本文選題：鹽 + PPARδ�。� 參考：《第三軍醫(yī)大學(xué)》2017年博士論文

【摘要】：背景和目的:糖尿病患者的高血壓管理是降低心血管死亡率和發(fā)病率的關(guān)鍵。長期以來,高血壓的飲食調(diào)節(jié)方案重點(diǎn)關(guān)注在食鹽攝入上。因此各大指南推薦糖尿病合并高血壓患者限制鹽的攝入。然而,限鹽的潛在效益仍存有爭議,一些證據(jù)顯示,限鹽會(huì)增加糖尿病合并高血壓患者的心血管及全因死亡率,且高糖飲食對(duì)升高血壓的影響遠(yuǎn)遠(yuǎn)大于高鹽攝入。然而,關(guān)于鹽攝入與血糖穩(wěn)態(tài)之間的緊密聯(lián)系的研究仍缺乏,人們對(duì)此知之甚少。人體腎臟可調(diào)節(jié)體液和電解質(zhì)的平衡,同時(shí)對(duì)葡萄糖的過濾和重吸收起著至關(guān)重要的作用。其中,分布在腎臟皮質(zhì)近端小管上皮細(xì)胞管腔側(cè)的鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白(SGLTs),具有調(diào)節(jié)鈉、糖重吸收的功能,能以較高效率以1:1協(xié)同轉(zhuǎn)運(yùn)Na+和葡萄糖。在高糖狀態(tài)下,SGLT2的活性增加,對(duì)葡萄糖和鈉的重吸收增強(qiáng)。而在糖尿病大鼠動(dòng)物模型中,SGLT2突變可防止高糖誘導(dǎo)的多器官功能損害。選擇性SGLT2抑制劑可改善糖尿病患者的高血糖,并有呈現(xiàn)出輕微的降壓作用。近10年來,過氧化物酶體增殖物激活受體(peroxisome proliferator-activated receptor,PPAR)已經(jīng)成為心血管代謝疾病的新型有效治療靶點(diǎn)。人類腎臟表達(dá)不同的三種PPAR亞型,PPARα,PPARγ和PPARδ,在機(jī)體的糖脂代謝中發(fā)揮了重要作用�，F(xiàn)今糖尿病治療用噻唑烷二酮類(TZD)藥物,就是通過激活脂肪組織PPARγ改善胰島素抵抗,從而發(fā)揮改善血糖的作用。然而,研究表明TZD類藥物可能導(dǎo)致水鈉潴留及心衰,大大限制了其臨床應(yīng)用。PPARδ在幾乎所有的細(xì)胞與組織中均存在表達(dá),被認(rèn)為參與了許多慢性病的發(fā)病過程,包括高血壓、糖尿病、粥樣硬化以及肥胖等,其特異性激動(dòng)劑或基因表達(dá)上調(diào)均可有效緩解肥胖伴糖尿病嚙齒類動(dòng)物的高血脂、血糖和胰島素抵抗。在糖尿病大鼠中,特異性激動(dòng)PPARδ表達(dá)后表現(xiàn)出腎臟保護(hù)作用。此外,PPARδ激動(dòng)劑增加的脂肪脂聯(lián)素的表達(dá),可在心血管疾病中發(fā)揮有益作用。然而,目前尚不清楚PPARδ是否通過調(diào)節(jié)脂聯(lián)素表達(dá)參與了腎臟對(duì)鈉的處置以及對(duì)葡萄糖的轉(zhuǎn)運(yùn)。脂聯(lián)素是脂肪組織尤其是內(nèi)臟脂肪組織分泌最豐富的蛋白質(zhì)產(chǎn)物。脂聯(lián)素通過其特異性受體,AdipoR1和AdipoR2,在多種組織和細(xì)胞中發(fā)揮其生理功能。已有研究發(fā)現(xiàn)PPARs在脂聯(lián)素的表達(dá)調(diào)控中發(fā)揮了重要作用。應(yīng)用PPARδ激動(dòng)劑可顯著升高內(nèi)臟脂肪脂聯(lián)素的表達(dá)水平,從而發(fā)揮改善心血管代謝紊亂的綜合效應(yīng)。血清脂聯(lián)素水平在多種代謝性心血管疾病中降低,同時(shí)低脂聯(lián)素水平可能是胰島素抵抗發(fā)生、發(fā)展的重要原因。攝鹽量對(duì)脂聯(lián)素分泌有重要作用,低鹽干預(yù)可顯著上調(diào)脂肪組織脂聯(lián)素分泌,同時(shí)改善胰島素抵抗以及全身炎癥反應(yīng)。但脂聯(lián)素如何參與鹽的代謝尚不明確。在本研究中,我們提出PPARδ通過調(diào)節(jié)脂聯(lián)素表達(dá)參與了腎小管SGLT2對(duì)鈉的轉(zhuǎn)運(yùn)和葡萄糖的重吸收過程,干預(yù)該環(huán)節(jié)中的一個(gè)或多個(gè)關(guān)鍵靶點(diǎn)可維持或恢復(fù)鈉和葡萄糖穩(wěn)態(tài)的科學(xué)假設(shè),并開展了一系列的細(xì)胞、動(dòng)物實(shí)驗(yàn)及臨床驗(yàn)證,為了驗(yàn)證上述假設(shè),本研究分為兩部分進(jìn)行:1、驗(yàn)證高鹽攝入影響血糖穩(wěn)態(tài)及鹽排泄,側(cè)重觀察PPARδ介導(dǎo)的脂聯(lián)素分泌對(duì)SGLT2產(chǎn)生作用及其對(duì)尿鈉及尿糖排泄的影響及其機(jī)制。2、在糖尿病動(dòng)物模型中觀察高鹽攝入對(duì)SGLT2作用的影響及其機(jī)制,并在臨床糖尿病患者中驗(yàn)證,結(jié)果表明脂肪PPARδ在脂聯(lián)素介導(dǎo)的腎臟SGLT2調(diào)節(jié)鈉糖平衡中發(fā)揮關(guān)鍵作用。材料與方法:本研究包括兩部分:1.驗(yàn)證高鹽對(duì)尿鈉排泄和葡萄糖穩(wěn)態(tài)的影響,研究高鹽致脂肪PPARδ激活后由脂聯(lián)素介導(dǎo)的促進(jìn)小鼠腎臟尿鈉和葡萄糖排泄的分子機(jī)制,同時(shí)在小鼠模型中測試SGLT2的急性功能改變。2.在第一部分實(shí)驗(yàn)基礎(chǔ)上,在db/db糖尿病動(dòng)物模型中研究高鹽攝入對(duì)SGLT2表達(dá)及功能的影響,并在臨床糖尿病患者中分析血糖、脂聯(lián)素、尿鈉三者的關(guān)系。1.3T3-L1前脂肪細(xì)胞以及C57BL/6小鼠原代脂肪細(xì)胞的分組培養(yǎng),免疫印跡檢測PPAR各亞型的表達(dá),并設(shè)立氯化鈉和甘露醇梯度的滲透壓濃度,作為對(duì)照觀察PPARδ的表達(dá)變化。2.脂肪特異敲除PPARδ小鼠(Fabp4-PPARδflox/flox)模型構(gòu)建,在高鹽(8%氯化鈉)和普食(0.4%氯化鈉)喂養(yǎng)條件下,觀察小鼠尿鈉排泄的變化、脂聯(lián)素的分泌及達(dá)格列凈(特異性SGLT2抑制劑)干預(yù)后腎臟SGLT2表達(dá)的變化。3.Adn-/-小鼠注射外源性脂聯(lián)素Acrp30,觀察其遷移表達(dá)特性。4.Adn+/+和Adn-/-小鼠分組培養(yǎng)后,予以PPARδ激動(dòng)劑,免疫印跡法檢測腎周脂肪及腎臟皮質(zhì)SGLT2、脂聯(lián)素的表達(dá),觀察小鼠尿鈉、尿糖排泄及糖耐量變化。5.高鹽及普食喂養(yǎng)db/db糖尿病小鼠后,觀察小鼠尿鈉、尿糖排泄等改變,予以達(dá)格列凈干預(yù),檢測小鼠腎臟SGLT2的表達(dá),并觀察小鼠24小時(shí)尿鈉、尿糖排泄及血糖變化。6.收集糖尿病患者血漿樣本,檢測患者空腹血糖、糖化血紅蛋白、血清脂聯(lián)素、24小時(shí)尿鈉,分析各指標(biāo)之間的相關(guān)性。結(jié)果:1.高鹽(8%鹽濃度)培養(yǎng)下3T3-L1前脂肪細(xì)胞和C57BL/6小鼠原代脂肪細(xì)胞中PPARδ表達(dá)顯著升高,氯化鈉和甘露醇(滲透壓對(duì)照)以濃度依賴的方式顯著增加PPARδ的表達(dá)。2.與Fabp4-PPARδflox/flox小鼠相比,8%高鹽攝入明顯降低PPARδflox/flox小鼠的空腹血糖水平。高鹽攝入顯著增加Fabp4-PPARδflox/flox小鼠和PPARδflox/flox小鼠尿量和尿鈉排泄以及血漿和腎周脂肪的鈉含量,同時(shí)降低血漿醛固酮水平。高鹽攝入顯著降低PPARδflox/flox小鼠腎臟皮質(zhì)SGLT2表達(dá)。達(dá)格列凈顯著增加高鹽喂養(yǎng)下PPARδflox/flox小鼠尿鈉及尿糖排泄。3.高鹽攝入的PPARδflox/flox小鼠腎周脂肪和腎皮質(zhì)中脂聯(lián)素表達(dá)顯著增加,血漿脂聯(lián)素水平在PPARδflox/flox小鼠升高而在Fabp4-PPARδflox/flox小鼠中降低。予以PPARδ激動(dòng)劑GW501516處理PPARδflox/flox小鼠原代培養(yǎng)的脂肪細(xì)胞致脂聯(lián)素表達(dá)升高,而PPARδ拮抗劑GSK0660則降低其表達(dá)。4.染色質(zhì)免疫共沉淀的結(jié)果表明,脂聯(lián)素(Acrp30)干預(yù)后,SLC5A2基因啟動(dòng)子部位HNF-1a和sp-1的結(jié)合水平顯著降低。5.GW501516顯著提高Adn+/+小鼠血漿脂聯(lián)素水平和腎周脂肪、腎皮質(zhì)脂聯(lián)素的表達(dá),但對(duì)Adn-/-小鼠無此效應(yīng),口服葡萄糖灌胃后,GW501516促進(jìn)尿鈉和尿糖排泄的作用在Adn-/-小鼠中削弱了。GW501516干預(yù)后腎臟SGLT2的表達(dá)明顯增強(qiáng),而高鹽對(duì)腎臟SGLT2表達(dá)的抑制作用在Adn-/-小鼠中消除了。6.高鹽飲食不僅增加db/db小鼠的尿鈉排泄,也增加尿量和尿糖。db/db小鼠腎臟SGLT2表達(dá)顯著高于db/m小鼠,而高鹽攝入可下調(diào)其表達(dá)。達(dá)格列凈干預(yù)后,高鹽喂養(yǎng)的db/db小鼠尿鈉排泄和尿糖的升高幅度低于db/m小鼠。7.在糖尿病患者中,尿鈉排泄與空腹血糖、糖化血紅蛋白存在顯著的負(fù)相關(guān)關(guān)系。此外,血糖或糖化血紅蛋白控制良好的糖尿病患者的尿鈉排泄更高,尿鈉排泄量和血漿脂聯(lián)素水平之間有明顯的相關(guān)性。結(jié)論:1.脂肪組織PPARδ激活促進(jìn)小鼠在高鹽攝入條件下的尿鈉和尿糖排泄增加,這與腎臟近端小管上SGLT2表達(dá)及功能抑制有關(guān)。脂肪組織PPARδ介導(dǎo)的脂聯(lián)素在抑制腎臟SGLT2中起著至關(guān)重要的作用。2.在生理情況下,高鹽攝入誘導(dǎo)的糖尿病小鼠尿鈉排泄受損源于高糖導(dǎo)致的SGLT2活性增加。3.血糖控制不佳的2型糖尿病患者尿鈉排泄減少,且糖尿病患者的血漿脂聯(lián)素水平尿鈉排泄密切相關(guān)。
[Abstract]:Background and purpose: the management of hypertension in diabetic patients is the key to reducing cardiovascular mortality and morbidity. For a long time, the diet regulation scheme of hypertension focuses on salt intake. Therefore, the major guidelines recommend diabetes and hypertension patients to limit salt intake. However, the potential benefits of salt restriction are still controversial, some evidence is still disputed. It is shown that salt restriction increases cardiovascular and total mortality in patients with diabetes and hypertension, and the effect of high sugar diet on high blood pressure is far greater than high salt intake. However, there is still a lack of research on the close link between salt intake and blood glucose homeostasis. At the same time, it plays a vital role in the filtration and reabsorption of glucose. Among them, the sodium glucose co transporter (SGLTs), distributed on the side of the proximal tubular epithelial cell of the renal cortex, has the function of regulating sodium and sugar reabsorption, and can transport Na+ and glucose at high efficiency with 1:1. In high glucose state, the activity of SGLT2 Increased heavy absorption of glucose and sodium. In the diabetic rat model, SGLT2 mutation prevents high glucose induced multiple organ dysfunction. Selective SGLT2 inhibitors can improve hyperglycemia in diabetic patients and have a slight hypotensive effect. In the last 10 years, the peroxisome proliferator activated receptor (peroxisome P) Roliferator-activated receptor, PPAR) has become a new and effective target for the treatment of cardiovascular metabolic diseases. Human kidneys express three different PPAR subtypes, PPAR alpha, PPAR gamma and PPAR Delta, which play an important role in the body's glycolipid metabolism. Nowadays, the thiazolidane two ketone (TZD) drug is used for the treatment of diabetes by activating the fat tissue PP AR gamma improves insulin resistance and thus plays a role in improving blood sugar. However, studies have shown that TZD drugs may lead to sodium retention and heart failure, which greatly restricts the clinical application of.PPAR Delta expression in almost all cells and tissues, and is considered to be involved in the pathogenesis of many chronic diseases, including hypertension, diabetes, and atheromatous disease. It can effectively alleviate hyperlipidemia, blood glucose and insulin resistance in obese and diabetic rodents. In diabetic rats, specific excitated PPAR Delta expression shows renal protection in diabetic rats. In addition, the expression of fat adiponectin, which is increased by PPAR delta irritation agent, may be in the heart. However, it is not clear whether PPAR delta is involved in the treatment of sodium and transshipment of glucose by regulating adiponectin expression. Adiponectin is the most abundant protein product secreted by adiponectin, especially visceral adipose tissue. Adiponectin, through its specific receptors, AdipoR1 and AdipoR2, is in a variety of ways. It has been found that PPARs plays an important role in the regulation of the expression of adiponectin. The application of PPAR delta activator can significantly increase the level of visceral adiponectin, thus exerting a comprehensive effect on the improvement of cardiovascular metabolic disorders. Low level of adiponectin may be an important factor in the development of insulin resistance. Salt intake plays an important role in adiponectin secretion. Low salt intervention can significantly increase adiponectin secretion, and improve insulin resistance and systemic inflammatory response. However, how lipoplin participates in the metabolism of salt is not clear. We suggest that PPAR delta participates in the process of sodium transport and glucose reabsorption in renal tubule SGLT2 by regulating adiponectin expression, and interferes with the scientific hypothesis that one or more key targets in this link can maintain or restore sodium and glucose homeostasis, and carry out a series of cell, animal experiments and clinical validation, in order to verify the above It is assumed that this study is divided into two parts: 1, to verify the effect of high salt intake on blood glucose homeostasis and salt excretion, and to observe the effect of PPAR delta mediated adiponectin secretion on SGLT2 and its effect on urine sodium and urine sugar excretion and its mechanism.2. In diabetic animal model, the effect of high salt intake on SGLT2 and its mechanism are observed and in clinical practice. The results showed that the fat PPAR delta plays a key role in the adiponectin mediated SGLT2 regulating sodium glucose balance in the kidney. Materials and methods: This study includes two parts: 1. the effect of high salt on urinary sodium excretion and glucose homeostasis, and the promotion of kidney urine induced by adiponectin in mice after high salt induced adipose PPAR delta activation The molecular mechanism of sodium and glucose excretion, and testing the acute functional change of SGLT2 in the mouse model.2. on the basis of the first part of the experiment, the effect of high salt intake on SGLT2 expression and function in the db/db diabetic animal model was studied, and the relationship between blood sugar, adiponectin, and urine sodium three was analyzed in the clinical diabetic patients with.1.3T3-L1 pre fat. The fat cells and the primary adipocytes of C57BL/6 mice were grouped, and the expression of PPAR subtypes was detected by Western blot, and the osmotic pressure of sodium chloride and mannitol gradient was set up. As a control observation, the expression of PPAR delta was observed by.2. fat specific knockout PPAR Delta (Fabp4-PPAR Delta Flox /flox) model, in high salt (8% sodium chloride) and universal food (0 The changes of urine sodium excretion, secretion of adiponectin and the changes of SGLT2 expression in renal SGLT2 after intervention were observed in mice. The.3.Adn-/- mice were injected with exogenous adiponectin Acrp30 after intervention. The migration expression characteristics of.4.Adn+/+ and Adn-/- mice were observed, and PPAR delta agonists were immunized and immunized with PPAR delta activator. The expression of SGLT2, renal cortex and renal cortex, the expression of adiponectin, mice urine sodium, urine sugar excretion and glucose tolerance change.5. high salt and universal diet feeding db/db diabetic mice were observed. The changes of urine sodium and urine sugar excretion were observed in mice. The expression of SGLT2 in kidney of rats was measured and the expression of renal SGLT2 was detected in mice, and the urine sodium and urine sugar were observed for 24 hours in mice. Excretory and blood glucose changes.6. collected plasma samples of diabetic patients, tested the patient's fasting blood glucose, glycated hemoglobin, serum adiponectin, 24 hour urine sodium, and analyzed the correlation between the indexes. Results: the expression of PPAR Delta in 3T3-L1 preadipocytes and C57BL/6 rat primary adipocytes increased significantly under the 1. high salt (8% salt concentration) culture, and the sodium chloride and sodium chloride were significantly increased. Mannitol (osmotic control) significantly increased the expression of PPAR Delta.2. in a concentration dependent manner compared with Fabp4-PPAR Delta flox/flox mice. 8% high salt intake significantly reduced the fasting blood glucose level of PPAR Delta flox/flox mice. High salt intake significantly increased the urine volume and sodium excretion of PPAR Delta flox/flox mice and PPAR Delta flox/flox mice, as well as the plasma and plasma levels. Sodium content of perirenal fat and plasma aldosterone levels decreased plasma aldosterone levels. High salt intake significantly reduced the expression of SGLT2 in renal cortex of PPAR Delta flox/flox mice. Da glitjing significantly increased the expression of PPAR Delta flox/flox mice in the urinary sodium and urine sugar excretion of.3. high salt intake of PPAR Delta flox/flox mice, and the expression of adiponectin in the renal cortex and renal cortex was significantly increased. Adding, plasma adiponectin levels were increased in PPAR Delta flox/flox mice and decreased in Fabp4-PPAR Delta flox/flox mice. PPAR delta agonist GW501516 treated the primary cultured adipocytes of PPAR Delta flox/flox mice to increase the expression of adiponectin, while PPAR delta antagonist GSK0660 decreased its expression of.4. chromatin immunoprecipitation. After Acrp30, the binding level of HNF-1a and SP-1 at the promoter of SLC5A2 gene significantly decreased.5.GW501516 significantly increased plasma adiponectin level and perirenal adiponectin and renal cortex adiponectin expression in Adn+/+ mice, but had no effect on Adn-/- mice. After oral glucose administration, GW501516 promoted urine sodium and urine glucose excretion in Adn-/-. In mice, the expression of kidney SGLT2 was markedly enhanced after.GW501516 drying, and the inhibition of SGLT2 expression in the kidney was eliminated in Adn-/- mice by the inhibition of.6. high salt diet not only to increase the urine sodium excretion of db/db mice but also to increase urine volume and urine sugar.Db/db mouse kidney SGLT2 expression to be higher than db/m mice, while high salt intake could reduce the expression of SGLT2. The urine sodium excretion and urine sugar in db/db mice fed with high salt were lower than that of db/m mice.7. in diabetic patients. There was a significant negative correlation between sodium excretion and fasting blood glucose and glycosylated hemoglobin. In addition, the urine sodium excretion of diabetic patients with good control of glycemic hemoglobin was higher, and urine excretion was higher. There is a significant correlation between sodium excretion and plasma adiponectin levels. Conclusion: 1. PPAR delta activation in adipose tissue increases the excretion of urine and urine sugar in mice under high salt intake, which is related to the expression of SGLT2 and function inhibition on the proximal tubules of the kidney. Adipose tissue PPAR delta mediated adiponectin plays a critical role in inhibiting renal SGLT2. The role of.2. in physiological conditions is that the impaired urinary sodium excretion in diabetic mice induced by high salt intake is derived from high glucose induced SGLT2 activity and the decrease of urine sodium excretion in type 2 diabetic patients with poor control of.3. glucose control, and the plasma adiponectin level in diabetic patients is closely related to the urinary sodium excretion.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R587.1;R544.1

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1 ;PPARγ phosphorylation mediated by JNK MAPK:a potential role in mac-rophage-derived foam cell formation[J];Acta Pharmacologica Sinica;2006年09期

2 任黔川;彭芝蘭;譚欣;;PPARγ在卵巢漿液性囊腺癌中的表達(dá)[J];重慶醫(yī)學(xué);2009年23期

3 張乾勇;PPAR的結(jié)構(gòu)與功能及其生物學(xué)作用[J];國外醫(yī)學(xué)(衛(wèi)生學(xué)分冊);2000年05期

4 白玉杰,牛丹,趙錦榮,張文紅,呂貫廷,閻小君;Rapid detection of PPAR_γ gene Pro12Ala polymorphism with fluorescence polarization in Chinese population[J];Journal of Medical Colleges of PLA;2003年03期

5 袁平戈;PPARα的主要功能是什么[J];中華肝臟病雜志;2003年05期

6 潘光棟;PPAR-γ及其配體在人體細(xì)胞的分子研究[J];職業(yè)衛(wèi)生與病傷;2003年02期

7 曹廷兵,葉治家,彭家和,鞏燕,黃剛;人PPARγ2 cDNA的克隆及其在大腸桿菌中的表達(dá)純化[J];第三軍醫(yī)大學(xué)學(xué)報(bào);2004年01期

8 王剛,陳繼俊,倪沛洲;PPARα受體亞型與新藥研究[J];藥學(xué)進(jìn)展;2004年01期

9 葉平;過氧化體增殖物激活型受體(PPAR)與心血管疾病[J];中華心血管病雜志;2004年07期

10 孫曙光,周智廣;PPARγ與1型糖尿病[J];國外醫(yī)學(xué).內(nèi)分泌學(xué)分冊;2005年02期

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1 ;Genetic polymorphisms of PPAR-γ,HHEX,PTPRD,KCNQ1,and SRR affect therapeutic efficacy of Pioglitazone in Chinese Patients with type 2 diabetes[A];傳承與發(fā)展，，創(chuàng)湖南省生理科學(xué)事業(yè)的新高——湖南省生理科學(xué)會(huì)2011年度學(xué)術(shù)年會(huì)論文摘要匯編[C];2011年

2 ;Dynamic analysis and ligand binding affinity investigation of PPAR mutations[A];華東六省一市生物化學(xué)與分子生物學(xué)會(huì)2003年學(xué)術(shù)交流會(huì)論文摘要集[C];2003年

3 童南偉;;過氧化物酶增殖物激活受體(PPAR)a與脂質(zhì)代謝[A];全國首屆代謝綜合征的基礎(chǔ)與臨床專題學(xué)術(shù)會(huì)議論文匯編[C];2004年

4 王偉銘;章慧娣;劉峰;陳佳韻;陳楠;;PPARγ活化對(duì)腎間質(zhì)成纖維細(xì)胞的作用研究[A];2007年浙滬兩地腎臟病學(xué)術(shù)年會(huì)資料匯編[C];2007年

5 陳剛;林新富;梁繼興;林麗香;沈曉麗;;過氧化物酶體增殖物激活受體γ(PPARγ)基因多態(tài)性與老年男性骨質(zhì)疏松癥相關(guān)性研究[A];2008內(nèi)分泌代謝性疾病系列研討會(huì)暨中青年英文論壇論文匯編[C];2008年

6 陳剛;林新富;梁繼興;林麗香;沈曉麗;;過氧化物酶體增殖物激活受體γ(PPARγ)基因多態(tài)性與老年男性骨質(zhì)疏松癥相關(guān)性研究[A];2008中國醫(yī)師協(xié)會(huì)內(nèi)分泌代謝科醫(yī)師分會(huì)年會(huì)論文匯編[C];2008年

7 李潔;戴愛國;胡瑞成;朱黎明;王梅芳;;PPARγ影響γ-谷氨酰半胱氨酸合成酶活性及表達(dá)在大鼠慢性阻塞性肺疾病中的作用[A];中國生理學(xué)會(huì)第23屆全國會(huì)員代表大會(huì)暨生理學(xué)學(xué)術(shù)大會(huì)論文摘要文集[C];2010年

8 管又飛;;脂質(zhì)過氧化物體增殖物激活受體γ(PPAR γ)與糖尿病腎病[A];中華醫(yī)學(xué)會(huì)腎臟學(xué)分會(huì)2004年年會(huì)暨第二屆全國中青年腎臟病學(xué)術(shù)會(huì)議專題講座匯編[C];2004年

9 孫莉;尚進(jìn)林;梁浩;程焱;;PPAR全激動(dòng)劑對(duì)小鼠局灶性腦缺血再灌注損傷的保護(hù)作用[A];第十一屆全國神經(jīng)病學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2008年

10 ;Endothelial PPARγmediates anti-inflammatory actions of rosiglitazone through dissociation of NF-κB[A];中國生理學(xué)會(huì)心血管生理學(xué)術(shù)研討會(huì)論文集[C];2011年

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1 徐錚奎;發(fā)現(xiàn)PPAR拮抗劑[N];醫(yī)藥經(jīng)濟(jì)報(bào);2012年

2 曾凡新邋林敏;PPAR激動(dòng)劑類抗糖尿病藥研發(fā)喜憂參半[N];中國醫(yī)藥報(bào);2007年

3 袁松范;開發(fā)PPAR多通道激動(dòng)劑須謹(jǐn)慎[N];中國醫(yī)藥報(bào);2006年

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1 孫芳;高鹽攝入通過SGLT2調(diào)控血糖穩(wěn)態(tài)的機(jī)制[D];第三軍醫(yī)大學(xué);2017年

2 劉炳婷;SUMO特異性蛋白酶1調(diào)控脂肪形成的作用及分子機(jī)制[D];上海交通大學(xué);2014年

3 陳宏;巨噬細(xì)胞PPARγ對(duì)皮膚傷口愈合的作用研究[D];第三軍醫(yī)大學(xué);2015年

4 韓晶;PPARγ在腦缺血再灌注損傷和過氧化氫損傷中的調(diào)控機(jī)制研究[D];天津醫(yī)科大學(xué);2014年

5 張鷗;阿托伐他汀對(duì)動(dòng)脈粥樣硬化患者外周血中PPAR γ的作用研究及相關(guān)炎癥因子與動(dòng)脈粥樣硬化關(guān)系的建模分析[D];鄭州大學(xué);2016年

6 周毅;PPARγ介導(dǎo)的抗氧化機(jī)制在血管平滑肌細(xì)胞表型轉(zhuǎn)化中作用和機(jī)制研究[D];第三軍醫(yī)大學(xué);2016年

7 滕志朋;PPARβ/δ在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及其機(jī)制研究[D];重慶醫(yī)科大學(xué);2016年

8 佟強(qiáng);PPARβ/δ激活在帕金森病中的保護(hù)作用及機(jī)制研究[D];南京醫(yī)科大學(xué);2016年

9 張花治;紅芪多糖對(duì)db/db小鼠糖尿病心肌病心肌保護(hù)作用及PPARγ/NF-κB信號(hào)通路的影響[D];甘肅中醫(yī)藥大學(xué);2017年

10 任凌云;T細(xì)胞PPARγ在心臟移植慢性排反應(yīng)中的作用及機(jī)制研究[D];華中科技大學(xué);2016年

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1 曹智麗;過氧化物酶增殖物激活受體α（PPARα）在大鼠酒精性肝病發(fā)生過程中的變化[D];河北醫(yī)科大學(xué);2015年

2 宋石;miR-27a通過靶向調(diào)控PPARγ對(duì)酒精誘導(dǎo)大鼠BMSC分化的影響[D];鄭州大學(xué);2015年

3 鄒佳楠;PPAR-γ在IgA腎病發(fā)生中的作用及其機(jī)理研究[D];復(fù)旦大學(xué);2014年

4 陶曉燕;PPAR δ激動(dòng)劑和siRNA對(duì)大鼠骨髓基質(zhì)干細(xì)胞及成骨細(xì)胞分化和礦化的作用研究[D];安徽醫(yī)科大學(xué);2015年

5 于飛;新型PPARγ激動(dòng)劑對(duì)人腎癌細(xì)胞增殖抑制及其機(jī)制的研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2015年

6 何修界;PPARγ激活對(duì)GDM小鼠胎盤脂肪酸運(yùn)輸?shù)鞍妆磉_(dá)水平的影響[D];安徽醫(yī)科大學(xué);2015年

7 魏璇;PPARγ通過對(duì)RUVBL2表達(dá)調(diào)控影響脂聯(lián)素分泌的研究[D];華中農(nóng)業(yè)大學(xué);2015年

8 游潔冰;PPARγ激動(dòng)劑、胰島素通過上調(diào)負(fù)性炎性因子TIPE2的表達(dá)抑制高糖、Aβ1-40引起的炎性反應(yīng)及神經(jīng)細(xì)胞調(diào)亡[D];山東大學(xué);2015年

9 劉常為;CTGF、COL-I、PPARγ在卵巢細(xì)胞外基質(zhì)的表達(dá)及與多囊卵巢綜合征的關(guān)系[D];暨南大學(xué);2015年

10 曹小潔;TLR4通過PPARγ下調(diào)ABCG1表達(dá)促進(jìn)血管平滑肌細(xì)胞內(nèi)炎癥反應(yīng)及脂質(zhì)沉積[D];第三軍醫(yī)大學(xué);2015年

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