甲基巴多索龙通过抑制NLRP3炎症小体活化缓解小鼠急性肝损伤
目的 探究小分子化合物甲基巴多索隆(CDDO-Me)抑制NLRP3炎症小体活化并缓解急性肝损伤的作用机制.方法 体外实验:CDDO-Me预处理小鼠骨髓来源巨噬细胞(BMDM)或人急性单核细胞白血病(THP-1)细胞后,利用多种NLRP3炎症小体活化剂(Nigericin、ATP、MSU、胞内LPS转染)活化NLRP3炎症小体,使用聚脱氧腺苷酸(poly A∶T)活化AIM2炎症小体,通过Western blotting和ELISA检测细胞培养上清中caspase-1和白细胞介素1β(IL-1β)的分泌水平,确定CDDO-Me对NLRP3炎症小体的抑制效果及其特异性.体内实验:将SPF级雄性C5...
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| Published in | 南方医科大学学报 Vol. 44; no. 9; pp. 1662 - 1669 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | Chinese |
| Published |
蚌埠医科大学慢性疾病免疫学基础与临床安徽省重点实验室,安徽 蚌埠 233030
2024
蚌埠医科大学第一附属医院检验科,安徽 蚌埠 233004%蚌埠医科大学慢性疾病免疫学基础与临床安徽省重点实验室,安徽 蚌埠 233030 |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1673-4254 |
| DOI | 10.12122/j.issn.1673-4254.2024.09.05 |
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| Abstract | 目的 探究小分子化合物甲基巴多索隆(CDDO-Me)抑制NLRP3炎症小体活化并缓解急性肝损伤的作用机制.方法 体外实验:CDDO-Me预处理小鼠骨髓来源巨噬细胞(BMDM)或人急性单核细胞白血病(THP-1)细胞后,利用多种NLRP3炎症小体活化剂(Nigericin、ATP、MSU、胞内LPS转染)活化NLRP3炎症小体,使用聚脱氧腺苷酸(poly A∶T)活化AIM2炎症小体,通过Western blotting和ELISA检测细胞培养上清中caspase-1和白细胞介素1β(IL-1β)的分泌水平,确定CDDO-Me对NLRP3炎症小体的抑制效果及其特异性.体内实验:将SPF级雄性C57BL/6J小鼠随机分为4组,即空白对照组(Control组)、急性肝损伤组(APAP组)、CDDO-Me低剂量治疗组(APAP+CDDO-Me20 mg/kg组)和CDDO-Me高剂量治疗组(APAP+CDDO-Me40 m/kg组),ELISA检测小鼠血清中IL-1β、肿瘤坏死因子α(TNF-α)、谷草转氨酶(AST)、谷丙转氨酶(ALT)的表达水平,HE染色观察肝组织结构变化.结果 CDDO-Me可剂量依赖性的抑制多种激动剂诱导的NLRP3炎症小体活化以及胞内转染LPS诱导非经典NLRP3炎症小体的活化(P<0.05),但对NLRP3炎症小体非依赖的相关炎性因子白细胞介素6(IL-6)、TNF-α的分泌无显著影响(P>0.05).此外,CDDO-Me对AIM2炎症小体的活化无显著影响(P>0.05).动物实验结果表明,相较急性肝损伤组(APAP组),CDDO-Me治疗组(APAP+CDDO-Me20 mg/kg组和APAP+CDDO-Me40 mg/kg组)小鼠血清IL-1β、AST和ALT的表达水平显著降低,肝组织HE染色结果显示CDDO-Me能明显改善ALI小鼠损伤的肝组织结构,减少炎性细胞浸润,且呈剂量依赖性(P<0.05).结论 CDDO-Me能够特异性抑制NLRP3炎症小体活化并缓解APAP诱导的小鼠急性肝损伤. |
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| AbstractList | 目的 探究小分子化合物甲基巴多索隆(CDDO-Me)抑制NLRP3炎症小体活化并缓解急性肝损伤的作用机制.方法 体外实验:CDDO-Me预处理小鼠骨髓来源巨噬细胞(BMDM)或人急性单核细胞白血病(THP-1)细胞后,利用多种NLRP3炎症小体活化剂(Nigericin、ATP、MSU、胞内LPS转染)活化NLRP3炎症小体,使用聚脱氧腺苷酸(poly A∶T)活化AIM2炎症小体,通过Western blotting和ELISA检测细胞培养上清中caspase-1和白细胞介素1β(IL-1β)的分泌水平,确定CDDO-Me对NLRP3炎症小体的抑制效果及其特异性.体内实验:将SPF级雄性C57BL/6J小鼠随机分为4组,即空白对照组(Control组)、急性肝损伤组(APAP组)、CDDO-Me低剂量治疗组(APAP+CDDO-Me20 mg/kg组)和CDDO-Me高剂量治疗组(APAP+CDDO-Me40 m/kg组),ELISA检测小鼠血清中IL-1β、肿瘤坏死因子α(TNF-α)、谷草转氨酶(AST)、谷丙转氨酶(ALT)的表达水平,HE染色观察肝组织结构变化.结果 CDDO-Me可剂量依赖性的抑制多种激动剂诱导的NLRP3炎症小体活化以及胞内转染LPS诱导非经典NLRP3炎症小体的活化(P<0.05),但对NLRP3炎症小体非依赖的相关炎性因子白细胞介素6(IL-6)、TNF-α的分泌无显著影响(P>0.05).此外,CDDO-Me对AIM2炎症小体的活化无显著影响(P>0.05).动物实验结果表明,相较急性肝损伤组(APAP组),CDDO-Me治疗组(APAP+CDDO-Me20 mg/kg组和APAP+CDDO-Me40 mg/kg组)小鼠血清IL-1β、AST和ALT的表达水平显著降低,肝组织HE染色结果显示CDDO-Me能明显改善ALI小鼠损伤的肝组织结构,减少炎性细胞浸润,且呈剂量依赖性(P<0.05).结论 CDDO-Me能够特异性抑制NLRP3炎症小体活化并缓解APAP诱导的小鼠急性肝损伤. |
| Abstract_FL | Objective To investigate the inhibitory effect of bardoxolone methyl(CDDO-Me)on activation of NLRP3 inflammasome and its mechanism for alleviating acute liver injury(ALI).Methods Mouse bone marrow-derived macrophages(BMDM)and THP-1 cells were pre-treated with CDDO-Me followed by treatment with Nigericin,ATP,MSU,intracellular LPS transfection for activation of NLRP3 inflammasomes,or poly A:T for activation of AIM2 inflammasomes.The levels of caspase-1 and IL-1β in the cell culture supernatant was determined with Western blotting and ELISA to assess the inhibitory effect of CDDO-Me on NLRP3 inflammasomes and its specificity.In the animal experiment,male C57BL/6J mouse models of acetaminophen-induced ALI were treated with low-dose(20 mg/kg)and high-dose(40 mg/kg)CDDO-Me,and the changes in serum levels of IL-1β,TNF-α,AST and ALT were measured by ELISA and liver tissue pathology was observed using HE staining.Results In mouse BMDM and THP-1 cells,CDDO-Me dose-dependently inhibited the activation of NLRP3 inflammasomes without significantly affecting the secretion of non-inflammasome-related inflammatory factors IL-6 and TNF-α or AIM2 inflammasome activation.In the mouse models of ALI,CDDO-Me treatment at both the low and high doses significantly reduced serum levels of IL-1β,AST and ALT,ameliorated histological changes and reduced inflammatory cell infiltration in the liver tissue,and the effects exhibited a distinct dose dependence.Conclusion CDDO-Me can specifically inhibit the activation of NLRP3 inflammasomes to alleviate acetaminophen-induced ALI in mice. |
| Author | 张玮 华梦晴 李明远 |
| AuthorAffiliation | 蚌埠医科大学慢性疾病免疫学基础与临床安徽省重点实验室,安徽 蚌埠 233030;蚌埠医科大学第一附属医院检验科,安徽 蚌埠 233004%蚌埠医科大学慢性疾病免疫学基础与临床安徽省重点实验室,安徽 蚌埠 233030 |
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| Author_FL | HUA Mengqing LI Mingyuan ZHANG Wei |
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| Keywords | NLRP3炎症小体 炎症小体相关疾病 甲基巴多索龙 NLRP3 inflammasomes inflammasome-related diseases bardoxolone methyl 急性肝损伤 acute liver injury |
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