Though the detailed pathological mechanism of post-infectious irritable bowel syndrome (PI-IBS) remains unclear, accumulating evidence indicates that oxidative stress and inflammation are implicated in the process of PI-IBS. Oxidative stress and inflammation are regulated by Nrf2 and NF-κB signaling pathways, respectively. EphA2, a member of Eph receptor family, promotes oxidative stress and inflammatory responses via regulation of Nrf2 and NF-κB signaling pathways in various types of human diseases. Understanding the mechanisms by which EphA2 regulate oxidative stress and inflammation in PI-IBS is important for the development of new strategies to treat PI-IBS. However, the effects of ALW-II-41-27, a novel EphA2 inhibitor on PI-IBS and the underlying molecular mechanisms have never been studied. In the present study, we showed that ALW-II-41-27 decreased gastrointestinal motility and abdominal withdrawal reflex (AWR) scores, markedly reduced the levels of oxidative stress markers [4-hydroxy-2-nonenal (4-HNE), protein carbonyl, and 8-hydroxy-2-de-axyguanine (8-OHdG)] and proinflammatory cytokines (TNF-α, IL-6, IL-17, and ICAM-1), and remarkably increased the level of anti-inflammatory cytokine (IL-10) in serum and colon of Trichinella spiralis-infected mice. Moreover, ALW-II-41-27 was effective in suppressing oxidative stress and inflammation in LPS-treated NCM460 colonic cells. Treatment of ALW-II-41-27 reversed the activation of NF-κB and inactivation of Nrf2 in LPS-treated NCM460 cells. Importantly, these protective effects of ALW-II-41-27 were partially inhibited by EphA2 KO and abolished by EphA2 overexpression. In conclusion, EphA2 may represent a promising therapeutic target for patients with PI-IBS and ALW-II-41-27 might function as a novel therapeutic agent for PI-IBS.
A growing body of evidence has demonstrated that Eph/ephrin signalling may serve a central role in intestinal diseases. However, whether erythropoietin-producing hepatocellular (Eph)/ephrin signalling is associated with the development of post-infectious irritable bowel syndrome (PI-IBS) is still unknown. In the present study, the role of Eph/Ephrin signalling in lipopolysaccharide (LPS)-induced intestinal injury was evaluated in vivo and in vitro. LPS treatment significantly increased the levels of proinflammatory mediators [monocyte chemoattractant protein-1, tumour necrosis factor α, interleukin (IL)-1β, IL-6, intercellular adhesion molecule 1 and vascular cell adhesion molecule-1], activated the EphA2-Ephrin A1, protein kinase B (Akt)-nuclear factor (NF)-κB, Src-NF-κB and Wnt/β-catenin signalling pathways, and inhibited EphB1-Ephrin B3 signalling in colon tissues, and primary cultured enteric neuronal and glial cells. Notably, EphA2 monoclonal antibody (mAb) treatment or Ephrin B3 overexpression could partially alleviate the LPS-induced upregulation of proinflammatory mediators, and Akt-NF-κB, Src-NF-κB and Wnt/β-catenin signalling pathways. In addition, EphA2 mAb treatment could partially inhibit LPS-induced inactivation of EphB-Ephrin B3 signalling, while Ephrin B3 overexpression could abrogate LPS-induced activation of EphA2-Ephrin A1 signalling. EphB1/Ephrin B3 signalling may antagonise the EphA2/Ephrin A1-dependent pathway following LPS treatment. The results associated with the EphA2 signaling pathway, indicated that Eph/ephrin signalling may serve a bidirectional role in LPS-induced intestinal injury. Eph/ephrin signalling may be a novel therapeutic target for LPS-induced intestinal injury and potentially PI-IBS.
Colorectal cancer (CRC) is the third most commonly malignance cancer worldwide. The quality of life and life expectancy of CRC survivors are seriously impacted by the recurrence after resection surgery. Therefore, there is a need to develop a reliable signature to predict the recurrence after resection surgery in CRC patients. Epigenetic alterations, especially gene methylation, have been found highly related to the metastasis of tumors. However, limited evidence is available for CRC patients. Moreover, there remains a knowledge gap of a comprehensive view of gene methylation in stage II CRC. In this study, we conducted and validated a differentially methylated 9-gene-pair prognosis signature to predict recurrence after resection surgery in stage II CRC patients. In addition, we use Univariable and Multivariable Cox regression to estimate the association between relapse free survival times in relation to each candidate gene pairs and the 9-gene-pair score. Moreover, the network analysis found 8 hub genes, including NDRG4 and BMP3, out of all candidate genes have large degree of interactions in the protein-protein interaction network. Seven hub genes have been found associated with CRC progression. Furthermore, the function enrichment analysis suggested that differentially methylated genes were mostly enriched in the cell cycle pathway. In summary, a 9-gene-pair signature was developed and validated in this study. The signatures identified in this study have the potential to be applied in the prognosis of post-surgery recurrence in the stage II CRC patents.
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