AbMole小課堂|MCC950—用于多種炎癥模型研究的NLRP3/焦亡抑制劑NLRP3炎癥小體是由模式識別受體、接頭蛋白ASC和半胱氨酸天冬氨酸蛋白酶-1（Caspase-1）組成的多蛋白復(fù)合物，其過度激活與多種生理異常過程的發(fā)生發(fā)展密切相關(guān)。MCC950（CP-456773，AbMole，M8083）作為一種高效、特異性的NLRP3炎癥小體抑制劑，能夠在納摩爾濃度下阻斷NLRP3的經(jīng)典及非經(jīng)典激活途徑。MCC950還能抑制細(xì)胞焦亡，并在多個研究領(lǐng)域中展現(xiàn)出良好的抗炎效果。MCC950的作用機(jī)制MCC950（CRID3，AbMole，M8083）能直接與NLRP3蛋白結(jié)合并發(fā)揮抑制作用。研究發(fā)現(xiàn)，它能特異性結(jié)合在NLRP3蛋白NACHT結(jié)構(gòu)域內(nèi)的特定基序上。NACHT結(jié)構(gòu)域在NLRP3炎癥小體激活中起核心作用，參與NLRP3的寡聚化以及與接頭蛋白ASC的相互作用。因此，MCC950能夠阻止NLRP3炎癥小體的組裝和激活（圖1）。圖SEQ圖\*ARABIC1.MCC950的作用機(jī)理ADDINEN.CITEADDINEN.CITE.DATA[1]MCC950在相關(guān)研究中的應(yīng)用MCC950抑制細(xì)胞焦亡細(xì)胞焦亡是一種由炎癥小體激活引發(fā)的程序性壞死，其特征性標(biāo)志為Caspase-1或Caspase-11/4/5激活后切割GSDMD，釋放GSDMD-N端片段形成細(xì)胞膜孔道，導(dǎo)致細(xì)胞內(nèi)容物釋放，引發(fā)炎癥反應(yīng)。MCC950（CP-456773，AbMole，M8083）通過抑制NLRP3炎癥小體的激活，減少了Caspase-1的活化，從而降低GSDMD的切割水平，減少細(xì)胞膜上孔道形成，阻斷細(xì)胞焦亡進(jìn)程。此外，MCC950還可能通過調(diào)控NLRP3炎癥小體下游信號通路，影響細(xì)胞內(nèi)相關(guān)炎癥因子和促焦亡蛋白的表達(dá)與活性，協(xié)同抑制細(xì)胞焦亡的發(fā)生。如果MCC950處理后細(xì)胞活力有所恢復(fù)，則通常可說明焦亡在上述細(xì)胞死亡過程中起到了一定的作用。MCC950在炎癥模型中的應(yīng)用在多種炎癥模型研究中，MCC950（CP-456773，AbMole，M8083）展現(xiàn)出良好的抗炎及抑制細(xì)胞焦亡的效果。在急性肺損傷炎癥模型中，通過氣管內(nèi)滴注脂多糖（LPS）構(gòu)建模型后，小鼠肺部出現(xiàn)明顯炎癥細(xì)胞浸潤、肺泡結(jié)構(gòu)破壞，同時細(xì)胞焦亡相關(guān)指標(biāo)顯著升高。給予MCC950處理后，可顯著減輕肺部炎癥反應(yīng)，降低IL-1β、TNF-α等炎癥因子水平，同時減少肺組織中GSDMD切割片段的表達(dá)，抑制細(xì)胞焦亡的發(fā)生，改善肺泡結(jié)構(gòu)完整性ADDINEN.CITEADDINEN.CITE.DATA[2]。?在小鼠、大鼠的急性腎損傷炎癥模型中，使用脂多糖（LPS，AbMole，M9524）誘導(dǎo)建立模型，可出現(xiàn)腎小管上皮細(xì)胞損傷，NLRP3炎癥小體激活，并引發(fā)炎癥反應(yīng)和細(xì)胞焦亡。同樣經(jīng)MCC950（CP-456773，AbMole，M8083）干預(yù)后，能夠抑制腎臟組織中NLRP3炎癥小體的激活，降低Caspase-1的活性，減少GSDMD的切割，從而減輕腎小管上皮細(xì)胞焦亡，緩解腎臟炎癥損傷，改善小鼠腎功能相關(guān)指標(biāo)ADDINEN.CITEADDINEN.CITE.DATA[3,4]。MCC950在其它模型中的應(yīng)用在C57BL/6

J小鼠的帕金森病模型中，MCC950（CP-456773，AbMole，M8083）能夠減弱NLRP3炎癥小體的激活以及Caspase-1、IL-1β的活化，并減少α-突觸核蛋白聚集體的量，保護(hù)多巴胺能神經(jīng)元ADDINEN.CITEADDINEN.CITE.DATA[5]。在Apoe基因敲除小鼠動脈粥樣硬化模型中，MCC950顯著降低其炎癥細(xì)胞的浸潤和炎癥因子的釋放ADDINEN.CITE<EndNote><Cite><Author>Ismailani</Author><Year>2023</Year><RecNum>117</RecNum><DisplayText><styleface="superscript">[6]</style></DisplayText><record><rec-number>117</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749783391">117</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ismailani,UzairS.</author><author>Buchler,Ariel</author><author>MacMullin,Nicole</author><author>Abdirahman,Faduma</author><author>Adi,Myriam</author><author>Rotstein,BenjaminH.</author></authors></contributors><titles><title>SynthesisandEvaluationof[11C]MCC950forImagingNLRP3-MediatedInflammationinAtherosclerosis</title><secondary-title>MolecularPharmaceutics</secondary-title></titles><periodical><full-title>MolecularPharmaceutics</full-title></periodical><pages>1709-1716</pages><volume>20</volume><number>3</number><dates><year>2023</year><pub-dates><date>2023/03/06</date></pub-dates></dates><publisher>AmericanChemicalSociety</publisher><isbn>1543-8384</isbn><urls><related-urls><url>/10.1021/acs.molpharmaceut.2c00915</url></related-urls></urls><electronic-resource-num>10.1021/acs.molpharmaceut.2c00915</electronic-resource-num></record></Cite></EndNote>[6]。在膿毒癥小鼠模型中，MCC950通過抑制NLRP3炎癥小體的激活，可減輕炎癥反應(yīng)和器官損傷ADDINEN.CITEADDINEN.CITE.DATA[7]。范例詳解ActaPharmSinB.2025Apr10.復(fù)旦大學(xué)的科研人員在上述文章中研究了一種從魚腥草（Houttuyniacordata）中提取的抗補(bǔ)體同質(zhì)多糖（HCPM），以及它對H1N1流感病毒和耐甲氧西林金黃色葡萄球菌（MRSA）共感染引起的急性肺炎的改善作用。實驗人員建立了H1N1和MRSA共感染的小鼠模型，評估了HCPM對共感染小鼠的生存率、體重、肺部和腸道損傷、炎癥因子水平等的影響。最終結(jié)果發(fā)現(xiàn)HCPM減輕了肺部和腸道的炎癥損傷，降低了炎癥因子（如TNF-α、IL-6、IFN-γ等）的水平。HCPM還通過調(diào)節(jié)腸道-肺軸中的Treg/Th17細(xì)胞平衡，改善了共感染引起的肺部和腸道損傷。AbMole的MCC950（CP-456773，AbMole，M8083）被用于驗證NLRP3炎癥體激活在H1N1和MRSA共感染中的作用，以及HCPM是否通過抑制NLRP3炎癥體來發(fā)揮其抗炎效果ADDINEN.CITE<EndNote><Cite><Author>Li</Author><Year>2025</Year><RecNum>119</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>119</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749785694">119</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Li,Xinxing</author><author>Ding,Wenxin</author><author>Lu,Yan</author><author>Zhu,Haiyan</author><author>Bao,Weilian</author><author>Liu,Yang</author><author>Lyu,Jiaren</author><author>Zhou,Lishuang</author><author>Li,Hong</author><author>Li,Jiyang</author><author>Chen,Daofeng</author></authors></contributors><titles><title>Ananti-complementhomogeneouspolysaccharidefromHouttuyniacordataamelioratesacutepneumoniawithH1N1andMRSAcoinfectionthroughrectifyingTreg/Th17imbalanceinthegut–lungaxisandNLRP3inflammasomeactivation</title><secondary-title>ActaPharmaceuticaSinicaB</secondary-title></titles><periodical><full-title>ActaPharmaceuticaSinicaB</full-title></periodical><keywords><keyword>Polysaccharides</keyword><keyword>H1N1</keyword><keyword>MRSA</keyword><keyword>Pneumonia</keyword><keyword>Complement</keyword><keyword>NLRP3</keyword><keyword>Treg/Th17

cellbalance</keyword><keyword>Gut-lungaxis</keyword></keywords><dates><year>2025</year><pub-dates><date>2025/04/10/</date></pub-dates></dates><isbn>2211-3835</isbn><urls><related-urls><url>/science/article/pii/S2211383525002400</url></related-urls></urls><electronic-resource-num>/10.1016/j.apsb.2025.04.008</electronic-resource-num></record></Cite></EndNote>[8]。圖SEQ圖\*ARABIC2.TherecoveryeffectofHCPMonTreg/Th17cellimbalancemayberelatedtoitseffectonNLRP3inflammasomesignalinginviral–bacterialcoinfectionmiceADDINEN.CITE<EndNote><Cite><Author>Li</Author><Year>2025</Year><RecNum>119</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>119</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749785694">119</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Li,Xinxing</author><author>Ding,Wenxin</author><author>Lu,Yan</author><author>Zhu,Haiyan</author><author>Bao,Weilian</author><author>Liu,Yang</author><author>Lyu,Jiaren</author><author>Zhou,Lishuang</author><author>Li,Hong</author><author>Li,Jiyang</author><author>Chen,Daofeng</author></authors></contributors><titles><title>Ananti-complementhomogeneouspolysaccharidefromHouttuyniacordataamelioratesacutepneumoniawithH1N1andMRSAcoinfectionthroughrectifyingTreg/Th17imbalanceinthegut–lungaxisandNLRP3inflammasomeactivation</title><secondary-title>ActaPharmaceuticaSinicaB</secondary-title></titles><periodical><full-title>ActaPharmaceuticaSinicaB</full-title></periodical><keywords><keyword>Polysaccharides</keyword><keyword>H1N1</keyword><keyword>MRSA</keyword><keyword>Pneumonia</keyword><keyword>Complement</keyword><keyword>NLRP3</keyword><keyword>Treg/Th17

cellbalance</keyword><keyword>Gut-lungaxis</keyword></keywords><dates><year>2025</year><pub-dates><date>2025/04/10/</date></pub-dates></dates><isbn>2211-3835</isbn><urls><related-urls><url>/science/article/pii/S2211383525002400</url></related-urls></urls><electronic-resource-num>/10.1016/j.apsb.2025.04.008</electronic-resource-num></record></Cite></EndNote>[8].CellRep.2020May19;31(7):107667.柏林自由大學(xué)的研究人員探究了鳥苷酸結(jié)合蛋白1（hGBP1）在限制沙眼衣原體（Chlamydiatrachomatis）生長和激活炎癥體中的作用，及其通過連續(xù)的GTP水解步驟產(chǎn)生GMP的酶學(xué)特性在宿主防御中的功能。研究揭示了hGBP1通過GTP水解產(chǎn)生的GMP進(jìn)一步代謝為尿酸（UA），從而激活NLRP3炎癥體的機(jī)制。AbMole的MCC950（CP-456773，AbMole，M8083）被用作NLRP3炎癥體的特異性抑制劑，以驗證hGBP1介導(dǎo)的GMP生成是否通過激活NLRP3炎癥體來發(fā)揮作用ADDINEN.CITEADDINEN.CITE.DATA[9]。圖SEQ圖\*ARABIC3.TheConsecutiveHydrolysisofhGBP1IsRequiredforInflammasomeActivationADDINEN.CITEADDINEN.CITE.DATA[9]參考文獻(xiàn)及鳴謝ADDINEN.REFLIST[1]Q.Liu,M.M.Zhang,M.X.Guo,Q.P.Zhang,N.Z.Li,J.Cheng,S.L.Wang,G.H.Xu,C.F.Li,J.X.Zhu,L.T.Yi,InhibitionofMicroglialNLRP3withMCC950AttenuatesMicroglialMorphologyandNLRP3/Caspase-1/IL-1βSignalingInStress-inducedMice,JNeuroimmunePharmacol17(3-4)(2022)503-514.[2]L.Mei,L.Zhang,D.Wu,H.Ding,X.Wang,X.Zhang,Y.Wei,Z.Li,J.Tong,[LiuweiBuqiFormuladelaysprogressionofchronicobstructivepulmonarydiseaseinratsbyregulatingtheNLRP3/caspase-1/GSDMDpyroptosispathway],NanFangYiKeDaXueXueBao44(11)(2024)2156-2162.[3]Y.Su,Y.Wang,M.Liu,H.Chen,HydrogensulfideattenuatesrenalI/R?inducedactivationoftheinflammatoryresponseandapoptosisviaregulatingNrf2?mediatedNLRP3signalingpathwayinhibition,MolMedRep24(1)(2021).[4]M.Yang,P.Shen,L.Xu,M.Kong,C.Yu,Y.Shi,Theacrinealleviatessepsis-inducedacutekidneyinjurybyrepressingtheactivationofNLRP3/Caspase-1inflammasome,PeerJ10(2022)e14109.[5]H.Gao,Y.Liang,M.Wang,W.Li,W.Zheng,Z.Wang,G.Sun,H.Liu,M.Liu,Y.Zhang,Inhibitionofα-synucleinaggregationbyMCC950attenuatesdopaminergicneuronaldamageinMN9Dcells,EurJPharmacol1001(2025)177774.[6]U.S.I