NF-κB, nuclear factor kappa beta

  • 文章类型: Journal Article
    人类经常暴露于季铵化合物(QAC)。QAC在医疗环境中普遍使用,餐馆,和家庭作为清洁剂和消毒剂。尽管流行,对长期低水平暴露对健康的影响一无所知.慢性QAC毒性,直到最近才在老鼠身上发现,导致了发育,生殖,和免疫功能障碍。基于细胞的研究表明炎症增加,线粒体功能下降,和胆固醇合成的中断。如果这些发现转化为人体毒性,多个生理过程可能受到影响。这项研究测试了是否可以在43名人类志愿者的血液中检测到QAC浓度,以及QAC浓度是否影响炎症标志物,线粒体功能,和胆固醇合成。在80%的研究参与者中检测到QAC浓度。血液QAC与炎症细胞因子的增加有关,线粒体功能下降,以剂量依赖的方式破坏胆固醇稳态。这是第一项测量人体血液中QAC的研究,也是第一个证明血液QAC和有意义的健康相关生物标志物之间有统计学意义的关系的人。此外,鉴于SARS-CoV-2大流行导致的QAC消毒剂暴露增加,结果是及时的。
    结果:这项研究发现,80%的研究参与者在他们的血液中含有QAC;以及炎症标志物,线粒体功能,固醇稳态随血液QAC浓度而变化。
    Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic.
    RESULTS: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.
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  • 文章类型: Journal Article
    越来越多的证据表明,caspase募集结构域(CARD)介导的caspase-1(CASP1)组装是其激活和随后的白细胞介素(IL)-1β释放的重要过程,导致炎症的开始。CARD16和CARD17以前都被报道为CASP1的抑制性同源物;然而,其分子功能尚不清楚。这里,我们确定寡聚化活性允许CARD16作为CASP1激活剂发挥作用。我们研究了瞬时转染HeLa细胞中CARD16和CARD17的分子特征。尽管CARD16和CARD17都与CASP1CARD相互作用,只有CARD16形成了同型寡聚体。低聚CARD16与CASP1CARD形成丝状结构,并与含有CARD的凋亡相关斑点样蛋白形成斑点。由CARD16形成的丝状结构促进CASP1细丝组装和IL-1β释放。相比之下,CARD17不形成同源寡聚体或细丝,并抑制CASP1依赖性IL-1β的释放。CARD16D27G突变,模拟CARD17氨基酸序列,形成同质低聚物,但未能形成丝状结构。因此,CARD16D27G弱促进CASP1细丝组装和随后的IL-1β释放。这些结果表明寡聚化的CARD16促进CARD介导的分子组装和CASP1活化。
    Increasing evidence indicates that caspase recruitment domain (CARD)-mediated caspase-1 (CASP1) assembly is an essential process for its activation and subsequent interleukin (IL)-1β release, leading to the initiation of inflammation. Both CARD16 and CARD17 were previously reported as inhibitory homologs of CASP1; however, their molecular function remains unclear. Here, we identified that oligomerization activity allows CARD16 to function as a CASP1 activator. We investigated the molecular characteristics of CARD16 and CARD17 in transiently transfected HeLa cells. Although both CARD16 and CARD17 interacted with CASP1CARD, only CARD16 formed a homo-oligomer. Oligomerized CARD16 formed a filament-like structure with CASP1CARD and a speck with apoptosis-associated speck-like protein containing a CARD. A filament-like structure formed by CARD16 promoted CASP1 filament assembly and IL-1β release. In contrast, CARD17 did not form a homo-oligomer or filaments and inhibited CASP1-dependent IL-1β release. Mutated CARD16D27G, mimicking the CARD17 amino acid sequence, formed a homo-oligomer but failed to form a filament-like structure. Consequently, CARD16D27G weakly promoted CASP1 filament assembly and subsequent IL-1β release. These results suggest that oligomerized CARD16 promotes CARD-mediated molecular assembly and CASP1 activation.
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