlated to the state of cell differentiation, as showed by lower response to enzLDL of the scavenger receptor-expressing MM6-sr and THP1 cells. Importantly, LDL modified by sPLA2 and 15LO did not efficiently induce upregulation CD36 in PPARgamma-deficient macrophage-differentiated embryonic stem cells confirming a role of PPARgamma in CD36 expression in cells stimulated with enzLDL. Our data show that LDL modified with physiologically relevant enzymes stimulates CD36 expression in non-differentiated monocytes and that this process involves PPARgamma activation. These effects of enzLDL can be considered pro-atherogenic in the context of early atherosclerosis.     

Peroxisome proliferator-activated receptor alpha regulates B lymphocyte development via an indirect pathway in mice

Peroxisome proliferator-activator receptor alpha (PPARalpha), a member of the nuclear receptor superfamily, has been implicated in the regulation of inflammation and immune response. Adaptive immune responses are suppressed by exposure to PPARalpha agonists, resulting in severe thymus and spleen atrophy. In addition, the decline in both T and B cells is due in part to the loss of splenocytes upon exposure to PPARalpha agonists. Thus, the current study was designed to examine the effect of Wy-14,643, a potent PPARalpha agonist, on B cell development in bone marrow from wild-type and PPARalpha-null mice. Significantly decrease in pro/pre-B cell and total B220(+) cell was observed in wild-type mice in bone marrow upon Wy-14,643 treatment, but not in PPARalpha-null mice. Immature and mature B cell populations are not affected. This suggests that PPARalpha is involved in the development of B cell during lymphoid lineage. However, surprisingly, PPARalpha mRNA was absent in bone marrow as revealed by RT-PCR. Therefore, the effect of PPARalpha on B cell development is by an indirect mechanism.