Inadequate dietary magnesium intake increases atherosclerotic plaque development in rabbits

Epidemiological studies have shown dietary magnesium (Mg) intake and serum Mg levels to be inversely correlated with the development of atherosclerosis. We hypothesized that low levels of Mg would promote atherosclerotic plaque development in rabbits. New Zealand white rabbits (4 months old, n = 22) were fed an atherogenic diet containing 0.12% (−Mg), 0.27% (control), or 0.43% (+Mg) Mg for 8 weeks. Blood samples were obtained at baseline, 2, 4, 6, and 8 weeks and were assayed for total cholesterol, high-density lipoprotein (HDL), non-HDL, triglycerides (TG), C-reactive protein, serum Mg, and erythrocyte Mg. Aortas from −Mg had significantly more plaque, with an intima thickness 42% greater than control and 36% greater than +Mg. Serum cholesterol levels rose over time, and at 8 weeks, −Mg had the highest and +Mg the lowest total and non-HDL cholesterol and TG levels, although these results did not reach significance. Over time, serum Mg levels increased, and erythrocyte Mg levels decreased. C-reactive protein significantly increased in all groups at 4 and 6 weeks but returned to baseline levels by 8 weeks. This study supports the hypothesis that inadequate intake of Mg results in an increase in atherosclerotic plaque development in rabbits.     

Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.     

PPARY2基因Pro12Ala和C1431T多态性及其单倍型与2型糖尿病和肥胖的相关性研究

目的 研究过氧化物体增殖活化受体γ2(peroxisome proliferator activated receptorγ2,PPARγ2)基因Pro12Ala和C1431T多态性及其单倍型与汉族人2型糖尿病、肥胖的关系.方法 应用聚合酶链反应-限制性片段长度多态性的方法,对207例2型糖尿病患者和101名非糖尿病对照者进行PPARγ2基因Pro12Ala和C1431T多态性研究.结果 (1)在非糖尿病对照人群中Aal 12等位基因频率是0.064,T1431等位基因频率是0.252.单倍型分析显示Pro12Ala和C1431T两个位点连锁不平衡(D'=0.63,r2=0.074),组成了3种常见单倍型Pro-C、Pro-T和Ala-T.(2)Pro12Ala和C1431T多态性分布及其单倍型分布频率在2型糖尿病组与对照组组间差异均无统计学意义(P>0.05).(3)Pro12Ala变异与糖尿病患者的血压、血脂相关,地等位基因降低非肥胖糖尿病患者的舒张压(P<0.05),而对肥胖糖尿病患者的血脂水平无保护作用(P<0.05);C1431T多态性与糖尿病患者的超重和肥胖相关,超重和肥胖的糖尿病者T等位基因频率相对较高(P<0.05).结论 Pro12Ala和C1431T多态性可能在汉族人糖尿病发病中不是起主要作用;C1431T多态性与糖尿病患者的超重和肥胖相关.     

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.     

PPAR-γ的激动剂抑制肺癌细胞生长的实验研究

目的　研究肺癌细胞上过氧化物酶体增生物激活受体γ(PPAR γ)的表达及其经配体 (激动剂 )活化后抑制肺癌细胞生长的机制。方法　以RT PCR和Westernblot检测肺癌细胞上PPAR γ的表达 ,并通过MTT和细胞计数检测经PPAR γ的激动剂作用后的细胞增殖情况 ,以TUNEL检测细胞的凋亡情况。结果　两种细胞上均有PPAR γ的表达 ;PPAR γ的配体作用后明显抑制细胞生长 ,且与时间和剂量有关 ;经配体活化的PPAR γ能诱导细胞凋亡 ,使其增殖受抑。结论　作为肺癌治疗的新靶点———PPAR γ在肺癌细胞上表达 ,且经配体活化后能通过诱导凋亡而抑制肺癌细胞的生长 ,从而为未来肺癌的治疗提供了新的途径     

Effects of di-(2-ethylhexyl)-phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast cells.

Di-(2-ethylhexyl)-phthalate (DEHP) is a widely used plasticizer and ubiquitous environmental contaminant. The potential health hazards, including teratogenicity, from exposure to DEHP may be related to the role of DEHP or its metabolites in the trans-activation of peroxisome proliferator-activated receptors (PPARs). Fetal essential fatty acid (EFA) homeostasis is controlled by directional transfer across the placenta through a highly regulated process, including PPAR activation. Using HRP-1 rat trophoblastic cells, the effects of DEHP and two of its metabolites, mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA), on the mRNA and protein expression of the three known PPAR isoforms (alpha, beta, and gamma), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), and the heart cytoplasmic fatty acid binding protein (HFABP) were investigated. This study also investigated the functional effects of exposure on the uptake and transport of six long chain fatty acids (LCFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), linoleic acid (LA), alpha-linolenic acid (ALA), oleic acid (OA), and stearic acid (SA). In the presence of DEHP, MEHP, and EHA, the expression of PPARalpha, PPARgamma, FATP1, and HFABP were up-regulated in a dose- and time- dependent manner, while PPARbeta and FABPpm demonstrated variable expression. The uptake rates of EFAs (AA, DHA, LA, ALA) increased significantly upon exposure, and the transport of AA (omega-6) and DHA (omega-3) were directionally induced. These results suggest that DEHP, MEHP, and EHA can influence EFA transfer across HRP-1 cells, implying that these compounds may alter placental EFA homeostasis and potentially result in abnormal fetal development.     

共轭亚油酸对肥胖大鼠PPARγ基因表达及血清瘦素水平的影响

目的　研究不同剂量共轭亚油酸 (CLA)对饮食诱导肥胖大鼠PPARγ基因、瘦素、血糖、血脂的影响。方法　选用雄性Wistar大鼠 ,随机分为对照组、高脂组、高脂 +CLA组 (每 10 0g饲料含CLA分别为 0 75g、1 5 0g、3 0 0g) ,于第 12周末处死动物 ,计算脂 体比 ,测定大鼠血糖、血脂及瘦素水平 ,并应用RT PCR的方法检测大鼠白色脂肪组织过氧化物酶体增殖物激活受体γ(PPARγ)的表达水平。结果　CLA可降低肥胖大鼠血糖、甘油三酯 (TG)、总胆固醇 (TC)及瘦素水平 ,增加脂肪组织PPARγmRNA的表达水平。结论　CLA可降低肥胖大鼠血糖、血脂 ,并可通过激活PPARγ下调瘦素水平 ,有改善肥胖大鼠的瘦素抵抗作用。     

基于分子对接技术靶向PPARγ的降糖药物虚拟筛选

目的:筛选出特异性靶向PPARγ的配体,为降糖药物的研发提供思路.方法:以核受体PPARγ配体结合区域的晶体结构作为靶点,运用Schrodinger分子对接技术虚拟筛选Drugbank中老药分子化合物,结合打分值以及化合物与靶蛋白受体的相互作用模式优化筛选结果,获得具有降糖潜在活性的小分子化合物.结果:经过SP和XP两...     

搜风祛痰法对ApoE基因敲除小鼠主动脉易损斑块炎症反应及PPARγ基因表达的影响

目的 观察搜风祛痰中药复方稳斑汤对动脉粥样硬化（AS）ApoE基因敲除小鼠不稳定斑块炎症反应及动脉组织过氧化物酶增殖体激活型受体γ（PPAR-γ）基因表达的影响.方法 建立ApoE基因敲除小鼠动脉粥样硬化不稳定斑块模型,并设立空白组、模型组、西药组、稳斑汤低、中、高剂量组.实验周期1个月,麻醉处死小鼠取主动脉组织HE染色后在光学显微镜下进行病理学观察,然后采用半定量RT-PCR技术检测PPAR-γ基因表达的变化.结果 与空白组相比,模型组PPAR-γ基因表达量明显增加（P＜0.01）;与模型组相比,西药组及稳斑汤各剂量组均能增加PPAR-γ基因表达量（P＜0.01）;与西药组相比,稳斑汤高剂量组增加PPAR-γ基因表达量无差异（P＞0.05）.光镜下观察中药各剂量组和西药组炎症反应均明显弱于模型组.结论 ApoE基因敲除小鼠AS不稳定斑块的形成与发展和炎症因子密切相关,搜风祛痰中药复方稳斑汤能够抑制斑块内的炎症反应并上调实验性AS不稳定斑块ApoE基因敲除小鼠PPAR-γ基因表达.     

岩藻黄质对高脂饮食诱导的肥胖小鼠胰岛素抵抗的影响

研究岩藻黄质对高脂饮食诱导的肥胖小鼠胰岛素抵抗的作用及其分子机制。将50只C57BL/6J雄性小鼠随机分为正常组(10只)、高脂组(40只),高脂组经高脂饲料喂养12周形成肥胖胰岛素抵抗模型,将其随机分为模型组、岩藻黄质0.2%剂量组、岩藻黄质0.4%剂量组和二甲双胍组,每组10只,连续喂养含有相应药物饲料6周后,测定各组小鼠体质量和附睾脂肪质量;检测血清中空腹血糖(FBG)、空腹胰岛素(FINS)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDL-C)含量,并计算胰岛素抵抗指数(HOMA-IR);HE染色法观察各组小鼠肝脏病理变化;Western blot法检测肝脏组织中胰岛素受体底物1(IRS-1)/磷酸肌醇-3-激酶(PI3K)/苏氨酸蛋白激酶(Akt)和过氧化物酶体增殖剂激活受体-γ(PPARγ)/胆固醇调节元件结合蛋白-1(SREBP-1)/脂肪酸合成酶(FAS)通路相关蛋白的表达。结果显示,与模型组相比,各给药组小鼠的体质量、附睾脂肪质量以及FBG,FINS,TC,TG,LDL-C,HOMA-IR水平,肝组织中PPARγ,SREBP-1和FAS蛋白表达显著降低(P<0.05或P<0.01),同时HDL-C水平及肝组织中p-IRS-1,IRS-1,PI3K,p-Akt的蛋白表达显著升高(P<0.05或P<0.01),且肝组织病理形态明显改善。结果表明,岩藻黄质可明显减轻肥胖小鼠的肥胖及糖脂紊乱,并改善胰岛素抵抗,其作用可能与调控IRS-1/PI3K/Akt和PPARγ/SREBP-1/FAS通路有关。