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Inflammation-induced activation and dysfunction of endothelial cells play an important role in the pathology of multiple vascular diseases. Nicaraven, a potent hydroxyl radical scavenger, has recently been found to have anti-inflammatory roles; however, the mechanism of its action is not fully understood. Here we investigated the effects of Nicaraven on tumor necrosis factor [alpha] (TNF[alpha])-induced inflammatory response in human umbilical vein endothelial cells and we explore the underlying mechanisms related to the nuclear factor-[kappa]B (NF-[kappa]B) signaling pathway. Our results showed that Nicaraven significantly reduced the reactive oxygen species production after TNF[alpha] stimulation. Nicaraven suppressed TNF[alpha]-induced mRNA expression of multiple adhesion molecules and proinflammatory cytokines, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, MCP-1, TNF[alpha], interleulon-1[beta] (IL-1[beta]), IL-6, and IL-8. In addition, Nicaraven inhibited monocyte adhesion and reduced the protein levels of VCAM-1 and ICAM-1. Mechanistically, Nicaraven prevented TNF[alpha]-induced activation of NF-[kappa]B signaling pathway by suppressing the phosphorylation of NF-[kappa]B p65, I[kappa]B[alpha], and I[kappa]B kinase (IKK)[alpha]/[beta], stabilizing I[kappa]B[alpha], and inhibiting the translocation of p65 from cytosol to nucleus. Finally, we showed that Nicaraven improved the functions of endothelial cells, seen as the upregulation of endothelial nitric oxide synthase and increased nitric oxide levels. Our findings indicated that Nicaraven effectively inhibits TNF[alpha] -induced endothelial activation and inflammatory response at least partly through inhibiting NF-[kappa]B signaling pathway. Key words: endothelial cells, Nicaraven, inflammation, TNF[alpha], nuclear factor-[kappa]B. L'activation et le dysfonctionnement des cellules endotheliales engendres par l'inflammation jouent un role important dans la pathologie de multiples maladies vasculaires. On a recemment observe que le nicaravene, un puissant piegeur des radicaux hydroxyl, joue des roles anti-inflammatoires. Toutefois, on ne comprend pas entierement son mode d'action. Nous avons etudie ici les effets du nicaravene sur les reactions inflammatoires provoquees par le TNF[alpha] dans des cellules endotheliales de veine ombilicale humaine et explore les modes d'action sous-jacents lies a la voie de signalisation du facteur NF-[kappa]B. Nos resultats ont montre que le nicaravene permet de faire diminuer de facon marquee la production de derives reactifs de l'oxygene apres une stimulation par le TNF[alpha]. Le nicaravene permettait d'inhiber completement l'expression en ARNm de multiples molecules d'adherence et cytokines proinflammatoires engendree par le TNF[alpha], y compris VCAM-1, ICAM-1, l'E-selectine, MCP-1, TNF[alpha], IL-1[beta], IL-6 et IL-8. De plus, le nicaravene permettait d'inhiber l'adherence des monocytes et de faire diminuer les taux en proteines de VCAM-1 et de ICAM-1. Du point de vue des mecanismes, le nicaravene permettait de prevenir l'activation de la voie de signalisation du facteur NF-[kappa]B engendree par le TNF[alpha] par l'intermediaire de l'inhibition complete de la phosphorylation de NF-[kappa]B p65, d'I[kappa]B[alpha] et d'IKK[alpha]/[beta], de la stabilisation de l'I[kappa]B[alpha] et de l'inhibition de la translocation de p65 du cytosol vers le noyau. Enfin, nous avons montre que le nicaravene permet d'ameliorer le fonctionnement des cellules endotheliales, amelioration observee par la regulation a la hausse de l'oxyde nitrique synthase endotheliale ainsi que par l'augmentation des taux d'oxyde nitrique. Nos resultats montraient que le nicaravene permet d'inhiber efficacement l'activation et la reaction inflammatoire de l'endothelium provoquees par le TNF[alpha], au moins en partie par l'intermediaire de l'inhibition de la voie de signalisation du facteur NF-[kappa]B. [Traduit par la Redaction] Mots-cles: cellules endotheliales, nicaravene, inflammation, TNF[alpha], NF-[kappa]B., Introduction Endothelial cells play an important role in systemic vascular homeostasis, and are the main target of circulating cells and humoral mediators under injury (Tousoulis et al. 2008). Therefore, they [...]

Nanozymes have drawn much attention owing to their low cost and high stability compared with natural enzymes. However, limited specificity intrinsically presents a challenge to their efficiency in sensing applications. Although specific biorecognition units and molecularly imprinted polymers have been introduced to enhance the specificity of nanozymes, they have some shortcomings like poor stability, high cost, complicated operation, and weakened activity. To address these issues, we developed here a simple and efficient surface engineering strategy to build the target-responsive sensing interface by weaving a molecular network on nanozymes to afford a pocket-like structure. Glutathione (GSH), an important intracellular biothiol, was used as the model target, considering the difficulty in distinguising GSH from other biothiols, especially cysteine (Cys) and homocysteine (Hcy). With high-performance single-atom nanozyme (SAzyme) Fe–N–C as the parent nanozyme, a meshy SAzyme Fe/PSAs-DTSSP containing GSH-cleavable disulfide bonds was fabricated via facile surface modification. Interestingly, the molecular network adhered onto the Fe–N–C surface modulated the peroxidase-like properties, including substrate affinity and catalytic stability under harsh conditions. Moreover, the molecular network could specifically respond to GSH over Cys, Hcy, and other interferents, which suppressed the oxidation of the chromogenic substrate 3,3′,5,5′-tetramethylbenzidine (TMB) due to the reversion of the surface charge property of Fe/PSAs-DTSSP, resulting in a sensitive response identified by the naked eye. The usefulness of this assay was validated by monitoring the fluctuation of the GSH level in cancer cells treated with glucose deprivation or incubated with doxorubicin, showing good accuracy and reliability. [ABSTRACT FROM AUTHOR]

Fe–N–C single-atom nanozymes readily achieved discriminative detection of glutathione (GSH) over other biothiols with similar structure due to the difference between POD-like and OXD-like activities regarding the kind of reactive oxygen species. This colorimetric sensor demonstrated the heterogeneity of GSH levels in different cells and accurately monitored cellular GSH fluctuation. [ABSTRACT FROM AUTHOR]

Author(s): Hong-Bo Xin [1, 3]; Takaaki Senbonmatsu [2]; Dong-Sheng Cheng [1]; Yong-Xiao Wang [3]; Julio A. Copello [1]; Guang-Ju Ji [3]; Mei Lin Collier [4]; Ke-Yu Deng [3]; Loice H. [...]

Disruption of the Mf1 gene which codes for a forkhead/winged helix transcription factor results in skeletal abnormalities, eye defects and hydrocephalus. This gene is expressed in mesenchymal tissues destined to be cartilages, meninges, periocular tissues, endothelium or kidney. Homozygous null mutation of this gene in mice results in hydrocephalic fetuses containing eye defects. These mice die at birth.