本文選題：Sirt1 + 白藜蘆醇��； 參考：《復(fù)旦大學(xué)》2013年碩士論文

【摘要】：研究背景與目的 痛風(fēng)是嘌呤代謝紊亂和(或)尿酸排泄障礙導(dǎo)致血尿酸升高的一組疾病,以在關(guān)節(jié)滑液和其他組織中形成單鈉尿酸鹽(monosodium urate, MSU)晶體為特點(diǎn)。痛風(fēng)性關(guān)節(jié)炎以反復(fù)發(fā)作的急性炎癥、慢性痛風(fēng)石形成及骨侵蝕為主要臨床表現(xiàn),高尿酸血癥是其重要的病理基礎(chǔ)。目前研究認(rèn)為痛風(fēng)性關(guān)節(jié)炎的機(jī)制主要是MSU晶體通過識(shí)別細(xì)胞表面的Toll樣受體激活NF-κB、AP-1信號(hào)通路啟動(dòng)炎癥。MSU晶體也能夠激活NALP3炎癥復(fù)合體,最終導(dǎo)致成熟的IL-1β的釋放。因此降低血尿酸濃度、抑制炎癥通路可能是預(yù)防及治療痛風(fēng)發(fā)作的有效措施。 近期研究發(fā)現(xiàn),沉默調(diào)節(jié)因子1(silent information regulator1, Sirtl)可能通過抑制NF-κB和AP-1的轉(zhuǎn)錄活性以及下調(diào)多種炎癥相關(guān)因子的表達(dá)來緩解炎癥。此外,Sirt1可調(diào)節(jié)細(xì)胞代謝,參與調(diào)控多種代謝性疾病,研究證明Sirt1激動(dòng)劑可降低高血糖并抑制肝臟脂肪變性。白藜蘆醇(resveratrol, Res)為Sirt1的激動(dòng)劑之一,是一種多酚類天然植物抗毒素。 本文通過建立持續(xù)的小鼠高尿酸血癥模型及MSU誘導(dǎo)的小鼠急性痛風(fēng)性關(guān)節(jié)炎模型,給予Sirt1激動(dòng)劑白藜蘆醇干預(yù)各模型,觀察白藜蘆醇在痛風(fēng)中的作用。 研究?jī)?nèi)容與方法 一、小鼠持續(xù)高尿酸血癥模型的建立及白藜蘆醇對(duì)小鼠高尿酸血癥的干預(yù)作用 以含25%酵母膏飼料喂食6周齡雄性昆明小鼠,聯(lián)合氧嗪酸鉀250mg/Kg腹腔注射,每天一次,連續(xù)3周建立高尿酸血癥模型。治療組在建模的同時(shí)予Sirt1激動(dòng)劑白藜蘆醇20mg/Kg灌胃,每天一次,不同時(shí)間點(diǎn)經(jīng)內(nèi)眥靜脈采血檢測(cè)小鼠血尿酸、肌酐濃度,HE染色法檢測(cè)腎臟組織的病理改變。 二、白藜蘆醇對(duì)MSU誘導(dǎo)的小鼠急性關(guān)節(jié)炎的干預(yù) 在6-8周齡的C57BL/6雄性小鼠足掌部注射MSU誘導(dǎo)痛風(fēng)關(guān)節(jié)炎模型,通過數(shù)顯卡尺測(cè)量足掌厚度評(píng)價(jià)關(guān)節(jié)腫脹程度,應(yīng)用檢測(cè)99mTc吸收率評(píng)價(jià)關(guān)節(jié)炎癥程度,于不同時(shí)間點(diǎn)給予不同劑量的白藜蘆醇干預(yù)治療,評(píng)估關(guān)節(jié)炎癥變化。 研究結(jié)果 酵母膏聯(lián)合氧嗪酸鉀可建立持續(xù)、穩(wěn)定的高尿酸血癥模型,其中建模的第3-14d血尿酸水平顯著升高且無腎功能損害表現(xiàn),而建模的第21d血尿酸水平上升幅度減緩,肌酐輕度上升,腎臟病理見腎小球囊壁增厚,腎間質(zhì)炎性細(xì)胞浸潤(rùn),腎小管上皮細(xì)胞腫脹。干預(yù)組在誘導(dǎo)高尿酸模型同時(shí)給予白藜蘆醇治療,小鼠血尿酸水平較模型組同期明顯下降(P0.05),且上述腎臟病變好轉(zhuǎn)。 MSU晶體局部注射可誘導(dǎo)小鼠急性關(guān)節(jié)炎,炎癥表現(xiàn)程度與MSU濃度呈正比,具有一定的時(shí)間限定性,在MSU注射后8-12h小鼠足掌炎癥表現(xiàn)最顯著,24小時(shí)后炎癥逐漸減輕。給予白藜蘆醇預(yù)處理后MSU誘導(dǎo)的關(guān)節(jié)炎癥較對(duì)照組有所緩解(P0.05),白藜蘆醇分別預(yù)處理3天、7天、14天后再予MSU誘導(dǎo)炎癥發(fā)現(xiàn)預(yù)處理14天組小鼠關(guān)節(jié)炎癥最輕,且該作用與白藜蘆醇的劑量呈正相關(guān)。 研究結(jié)論 1.酵母膏聯(lián)合氧嗪酸鉀可建立持續(xù)、穩(wěn)定的高尿酸血癥模型。 2. Sirt1激動(dòng)劑白藜蘆醇可以通過其降尿酸作用和炎癥調(diào)節(jié)作用來預(yù)防和治療痛風(fēng)發(fā)作。
[Abstract]:Research background and purpose
Gout is a group of diseases characterized by a disorder of the purine metabolism and / or uric acid excretion, which is characterized by the formation of monosodium urate (MSU) crystals in synovial fluid and other tissues. The main clinical manifestations of gouty arthritis are recurrent acute inflammation, chronic gout formation and bone erosion, and high uric acid The main mechanism of hyperarthritis is that the mechanism of gouty arthritis is that the MSU crystal activates NF- kappa B by identifying the Toll like receptor on the surface of the cell, and the AP-1 signaling pathway activates the NALP3 inflammatory complex and eventually leads to the release of the mature IL-1 beta, thus reducing the concentration of blood uric acid and inhibiting the inflammation. The disease pathway may be an effective measure to prevent and treat gout attacks.
Recent studies have found that silent information regulator1 (Sirtl) may alleviate inflammation by inhibiting the transcriptional activity of NF- kappa B and AP-1 and down regulating the expression of a variety of inflammatory related factors. In addition, Sirt1 can regulate cell metabolism and participate in the regulation of various metabolic diseases. Studies have shown that Sirt1 agonists can reduce hyperglycemia and Inhibition of hepatic steatosis, resveratrol (Res) is one of the agonists of Sirt1, and is a polyphenol natural plant antitoxin.
By establishing a continuous hyperuricemia model in mice and the model of acute gouty arthritis in mice induced by MSU, the effects of resveratrol on the gout were given by the intervention of resveratrol in each model with Sirt1 agonist.
Research content and method
Establishment of a mouse model of persistent hyperuricemia and intervention of resveratrol on hyperuricemia in mice
6 weeks of male Kunming mice were fed with 25% yeast extract, combined with potassium oxazine 250mg/Kg intraperitoneally, once a day for 3 weeks to establish hyperuricemia model. The treatment group was given Sirt1 agonist resveratrol 20mg/Kg at the same time, once a day, blood uric acid and creatinine concentration were detected at different time points through the canthus vein. The pathological changes of renal tissue were detected by HE staining.
Two, the effect of resveratrol on MSU induced acute arthritis in mice.
The model of gouty arthritis was induced by MSU in the foot of the 6-8 week old C57BL/6 male mice. The degree of joint swelling was evaluated by measuring the thickness of the foot of the foot by measuring the thickness of the palmar palmar. The degree of arthritis was evaluated by measuring the 99mTc absorption rate, and the different doses of resveratrol were given at different time points to evaluate the changes of arthritis.
Research results
The yeast ointment combined with potassium oxazine could establish a continuous and stable hyperuricemia model, in which the level of serum uric acid in the model 3-14d increased significantly and had no renal impairment, but the level of serum uric acid in the modeling 21d was slowed down, creatinine was slightly increased, the renal small balloon wall thickening, renal interstitial inflammatory cell infiltration and renal tubules were found in the kidney pathology. The epithelial cells were swollen. The intervention group was treated with resveratrol at the same time in the induced hyperuricic acid model. The serum uric acid level of the mice was significantly lower than that of the model group (P0.05), and the above renal pathological changes were improved.
Local injection of MSU can induce acute arthritis in mice. The degree of inflammation is proportional to the concentration of MSU, and it has a certain time limit. After MSU injection, the inflammation of the foot palms of 8-12h mice is the most obvious. After 24 hours, the inflammation gradually decreases. After the resveratrol pretreatment, the MSU induced arthritis is relieved (P0.05), resveratrol Resveratol was pretreated for 3 days, 7 days, and 14 days later, and then MSU induced inflammation was found to be pretreated for 14 days in mice with the lightest inflammation, and the effect was positively correlated with the dose of resveratrol.
research conclusion
1. yeast extract combined with potassium oxazinate can establish a sustained and stable hyperuricemia model.
2. Sirt1 agonist resveratrol can prevent and treat gout attacks through its lowering of uric acid and inflammatory regulation.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R589.7;R-332

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