Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.
Nrf2-small Maf (sMaf) heterodimer is essential for the inducible expression of cytoprotective genes upon exposure to oxidative and xenobiotic stresses. While the Nrf2-sMaf heterodimer recognizes DNA sequences referred to as the antioxidant/electrophile responsive element (ARE/EpRE), we here define these DNA sequences collectively as CNC-sMaf binding element (CsMBE). In contrast, large and small Maf proteins are able to form homodimers that recognize the Maf recognition element (MARE). CsMBE and MARE share a conserved core sequence but they differ in the 5'-adjacent nucleotide neighboring the core. Because of the high similarity between the CsMBE and MARE sequences, it has been unclear how many target binding sites and target genes are shared by the Nrf2-sMaf heterodimers and Maf homodimers. To address this issue, we introduced a substitution mutation of alanine to tyrosine at position 502 in Nrf2, which rendered the DNA-binding domain structure of Nrf2 similar to Maf, and generated knock-in mice expressing the Nrf2(A502Y) mutant. Our chromatin immunoprecipitation-sequencing analyses showed that binding sites of Nrf2(A502Y)-sMaf were dramatically changed from CsMBE to MARE in vivo. Intriguingly, however, one-quarter of the Nrf2(A502Y)-sMaf binding sites also bound Nrf2-sMaf commonly and vice versa. RNA-sequencing analyses revealed that Nrf2(A502Y)-sMaf failed to induce expression of major cytoprotective genes upon stress stimulation, which increased the sensitivity of Nrf2(A502Y) mutant mice to acute acetaminophen toxicity. These results demonstrate that the unique cistrome defined as CsMBE is strictly required for the Nrf2-sMaf heterodimer function in cytoprotection and that the roles played by CsMBE differ sharply from those of MARE.
Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO.
Background and study aims Endoscopic submucosal dissection (ESD) is a technically advanced procedure for colorectal tumors. Hayashi et al. invented the “pocket-creation method (PCM),” and reported that Is-type lesions with fibrosis could be efficaciously and safely resected. However, only case studies have been published, and there are no previous reports on the usefulness of PCM in colorectal ESD for all lesions, as compared with the conventional method. This study aimed to evaluate the effectiveness and safety of PCM in colorectal ESD. Patients and methods Ninety-six colorectal tumors were treated: 47 using the PCM and the other 49, considered the control group, using the conventional method. Therapeutic effectiveness and safety were retrospectively assessed. Results The comparison between the PCM and control groups revealed higher rates of en bloc resection (100 % vs. 88 %, P = 0.015) and curative endoscopic resection (100 % vs. 84 %, P = 0.0030) with PCM. There was no significant difference in perforation as an adverse event (AE) between the two groups, though perforation was observed in only 6 % of the control group and none of the PCM group. Compared with the control group, the PCM group had lower incidences of perforation and post-ESD coagulation syndrome, and both AEs were associated with excessive thermal denaturation of the muscle layer (2 % vs. 16 %, P = 0.018). Conclusions This study demonstrated the effectiveness and safety of ESD with PCM for colorectal tumors. Although there is a possible learning curve, PCM enables the endoscopist to safely perform ESD in most cases without encountering the difficulties associated with conventional ESD.
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