English
聯系我們
網站地圖
郵箱
舊版回顧



【解放日報】科學家合作揭示環形RNA在天然免疫過程中的重要功能

文章來源:解放日報 黃海華   發布時間:2019-04-26  【字號:     】  

  中科院生物化學與細胞生物學研究所陳玲玲研究組發現,環形RNA(核糖核酸)管理著抗病毒“衛士”——天然免疫因子PKR的活性。在細胞受到病毒感染時,環形RNA會被大規模“清除”,從而釋放PKR參與抗病毒免疫反應;而在PKR過度激活的紅斑狼瘡病人體內,環形RNA含量顯著降低。該研究不僅為環形RNA代謝和功能研究奠定了重要基礎,也為紅斑狼瘡等自身免疫疾病的臨床診斷和治療提供了新思路。相關論文昨天發表于國際權威學術期刊《細胞》。

  生命體中也有“暗物質”

  宇宙中存在著暗物質,生命體中也存在著“暗物質”——非編碼RNA。人類基因組序列中僅1%—2%為蛋白質編碼序列,98%為非編碼序列。已經有越來越多的證據表明,一些重大疾病與非編碼RNA調控失衡相關。2011年以前,人們以為RNA只有線形結構,近年來,隱身于細胞中數以萬計的非編碼環形RNA逐漸浮出水面,但其至今仍有許多未解之謎。

  在之前的研究中,陳玲玲研究組和中國科學院—馬普學會計算生物學伙伴研究所楊力研究組發現環形RNA“生得曲折”——生成速度特別緩慢。他們在近期研究環形RNA的二級結構過程中發現,它們能夠被天然免疫因子PKR識別并結合,PKR活性因此受到抑制,這樣可以避免體內因PKR過度激活引起的免疫反應。而細胞中的核糖核酸酶RNase L則可以讓PKR恢復自由身,這類酶在細胞受病毒刺激下可作用于環形RNA,將其“切割”降解。“90%以上的環形RNA會被降解,算是‘死得其所’吧!”陳玲玲說,環形RNA由于生成速度特別緩慢,不足以回補這些被降解的環形RNA,天然免疫因子PKR因此得以釋放,參與細胞的抗病毒免疫過程。

  環形RNA過少會怎樣

  顯而易見,過多的環形RNA不利于細胞天然免疫應答,如果環形RNA過少會怎樣?研究人員發現,當環形RNA含量顯著降低,天然免疫因子PKR則會被過度激活。“對于這一結果,我們猜想這一異常情況是否會與炎癥性自身免疫疾病相關。”帶著這樣的疑問,陳玲玲開始了與上海交通大學醫學院附屬仁濟醫院上海風濕病研究所所長沈南教授的合作。

  他們檢測紅斑狼瘡病人體內免疫細胞發現,環形RNA含量相對正常人明顯降低,PKR免疫因子一直處于過度激活狀態,從而引發體內免疫應答系統過度“運轉”。科研人員通過技術手段讓環形RNA在病人來源的免疫細胞內數量增多,可以觀察到過度激活“運轉”的PKR及其下游免疫信號通路被顯著“控制”。

  “這一發現對于我們臨床醫生來說,真是激動人心!”沈南連聲贊嘆。紅斑狼瘡會造成患者多個器官受損,致死率在自身免疫病中居高不下。亞洲人的發病率較高,其中女性患者占90%。我國紅斑狼瘡的發病率為1‰,是西方白種人群的8—10倍,發病人群高達數百萬。盡管在10多年前人們已經知道,抗病毒相關的先天免疫反應在病人身上過度被激活,但究竟是如何被激活的一直不清楚,因此缺乏有效的藥物靶點。目前的臨床治療副作用危害極大,已成為病人死亡的主要原因。“先天免疫反應就像是一匹馬,脫韁了就會橫沖直撞,而環形RNA就像是套在馬上的韁繩。這為解決一直以來困擾我們臨床醫生的發病機理問題提供了新的視角。今年以來,國際上已有多個基于RNA治療的藥物完成了三期臨床試驗。盡管這一發現還是個基礎研究工作,但給紅斑狼瘡的新藥開發帶來了希望。”

  中國工程院院士曹雪濤認為,該工作把環形RNA與天然免疫應答調控機制以及紅斑狼瘡發病機制聯系在一起開展研究,為炎癥性自身免疫疾病發病機制及未來的干預治療提出了新的思路與潛在靶點。

  論文的插圖是一盆盛開的銅錢草,藝術化地展現了如銅錢草葉般的環形RNA,借用銅錢草的藥用價值暗示環形RNA具有潛在應用價值。“如果能夠服務人們的健康,我會歡呼雀躍,但免疫應答是一個非常復雜的過程,未來的路還很長。”陳玲玲說,目前的研究還在細胞水平,接下來將會利用小鼠模型做進一步的嘗試。

  (原載于《解放日報》 2019-04-26 06版)




(責任編輯:侯茜)

附件:

專題推薦

相關新聞


© 1996 - 中國科學院 版權所有 京ICP備05002857號  京公網安備110402500047號  聯系我們

地址:北京市三里河路52號 郵編:100864

亚投彩票www.ya390.com www.102508.com | 9896.net | www.26hb.com | www.113946.com | www.920091.com | 985904.com | 世彩堂www.5854x.cc | www.rp57.com | 794511.com | www.790280.com | www.34213.com | www.979330.com | 389531.com | 974215.com | dn99.cc | www.647447.com | www.152913.com | www.b32.top | www.7718.com | www.381854.com | www.823.tv | www.715478.com | www.11nsb.com | www.wo23.com | 553112.com | www.36qo.com | www.251800.com | www.684489.com | www.408484.com | 088307.com | www.969372.com | 杏彩www.00840g.com | www.12995.cc | www.652661.com | 056805.com | www.zw87.com | www.800988.com | www.53375.cc | www.388249.com | www.669908.com | www.3833.cn | www.225010.com | www.900249.com | 654940.com | www.150146.com | www.93hu.com | www.362142.com | www.87477.cc | www.608687.com | www.869.cc | 804415.com | www.651140.com | www.905004.com | www.894865.com | www.847321.com | 900207.com | 116931.com | www.nz97.com | 269233.com | www.940037.com | www.go48.com | www.532099.com | 946630.com | www.hc63.cc | 356956.com | www.57vz.com | 312192.com | www.d15.club | www.028446.com | www.760348.com | 98117.com | www.505464.com | 彩多多www.78949y.com | www.437413.com | www.ck54.com | www.39158.com | www.706071.com | 649111.com | 955155.com | www.1237.site | www.609151.com | www.924440.com | www.71ug.com | www.858822.com | www.349619.com | www.620404.com | 693713.com | 348532.com | www.357104.com | www.924666.com | 507555.com | www.920907.com | www.115477.com | www.6396.cm | 761784.com | www.665328.com | www.19255.cc | www.268484.com | www.84hn.com | www.95491.com | www.100085.com | www.244822.com | www.732552.com | 055524.com | www.968722.com | www.979086.com | 5777.hk--747.hk | 081016.com | 561478.com | www.65yy.com | www.303.cx | www.81xy.com | www.177385.com | www.203147.com | www.263584.com | www.256508.com | www.957143.com | www.901546.com | www.748253.com | www.158903.com | www.208988.com | www.743464.com | www.415908.com | 680772.com | www.169935.com | www.16vt.com | www.12nz.com | www.tt52.cc | www.163218.com | www.86885.cc | www.138555.com | www.do03.com | www.96py.com | www.134689.com | www.460888.cc | www.868396.com | 907909.com | 609551.com | 770219.com | 983660.com | 990108.com | www.987098.com | www.875867.com | www.cai3912.com | www.342033.com | www.676022.com | www.014933.com | www.as97.com | www.tc10.cc | www.49xg.com | 979706.com | www.825493.com | 935016.com | 472360.com | 463803.com | www.772911.com | www.286931.com | www.69ja.com | www.985904.com | 872307.com | www.027735.com | 733523.com | www.797058.com | www.852385.com | 500彩票www.602430.com | www.68bv.com | www.e23.club | www.022734.com | www.90ja.com | 788460.com | www.723333.com | www.992004.com | www.425214.com | www.90re.com | 250317.com | 042333.cc | www.570582.com | www.502683.com | www.03838.com | 630878.com | www.667928.com | www.185269.com | 824931.com | www.644428.com | 68彩票www.68682h.com | www.44bc.com | www.85056.com | www.154686.com | 288518.com | www.714071.com | www.168067.com | www.893088.com | 701157.com | www.cp077.com | www.jy20.com | www.2076.net | www.881880.com | www.77ce.com | www.8357.wang | www.854000.com | www.9892.cn | www.088746.com | www.169121.com | www.361650.com | www.010073.com | 636470.com | 682881.com | www.164047.cc | www.914025.com | 220680.com | 632113.com | www.004760.com | www.2867.pw | www.ed45.com | www.713.bid | www.061125.com | www.55033.cc | www.609029.com | www.692881.com | 990105.com | 922856.com | 573221.com | www.888578.com | 571579.com | www.128521.com | www.795878.com | 93937.com | www.592667.com | www.yk96.com | www.46cv.com | 693096.com | www.111375.com | www.85eb.com | www.019278.com | www.184111.cc | www.870609.com | 大玩家彩票www.84499m.com | www.5nl.com | www.378443.com | www.937300.com | 38303.cc | www.42cr.com | www.pz7.com | www.tt24.com | www.zq8.com | 556501.com | www.408943.com | www.828415.com | 035790.com | www.954855.com | 872706.com | 671397.com | www.50868.com | 中华彩票www.914909.com | www.222431.com | www.956209.com | 500彩票www.50788w.com | www.409398.com | www.655431.com | www.839399.com | www.804450.com | www.yo49.com | www.s46.xyz | www.715958.com | www.113270.com | www.330298.com | 666616.com | www.3285.vip | www.87ak.com | www.324726.com | 241133.com | 64ah.com | 900626.com | 261620.com | 中彩网www.71233l.com | www.05tc.com | www.982414.com | www.5708.cc | www.3732.cc | www.99213.cc | www.138579.com | www.381133.com | www.527379.com | www.qa79.com | www.3942.top | www.678005.cc | www.750234.com | www.915295.com | www.136222.com | www.920679.com | www.899458.com | www.401618.com | www.688365.com | www.051263.com | www.509506.com | 557322.com | 740148.com | www.08952.com | www.569607.com | www.992181.com | www.873960.com | 858347.com | 238352.com | www.888759.com | www.063429.com | 611222.com | www.644890.com | www.115314.com | www.944936.com | www.719795.com | www.883305.com | 大赢家彩票平台www.068630.com | 831274.com | 963584.com | 6915.biz | www.3eg.com | www.12sl.com | www.32122.cc | www.96625.cc | www.760270.com | www.607661.com | www.441070.com | 486481.com | www.336355.com | www.87653.com | www.528434.com | www.88ks.cc | www.9644.cm | www.445541.com | www.3398.biz | 655871.com | www.788827.com | www.74577.cc | www.lr96.com | 811205.com--163a.com | www.a34.online | www.971222.com | 714103.com | www.kk36.com | www.51nf.com | www.88il.com | www.98pb.com | www.68248.com | www.190316.com | www.318511.com | www.dt01.com | www.096.link | www.6518.xyz | www.35361.cc | www.505795.com | www.205553.com | www.040869.com | www.333152.com | www.370229.com | www.551334.com | www.4989.biz | uc08.cc | www.525888.com | www.781331.com | www.54068.com | www.121499.com | www.7168.net | www.160318.com | 名门彩www.33997d.com | www.5185.me | www.088401.com | www.763667.com | www.523639.com | www.771096.com | www.702837.com | www.679184.com | 302332.com | 397254.com | www.29176.cc | www.237784.com | www.205633.com | www.665100.com | www.666858.com | www.611266.com | www.sc59.com | www.49cc.com | www.42574.com | www.22965.com | 035036.com | www.53zd.com | www.974061.com | www.91ts.com | www.087.org | 日彩网www.rcw8855.com | www.82wl.com | www.7956.biz | www.557494.com | www.871374.com | www.qd59.com | www.06101.com | www.ez71.com | www.922044.com | 781533.com | www.ca50.com | www.74vp.com | www.750474.com | www.666033.com | www.751643.com | www.760688.com | www.706033.com | www.974381.com | www.019980.com | www.857532.com | www.897436.com | www.903148.com | 365363.cc | www.260002.com | www.631098.com | www.5174.biz | www.0152.cc | www.050896.com | www.739362.com | www.289359.com | www.3526.win | www.041390.com | www.506988.cc | www.xj45.cc | 332608.com | www.898117.cc | 95彩票www.767397.com | 9669.tv | www.490728.com | 427734.com | 869307.com | 633061.com | www.228330.com | 742368.com | www.0xf.com | www.67uq.com | www.266714.com | www.681136.com | www.9500.vip | www.633207.com | www.694881.com | www.648945.com | www.213643.com | www.82664.com | 286675.com | www.8932.xyz | 85669.com | www.377562.com | www.851755.com | www.165056.com | www.f20.club | www.960625.com | www.099824.com | www.906708.com | www.49072.com | www.77718.com | 彩票5www.572102.com | www.639804.com | www.152035.com | www.895019.com | www.y31.cn | www.6689.pw | www.36653.cc | www.627093.com | 600万彩票www.718322.com | www.849091.com | www.508856.com | www.78188.com | www.956629.com | www.888727.com | www.859976.com | 中国福利彩票www.6364o.com | www.v24.xyz | www.6071.biz | www.024058.com | www.196237.com | www.521608.com | 246332.com | www.cai2699.com | www.cai6177.com | www.al91.com | www.75gi.com | www.7685.xyz | www.119272.com | www.377858.com | 2646.com | 大赢家彩票平台www.978137.com | www.9163.org | www.231810.com | www.984830.com | 68彩票www.68689x.com | www.73th.com | www.7598.cm | www.0429.me | www.5565.cc | www.86oy.com | www.44080.com | www.333739.com | www.512581.com | www.561630.com | www.856491.com | www.578317.com | www.339230.com | www.6417.vip | www.eo31.com | www.019520.com | www.47662.com | www.82499.com | www.117272.com | www.2896.biz | www.01fh.com | www.459158.com | www.271114.com | www.177807.com | www.888824.cc | www.996791.com | www.728073.com | www.578362.com | www.211081.com | 249679.com | www.11237.cc | 450999.com | www.99175.cc | www.369550.com | 879162.com | 983476.com | 356145.com | 311058.com | 994353.com | 500彩票网www.680227.com | www.dj79.com | www.8184.loan | www.70570.cc | www.217120.com | 661879.com | 326293.com | www.872607.com | www.ta61.com | www.728472.com | www.08606.com | www.997594.com | www.986431.com | www.845701.com | www.050.pw | www.304189.com | 571414.com | 085992.com | 949772.com | www.8vp.com | www.497669.com | www.194368.com | 579092.com | 275728.com | www.46925.com | www.55vy.com | www.33658.com | www.191081.com | www.160358.com | www.04aw.com | www.89rp.com | www.0736.xyz | www.3977.biz | www.6662.in | www.60355.cc | www.05655.com | www.004720.com | www.93722.com | www.51vt.com | www.325338.com | www.446762.com | 671932.com | www.cp6625.com | 998139.com | www.744328.com | www.250335.com | www.111.cm | www.7243.com | www.05nt.com | www.cp0.com | 952460.com--8159.com | www.bb07.com | www.698995.com | www.111722.com | 双龙娱乐www.slyl1.com | www.516109.com | www.962588.com | www.939548.com | 037712.com | www.40637.com | 338855.com | www.347197.com | www.76gr.com | www.838787.com | www.078298.com | www.666190.com | www.625206.com | www.981953.com | www.956809.com | www.f37.cc | www.217.net | www.022731.com | www.18115.cc | www.026590.com | www.781.biz | www.4582.vip | www.689590.com | www.za45.com | www.tu56.com | 598698.com | www.149178.com | 426001.com | www.le31.com | 757714.com | www.509650.com | www.5879.cm | 892374.com | www.617706.com | www.93895.cc | 542335.com--0927.cc | www.318250.com | www.199107.com | www.558199.com | www.805862.com | www.902651.com | 083615.com | www.0435.com | kr90.com--kr90.com | www.315230.com | www.70mj.com | www.869262.com | www.pk19.com | www.mo89.com | 464552.com | 272234.com | www.987318.com | www.998381.com | 655845.com | www.367837.com | www.87898.com | www.634.cn | www.535723.com | www.419268.com | www.556157.com | 804555.com | www.579144.com | www.96669.cc | 99980.com | www.lf23.com | www.221035.com | www.143844.com | www.739214.com | www.957431.com | www.7995.com | www.993862.com | www.307089.com | 81299.com | www.495605.com | www.158880.com | www.441185.com | www.861003.com | 249638.com | 696864.com | 564853.com | 954116.com | 823026.com | www.cp6630.com | www.830424.com | www.pi28.com | www.w58.biz | www.4383.xyz | www.9446.cn | www.9698.biz | www.28619.cc | www.240344.com | 720630.com | www.526043.com | 686454.com | www.987329.com | www.771564.com | 804655.com | 国彩网www.guocai667.com | www.kc55.cc | www.04jt.com | www.025692.com | www.0283.loan | www.3945.com | www.66yh.cc | www.62cc.cc | www.cp8587.com | 848869.com | www.915298.com | www.679626.com | www.7800.vip | 22pj.com | 449649.com | www.8610.me | www.050499.com | www.138489.com | www.379111.com | www.839263.com | 辉煌彩票www.2875u.com | www.54wf.com | www.23oz.com | www.vc47.com | www.51fe.com | www.mt22.cc | www.pm15.com | 盛彩网www.41518w.com | K彩www.kc37.com | www.cai6988.com | 博亿彩票www.636by.com | www.8nl.com | www.pb56.com | www.2at.com | www.195855.com | www.496644.com | www.503098.com | www.398332.com | 602959.com | www.987305.com | www.851239.com | 493394.com--www.ag88.com | 易彩堂www.55885c.com | www.nr38.com | www.586.cm | www.62889.cc | www.011776.com | www.332350.com | www.636560.com | www.531078.com | www.923031.com | www.606951.com | www.259371.com | www.268902.com | www.272065.com | www.939183.com | www.889792.com | www.977961.com | www.713509.com | www.998934.com | 500万彩票www.5441h.com | 天天中www.6ttz.com | 659341.com | 731446.com | www.343955.com | www.313189.com | www.42rt.com | www.89ur.com | www.1840.net | www.11310.com | www.18089.com | www.318699.com | www.15hh.com | 400396.com | www.292116.com | 500万彩票www.39500x.com | 68彩票www.68689x.com | www.jk2.com | www.55nz.com | www.056399.com | www.53199.cc | www.057395.com | www.7482.com | www.104059.com | www.128040.com | www.320575.com | www.ot85.com | www.022704.com | www.31418.com | www.95381.com | www.001766.com | www.312470.com | www.241794.com | www.179985.com | www.758617.com | www.569396.com | www.403794.com | www.192288.com | www.602636.com | www.49lb.com | www.316558.com | www.98812.cc | www.046.online | www.088163.com | www.228888.cc | www.985253.com | www.652921.com | 004572.com | 419040.com | 068722.com | www.682234.com | www.19992.com | www.9610.cn | www.759.cm | www.54lh.com | www.86413.com | www.001863.com | www.57942.com | www.126065.com | www.062482.com | www.70218.com | www.248168.com | www.450311.com | www.845320.com | www.964651.com | www.768995.com | www.730291.com | www.96116.cc | 599287.com | www.176239.com | www.fh01.cc | www.672585.com | www.1047.vip | www.796467.com | www.169176.com | www.734301.com | www.535886.com | www.812523.com | www.889493.com | 410770.com | 883218.com | 414687.com | 809607.com | lk43.com | 790316.com | www.858412.com | www.933298.com | www.789241.com | 365266.cc | www.ml83.com | www.007.site | www.107081.com | www.237043.com | www.072072.cc | www.142786.com | www.053370.com | www.548666.com | www.412396.com | www.722365.cc | www.534364.com | www.553818.com | www.330545.com | www.438833.com | www.306446.com | 662813.com | www.445597.com | www.74go.com | www.980073.com | www.23763.com | www.29816.cc | www.97zh.com | www.38799.cc | www.9561.xyz | www.4599.biz | www.u72.net | www.05204.com | www.794611.com | www.784888.com | www.498558.com | www.314955.com | www.648766.com | www.773194.com | 690376.com | 011242.com | www.101938.com | www.ty19.com | www.633954.com | www.74767.com | 37467.com | www.423399.com | www.ee96.com | www.879644.com | www.125340.com | 884620.com | www.428698.com | www.tr01.com | 872715.com | 05183.com | www.868875.com | www.742512.com | www.ya97.com | www.1189.cn | www.603186.com | www.4835.vip | www.983365.com | www.14rf.com | www.yd5.cc | www.07583.com | www.98fp.com | www.683.red | www.330227.com | 085230.com | www.373808.com | 中彩网www.81233j.com | www.x59.club | www.567284.com | www.717311.com | www.478081.com | www.465969.com | www.561607.com | www.50lo.com | www.29916.cc | www.6470.cn | www.026023.com | www.35516.cc | www.882208.com | www.752173.com | www.576954.com | www.853433.com | www.501151.com | www.309555.com | 639864.com | www.392064.com | 386773.com | www.916087.com | www.984802.com | www.189001.com | www.787257.com | www.843379.com | www.593895.com | www.456329.com | www.408049.com | www.144242.com | www.522120.com | www.533353.com | www.955788d.com | www.523531.com | www.034089.com | 128475.com | www.892909.com | www.12260.com | www.956333.com | www.018510.com | 007972.com | www.501022.com | www.87hs.cc | www.973380.com | 550277.com | 520309.com | 660540.com | www.pl9.cc | www.473607.com | www.366949.com | www.111232.com | www.73511.cc | www.jl78.com | www.485456.com | www.gf04.com | www.607732.com | 032976.com | www.924199.com | www.778082.com | 369204.com | 150362.com | www.987448.com | 113416.com | www.880652.com | www.950257.com | www.513095.com | www.568507.com | www.812231.com | www.587201.com | www.460002.com | www.cai3466.com | 340081.com | www.874132.com | k40.cc | www.954276.com | www.616585.com | www.427199.com | www.193156.com | www.787567.com | www.717840.com | www.727212.com | www.299888.com | www.91186.com | www.1152.net | www.75mj.com | 852246.com | www.897566.com | 074633.com | www.626760.com | www.10182.com | www.929957.com | 834477.com | www.878841.com | www.889135.com | www.664980.com | www.771875.com | www.573562.com | 909374.com | www.237060.com | 748014.com | www.780128.com | 719169.com | www.761452.com | www.985180.com | 000372.com | www.947781.com | www.808645.com | 035071.com | www.092589.com | 500彩票www.50080s.com | www.442868.com | www.53xu.com | www.774358.com | www.wh45.com | 博亿彩票www.664by.com | 119487.com | www.763785.com | www.951795.com | www.420869.com | www.6662.in | www.859722.com | www.225600.com | www.lm84.com | www.gk9.com | www.su85.com | 500彩票www.798288.com | 博友彩www.267by.com | 483234.com | 500彩票www.26299h.com | 968384.com | 31688.cc | www.893277.com | www.971316.com | www.736933.com | www.630405.com | www.443530.com | www.155327.com | www.520452.com | www.886156.com | 539451.com | 352884.com | 745315.com | 974054.com | 亿彩堂www.87668w.com | www.2927.xyz | www.ud4.com | 247838.com | 224699.com | 056933.com | www.934544.com | www.949564.com | www.674484.com | www.669742.com | 09ix.com | www.752318.com | www.866.tv | www.50755.cc | www.2554.vip | 天下彩www.461770.com | 971934.com | www.872703.com | 鸿运彩票www.hy2733.com | www.353058.com | 175710.com | www.571619.com | www.145451.com | www.112198.com | 大赢家彩票平台www.958351.com | www.840990.com | www.974393.com | www.103045.com | 948066.com | www.369407.com | www.pk79.com | www.617336.com | www.8183.bid | www.885198.com | www.177587.com | www.zw45.com | www.551709.com | www.91ht.com | www.677298.com | www.020135.com | 011993.com | www.645625.com | www.58726.com | 978339.com | www.327307.com | bt37.com | www.267166.com | www.vt99.com | www.694564.com | www.155394.com | 984780.com | www.275984.com | www.li8.com | www.895663.com | www.595005.com | www.96sz.com | www.897741.com | 690263.com | www.825733.com | www.488806.com | www.234897.com | www.673209.com | www.680925.com | www.379342.com | www.840658.com | www.976353.com | 56878.com | 974437.com | 587888.com | www.971000.com | www.697638.com | www.398032.com | www.644409.com | www.820059.com | www.828293.com | www.610963.com | www.578568.com | www.714140.com | www.335874.com | www.171851.com | www.120343.com | www.9457.vip | www.38sc.com | www.m17.bid | 917207.com | 921467.com | 648018.com | www.875988.com | www.655619.com | www.652356.com | www.322527.com | www.102693.com | www.110973.com | www.9862.com | www.0048.cm | www.7272.club | 728003.com | www.2257b.com | www.866570.com | www.670177.com | www.374410.com | www.238982.com | www.9163.cc | www.171878.com | www.201592.com | www.69245.com | www.026351.com | www.4469.top | www.xw58.com | 025265.com | 125172.com | www.900933.com | www.614666.com | www.589749.com | www.703996.com | www.337332.com | www.639377.com | www.922076.com | www.715038.com | www.823493.com | www.521927.com | www.161117.com | 957482.com | www.305336.com | www.701896.com | www.885055.com | www.942163.com | www.711000.com | www.385093.com | www.468263.com | www.285713.com | www.040932.com | www.339466.com | www.047900.com | www.1205.com | www.yc6.com | 374904.com | www.985213.com | www.607910.com | www.883837.com | www.665973.com | www.379520.com | www.662560.com | www.695888.com | www.590301.com | www.736848.com | www.771938.com | www.500850.com | www.48244.com | www.3010.net | 135631.com | www.778831.com | www.206750.com | www.26ip.com | 19384.cc | 244249.com | www.732977.com | www.381294.com | www.058857.com | www.38st.com | www.8181.me | www.64546.com | www.0188.xyz | www.lx92.com | 625103.com | 581163.com | 126彩票网www.du126.com | www.974894.com | www.637234.com | www.605936.com | www.292163.com | www.125658.com | www.03416.com | www.14hd.com | www.45ma.com | 500彩票www.676477.com | www.p77.cn | 500彩票www.66621w.com | 4444.pw | www.789299.com | www.426306.com | www.541244.com | www.172392.com | www.165147.com | www.73007.com | www.58797.cc | www.cz34.com | 758003.com | www.620591.com | www.800301.com | www.920400.com | www.655318.com | www.595717.com | www.867366.com | www.875052.com | www.668146.com | www.400477.com | www.285440.com | www.13861.cc | www.8384.org | www.012134.com | www.85385.com | www.949152.com | www.27262.com | 721133.com | www.304569.com | 608118.com | www.292591.com | www.25ei.com | www.569873.com | www.599500.com | www.93vs.com | www.637308.com | www.66591.com | 497589.com | www.017673.com | www.ew87.com | www.721232.com | www.67pe.com | www.734036.com | www.88222.cc | www.978707.com | www.88156.cc | 91彩票www.9155b.com | www.344144.com | 528009.com | www.385133.com | www.9969.top | www.782978.com | www.362.gg | www.821928.com | www.95cr.com | 网易彩票www.074wy.com | 770268.com | cp9548.com | 226930.com | 110450.com | www.884061.com | www.576251.com | www.334068.com | www.106791.com | www.901311.com | www.516436.com | www.529249.com | www.210120.com | www.162311.com | www.109115.com | www.95628.cc | www.501922.com | www.sf75.com | www.688317.com | 网易彩票www.069wy.com | 491286.com | www.802644.com | www.388362.com | www.246635.com | www.037461.com | www.114356.com | www.4094.biz | www.qb89.com | 博友彩www.866269.com | 325730.com | www.919397.com | www.543286.com | www.566761.com | www.565342.com | www.432342.com | 幸运彩票www.73166b.com | www.359709.com | www.54vl.com | www.594985.com | www.82457.com | 087982.com | www.511171.com | 948421.com | www.962537.com | www.569406.com | www.429018.com | www.802537.com | www.630905.com | www.359619.com | www.335345.com | www.041302.com | www.463468.com | www.176045.com | www.208445.com | www.18873.com | www.p45.me | 254975.com | www.820308.com | www.502075.com | www.117482.com | www.076844.cc | www.223688.com | www.33144.cc | www.01mw.com | www.121334.com | www.51575.cc | www.65685.com | www.9049.xyz | www.vw30.com | www.523771.com | www.mu72.com | www.637087.com | www.00315.com | www.908822.com | www.00601.com | www.861274.com | www.153239.com | www.615615.com | www.993703.com | www.608078.com | www.619393.cc | www.460083.com | www.508749.cc | www.115920.com | www.038701.com | www.047139.com | www.xh27.cc | 021293.com | 191405.com | www.036568.com | 981194.com | www.192955.com | 773031.com | www.080006.com | 网易彩票www.504833.com | www.528350.com | 吉彩www.602891.com | www.04754.com | www.on54.com | 739104.com | 124942.com | 63gw.com | www.778017.com | www.994893.com | www.690310.com | www.278058.com | www.31692.cc | www.4767