共查询到20条相似文献,搜索用时 78 毫秒
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Navab M Anantharamaiah GM Reddy ST Van Lenten BJ Fogelman AM 《Current drug targets》2008,9(3):204-209
The mouse has proven to be an excellent model for testing apolipoprotein mimetic peptides as agents to treat a variety of vascular inflammatory conditions including atherosclerosis, cognitive dysfunction associated with arteriole inflammation, chronic rejection of transplanted hearts, and scleroderma. The mechanism of action appears to relate to the ability of these peptides to preferentially bind pro-inflammatory oxidized lipids and is independent of the chirality of the peptides since peptides synthesized from either D- or L-amino acids appear to be equally effective. 相似文献
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《Expert opinion on drug discovery》2013,8(1):61-69
Background: The development of effective and safe lipid-lowering agents should set out from and rely on robust preclinical investigation. Objective: To accomplish this aim, the selection of proper cellular and animal models is crucial. Results: Because lipid-lowering agents are ultimately supposed to reduce the atherosclerotic burden in the arterial wall, they need to tackle directly or indirectly the multifactorial nature of atherosclerotic disease. Hence, these drugs may essentially prevent triglyceride-rich lipoprotein assembly or enhance low-density lipoprotein (LDL) clearance through the LDL or related receptors in the liver. Established animal models such as the apolipoprotein E- and the LDL-receptor knockout mice are widely used to test drug actions on these pathways. A different approach is testing the ability of candidate drugs to increase plasma high-density lipoprotein (HDL) levels. More recently, the focus has shifted to drugs enhancing HDL function rather than just plasma HDL levels. This in turn requires in vitro and particularly in vivo models of reverse cholesterol transport, which have become available by now. Conclusion: A positive outcome of preclinical studies is necessary but not sufficient for an investigational new drug to be eventually approved for clinical use. 相似文献
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Lilley SH Spivey JM Vadlamudi S Otvos J Cummings DM Barakat H 《Journal of clinical pharmacology》1998,38(12):1107-1115
This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease. 相似文献
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The objectives of this study were to determine if lipid transfer protein I (LTP I)-facilitated phospholipid (PC) transfer activity regulates the plasma lipoprotein distribution of cyclosporine (CSA) and if the association of CSA with high-density lipoproteins (HDL) is due to the high protein and/or alterations in coat lipid content of HDL. To assess if LTP I-facilitated PC transfer activity regulates the plasma lipoprotein distribution of CSA, (14)C-PC- or (3)H-CSA-enriched HDL or low-density lipoproteins (LDL) were incubated in T150 buffer [pH 7.4, containing a (14)C-PC- or (3)H-CSA-free lipoprotein counterpart +/- exogenous LTP I (1.0 microg protein/mL)] or in delipidated human plasma that contained 1.0 microg protein/mL of endogenous LTP I in the presence or absence of a monoclonal antibody TP1 (30 microg protein/mL) directed against LTP I for 90 min at 37 degrees C. To assess the influence of HDL subfraction lipid composition and structure on the plasma distribution of CSA, CSA at 1000 ng of drug/mL of plasma was incubated in human plasma pretreated for 24 h with a lecithin:cholesterol acyltransferase (LCAT) inhibitor, dithionitrobenzoate (DTNB; 3 mM). To assess the binding of CSA to apolipoproteins AI, AII, and B, increasing concentrations of CSA were added to a constant concentration of either apolipoprotein AI, AII, or B. Equilibrium dialysis was used to determine free and bound fractions and Scatchard plot analysis was used to determine binding coefficients. To assess the influence of hydrophobic core lipid volume on the plasma distribution of CSA, CSA was incubated in plasma from patients with well-characterized dyslipidemias. The hydrophobic core lipid volume (CE + TG) within each lipoprotein subfraction was correlated to the amount of CSA recovered in each plasma sample from the different human subjects. The percent transfer of PC from LDL to HDL was different than the percent transfer of CSA in T150 buffer or human plasma source. In the presence of TP1, only PC transfer from LDL to HDL decreased. For plasma incubated with CSA and separated into HDL(2) and HDL(3), 35-50% of drug originally incubated was recovered in the HDL(3) fraction, with the remaining drug being found within the other fractions. When CSA was incubated in plasma pretreated with DTNB, the percentage of CSA recovered in the HDL(3) and HDL(2) fractions was not significantly different compared with that in the HDL(3) and HDL(2) fractions from untreated control plasma. CSA distribution into HDL inversely correlated with the hydrophobic core lipid volume of HDL, whereas distribution into LDL and triglyceride-rich lipoproteins directly correlated with their respective hydrophobic core lipid volumes. We further observed that CSA has high binding affinity and multiple binding sites with apolipoproteins AI (k(d) = 188.9 nM; n = 2), AII (k(d) = 184.7 nM; n = 2), and B (k(d) = 191 nM; n = 3). These findings suggest that the transfer of CSA between different lipoprotein particles is not influenced by LTP I-facilitated PC transfer activity probably because of the high affinity of CSA for the protein components of HDL and LDL. 相似文献
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冠状动脉病变与血脂水平关系的研究 总被引:2,自引:1,他引:1
目的 探讨血脂水平与冠状动脉病变程度的关系。方法 病人100例行冠状动脉造影,明确其病变程度;病人均检测CHO、LDL、VLDL、HDL、TG,ApoAl,ApoB水平,并计算ApoAl/ApoB值,比较冠脉不同病变水平时各血脂的差异性。结果 冠状动脉正常组与病变各组间比较,各组年龄差异无显著性;CHO,LDL、VLDL、HDL、TG、ApoAl,ApoB,ApoA1/ApoB比值等差异有显著性;在冠脉病变三个亚组间,三支病变组的HDL,LDL,ApoB与单支,双支病变组比较差异有显著性,将冠脉病变三个亚组合并为冠心组后与正常对照组比较,上述指标差异均有显著,ApoB在P=0.01水平差异有显著性。结论 血脂紊乱尤其是高LDL,ApoB血症,低HDL血症对判断冠状动脉病变程度有一定临床意义。 相似文献
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Aviram M Dornfeld L Kaplan M Coleman R Gaitini D Nitecki S Hofman A Rosenblat M Volkova N Presser D Attias J Hayek T Fuhrman B 《Drugs under experimental and clinical research》2002,28(2-3):49-62
The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation. 相似文献
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目的观察血液灌流对血液透析患者血脂[LP(α)]的影响。方法选取多个血液净化中心血液透析患者40例,比较单次血液透析串联血液灌流前后患者血脂的变化。结果慢性肾衰竭患者多数存在血脂代谢的紊乱,血液灌流后学[Lp(a)]以及甘油三酯(TG)的浓度下降,高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、载脂蛋白A(APOA)、载脂蛋白B(APOB)、总胆固醇(TC)的浓度无明显变化。结论血液灌流可以降低维持性血液透析患者的Lp(a)及TG,改善其脂代谢紊乱。 相似文献
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Beneficial effect of laserpitin, a coumarin compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats 总被引:1,自引:0,他引:1
Ogawa H Nakamura R Baba K 《Clinical and experimental pharmacology & physiology》2005,32(12):1104-1109
Recently, we found that 4-hydroxyderricin, one of the major chalcones in Angelica keiskei extract (an ethyl acetate extract from the yellow liquid of stems), suppressed increases in systolic blood pressure and reduced both serum very low-density lipoprotein levels and liver triglyceride content in stroke-prone spontaneously hypertensive rats (SHRSP). In the present study, we have isolated laserpitin, a characteristic coumarin, from the A. keiskei extract and examined the effect of dietary laserpitin on blood pressure and lipid metabolism in SHRSP. Six-week-old male SHRSP were fed diets containing 0.1% laserpitin for 7 weeks with free access to the diet and water. Bodyweight gain was reduced by dietary laserpitin after 4 weeks through to 7 weeks without any significant change in daily food intake. Serum total cholesterol, phospholipid and apolipoprotein (apo) E levels were significantly increased, which was due to significant increases in cholesterol, phospholipid and apoE contents in the low- and high-density lipoprotein (LDL and HDL, respectively) fractions. These results suggest that dietary laserpitin increases serum apoE-HDL levels. In the liver, significant decreases in relative liver weight and triglyceride content were found after treatment with laserpitin for 7 weeks. An investigation of hepatic mRNA expression of proteins involved in lipid metabolism indicated that a significant decrease in hepatic triglyceride lipase may be responsible for the increase in serum HDL levels and also indicated that a marked decrease in adipocyte determination and differentiation factor 1 may be responsible, at least in part, for the decrease in hepatic triglyceride content. In conclusion, dietary laserpitin produces increases in serum HDL levels, especially apoE-HDL, and decreases in the hepatic triglyceride content in SHRSP. 相似文献
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Sixty-seven male patients with hypercholesterolemia, divided into three groups according to apolipoprotein E phenotype (33 with apoE3/ 3 phenotype, E3 group; 23 with 2/2 or 2/3, E2+ group; 11 with 4/4 or 4/3, E4+ group), received daily 20-40 mg of fluvastatin for 12 weeks. The levels of triglyceride (TG), cholesterol (Chol), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured after 0, 4, 8 and 12 weeks on fluvastatin and after 4 weeks washout period. Lipid percentage changes (delta) were not associated with apoE phenotype for any treatment time. Cholesterol decreased by 14% after 12 weeks and HDL-C increased by 14-16% after 12 weeks for three phenotype groups. deltaTG, deltaChol, deltaLDL-C were associated positively, while negatively for deltaHDL-C, with the corresponding basal lipid values for the three groups. The positive deltaTG values occurred at a low basal TG0 level and became negative at TG0 > 1.6-1.9 mM. For E3 and E4+ groups, only a single parameter contributed significantly into a variation of lipid percentage changes. For the E2+ group, TG0 and Chol0 contributed in a reciprocal manner into deltaTG12/0, both positively into deltaChol8/0; Chol0 and HDL-C0 both negatively contributed into deltaHDL-C12/0. HDL-C0 contributed reciprocally into LDL-C variability for E2+ and E4+ groups. Three effects seem to contribute differently into lipid response among patients with different apoE phenotype: the inhibition of hepatic and lipoprotein lipase activities, the competition between TG-rich and low-density lipoproteins for LDL-receptor and the accumulation of intermediate-density lipoproteins in patients bearing E2 isoform. 相似文献
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Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice 总被引:1,自引:0,他引:1
Burleigh ME Babaev VR Patel MB Crews BC Remmel RP Morrow JD Oates JA Marnett LJ Fazio S Linton MF 《Biochemical pharmacology》2005,70(3):334-342
Non-selective inhibition of cyclooxygenase (COX) has been reported to reduce atherosclerosis in both rabbit and murine models. In contrast, selective inhibition of COX-2 has been shown to suppress early atherosclerosis in LDL-receptor null mice but not more advanced lesions in apoE deficient (apoE(-/-)) mice. We investigated the efficacy of the novel COX inhibitor indomethacin phenethylamide (INDO-PA) on the development of different stages of atherosclerotic lesion formation in female apoE(-/-) mice. INDO-PA, which is highly selective for COX-2 in vitro, reduced platelet thromboxane production by 61% in vivo, indicating partial inhibition of COX-1 in vivo. Treatment of female apoE(-/-) mice with 5mg/kg INDO-PA significantly reduced early to intermediate aortic atherosclerotic lesion formation (44 and 53%, respectively) in both the aortic sinus and aorta en face compared to controls. Interestingly, there was no difference in the extent of atherosclerosis in the proximal aorta in apoE(-/-) mice treated from 11 to 21 weeks of age with INDO-PA, yet there was a striking (76%) reduction in lesion size by en face analysis in these mice. These studies demonstrate the ability of non-selective COX inhibition with INDO-PA to reduce early to intermediate atherosclerotic lesion formation in apoE(-/-) mice, supporting a role for anti-inflammatory approaches in the prevention of atherosclerosis. 相似文献
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《Current medical research and opinion》2013,29(5):1169-1176
ABSTRACTBackground: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia.Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment.Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL?C) and non-high-density lipoprotein cholesterol (HDL?C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL?C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concentrations of dense LDL subfractions was observed. Patients with triglyceride values >1.7?mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL?C mainly due to a fall in the concentration of dense HDL subfractions.Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles. 相似文献
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Sharifov OF Nayyar G Garber DW Handattu SP Mishra VK Goldberg D Anantharamaiah GM Gupta H 《Am J Cardiovasc Drugs》2011,11(6):371-381
Apolipoprotein E (apoE) is a ligand for clearance of lipoprotein remnants such as chylomicrons and very low-density lipoproteins. It has anti-atherogenic and anti-inflammatory properties. Therefore, there is extensive ongoing research to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states, including Alzheimer disease. However, peptides that clear atherogenic lipoproteins, analogous to apoE, via enhanced hepatic uptake have not been previously reviewed. Toward this end, we describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH(2). This peptide consists of residues 141-150, the putative receptor-binding region of human apoE, covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol levels in dyslipidemic mouse and rabbit models. We discuss the scientific rationale and review the literature for the design and efficacy of the peptide. Analogous to apoE, this peptide bypasses the low-density lipoprotein receptor for the hepatic uptake of atherogenic lipoproteins via heparan sulfate proteoglycan (HSPG). ApoE mimetics such as Ac-hE18A-NH(2) may therefore restore or replace ligands in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional low-density lipoprotein receptors. Therefore, this and similar peptides may be useful in the treatment of dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis. 相似文献
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烟酸对幼年肥胖大鼠血脂及血管内皮粘附功能的影响 总被引:2,自引:0,他引:2
目的研究烟酸对幼年肥胖大鼠血脂及血管内皮粘附功能的影响,探讨烟酸防治动脉粥样硬化(AS)的作用机制。方法Wistar大鼠随机分为对照组和试验组,分别饲予基础饲料和高脂饲料,8周后肥胖大鼠造模成功。肥胖大鼠再随机分为3组:A组:单纯控制食谱,B组:控制食谱+烟酸,F组:继续高脂饮食。原对照组继续饲予基础饲料,为N组。干预12周后,处死全部大鼠,测定血脂指标:总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、计算动脉粥样硬化指数(AI);血管内皮粘附因子:血清可溶性细胞间粘附分子1(sICAM-1),免疫组化法检测腹主动脉ICAM-1蛋白的表达,RT-PCR法检测腹主动脉ICAM-1mRNA的表达。结果与F组比较,B组的TC、TG、LDL、AI、sICAM-1、ICAM-1蛋白和mRNA表达水平显著降低,HDL显著升高,且均与N组无显著差异。结论控制食谱联合烟酸可以改善血脂、血管内皮粘附功能,因此调节血脂紊乱和血管内皮粘附功能障碍是烟酸类药物改善AS预后的可能机制。 相似文献
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Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)-cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. Moreover, clinical and epidemiologic data highlight the need of therapies to reduce the residual cardiovascular risk associated with low high-density lipoprotein(HDL)-cholesterol and elevated triglyceride levels. There are several novel agents undergoing preclinical or clinical development for the treatment of dyslipidemia. Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD. 相似文献
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Although the levels of low-density lipoprotein (LDL) cholesterol remain the main therapeutic goal when treating dyslipidaemias, there is a need to consider high-density lipoprotein (HDL) concentrations. This conclusion is based on the findings of epidemiological surveys and appropriately designed trials using statins or fibrates. The importance of HDL, as a 'protective' lipoprotein fraction, has been recognised by major treatment guidelines. This review considers the differences in HDL-raising capacity of two of the most commonly prescribed statins--atorvastatin and simvastatin. When compared with simvastatin, atorvastatin is associated with progressively decreasing rises in the levels of HDL as the dose increases (negative dose response), an effect not reported with other statins. In contrast, simvastatin shows a positive dose response (increasing concentrations of HDL with increasing dose). This effect is paralleled by changes in apolipoprotein A-I levels. Apolipoprotein A-I is the main apolipoprotein associated with HDL. This dissimilarity in HDL response is an example of several differences that have been reported when comparing various statins. If 'all statins are not created equal', we should focus prescribing on those statins that have end point evidence originating from appropriately designed trials. 相似文献
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HDL和ApoA-Ⅰ模拟肽对3T3-L1脂肪细胞脂联素表达的影响 总被引:2,自引:0,他引:2
目的观察高密度脂蛋白(HDL)和载脂蛋白A-I(ApoA-Ⅰ)模拟肽对炎症状态下3T3-L1脂肪细胞脂联素的分泌和mRNA表达的影响,并探讨其可能的作用机制。方法3T3-L1脂肪细胞促分化成熟后,脂多糖(LPS)刺激脂肪细胞处于炎症状态,给予不同浓度的HDL(10~100mg·L-1)和ApoA-Ⅰ模拟肽(1~50mg·L-1)干预,收集细胞和培养上清液,测定细胞上清液脂联素浓度,脂肪细胞脂联素和PPARγmRNA表达水平,及核因子-κB(NF-κB)活性。结果LPS刺激使上清液中脂联素浓度由0·25±0·03μg·L-1降低至0·14±0·02μg·L-1(P<0·05)。HDL和ApoA-Ⅰ模拟肽呈剂量依赖性增加炎症状态下脂肪细胞脂联素分泌和mRNA表达。与LPS刺激组(0·36±0·05)比较,10、50、100mg·L-1HDL分别使脂联素mRNA表达升高2、2·9和4·2倍,而1、10、50mg·L-1ApoA-Ⅰ模拟肽分别使脂联素mRNA表达升高2·2、3·9和4·4倍(P均<0·05)。PPARγ在分化成熟的3T3-L1脂肪细胞有较高水平的表达,与炎症状态下比较,PPARγ表达在HDL和ApoA-Ⅰ模拟肽干预后明显升高(2·85±0·69vs0·38±0·19,2·92±0·96vs0·38±0·19;P<0·05);而NF-κB活性在HDL和ApoA-Ⅰ模拟肽干预后明显减低(0·48±0·09vs1·93±0·59,0·43±0·08vs1·93±0·59;P<0·05)。结论HDL和ApoA-Ⅰ模拟肽能上调炎症状态下脂肪细胞脂联素的表达和分泌,其作用机制可能与PPARγ和NF-κB途径有关。 相似文献
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Taro Tokui Chitose Kuroiwa Shigeki Muramatsu Yoko Tokui Kazuhiko Sasagawa Toshihiko Ikeda Toru Komai 《Biopharmaceutics & drug disposition》1995,16(2):91-103
We synthesized 14C-warfarin hexadecyl ether (14C-WHE) by addition of a palmityl moiety to the hydroxyl group at the 4-position of 14C-warfarin, a compound known to bind to serum albumin. 14C-WHE preferentially bound to the lipoproteins, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), in mouse plasma both in vitro and in vivo. 14C-Warfarin mainly concentrated in the liver immediately after intravenous administration to mice bearing M5076 sarcoma, and was found at only low concentrations in other tissues including the tumour. 14C-WHE highly distributed to the tumour, in other tissues including the tumour. 14C-WHE highly distributed to the tumour, adrenal, and spleen, as well as the liver. These tissues coincided with those in which human 125I-LDL was vigorously incorporated. The results indicate that chemical modification of an agent, giving it high lipophilicity, will enable it to bind to lipoproteins after intravenous administration. These modifications raise the possibility of lipoproteins as endogenous targeting carriers into tumour cells, which have high LDL-receptor activity. 相似文献