PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function

Chen, Ying; Zhang, Hai-Sheng; Fong, Guo‐Hua; Xi, Qiulei; Wu, Guohao; Bai, Chenguang; Ling, Zhi‐Qiang; Фан, Ли; Xu, Yiming; Qin, Yan-Qing; Yuan, Tanglong; Sun, Heng; Fang, Jing

doi:10.1074/jbc.m115.653584

Cited by 56 publications

(47 citation statements)

References 51 publications

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“…Previous studies have indicated a potential linkage between genetic mutations or deletions in tight junctionassociated proteins and development of IBD [45]. Further studies also have proven that stabilizing junctional complex in intestinal barrier could attenuate intestinal inflammation [46]. In this paper, tight junction proteins claudin-5 and ZO-1 were notably downregulated in mice after DSS treatment, and further H&E identically supported our findings, indicating the impairment of intestinal mucosal barrier in DSS-induced colitis mice.…”

Section: Discussionsupporting

confidence: 87%

Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

et al. 2020

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Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPARγ tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPARγ agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPARγ signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-κB in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSSinduced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the Yulin Huang and Chenchen Wang contributed equally to this work.

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Section: Discussionsupporting

confidence: 87%

Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

et al. 2020

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“…Furthermore, HIF-1α is critical for 86). Interestingly, the expression of these enzymes was reported to be altered in inflammatory bowel disease, where the intestinal barrier is significantly perturbed (85)(86)(87). In keratinocytes, loss of PHD2 alters cell migration and subsequent wound healing in a HIF-dependent manner (88).…”

Section: Hif In Adaptive Immunitymentioning

confidence: 99%

“…While our understanding of the role of HIF hydroxylases in the regulation of immune cell function is far from complete, recent studies investigating individual HIF hydroxylase isoforms in discreet immune and epithelial cell subtypes have identified isoform-specific roles (80)(81)(82)(83)(84)(85)(86)(87)(88)(89). Notably, these phenotypes are not fully accounted for by downstream HIF-dependent effects, further supporting the existence of alternative hydroxylase-regulated pathways such as NF-κB in immune cells.…”

Section: Regulation Of Immune Cell Function By Phdsmentioning

confidence: 99%

Hypoxia-dependent regulation of inflammatory pathways in immune cells

Taylor¹,

Doherty²,

Fallon³

et al. 2016

Journal of Clinical Investigation

166

131

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“…It has previously been suggested that PHD3 is associated with the local tissue hypoxia that accompanies tumorigenesis, and may act as a tumor suppressor (18). Chen et al (19) demonstrated that PHD3 protected the intestinal epithelial barrier from ulcerative injury, which is one of the causes leading to the development of gastric cancer. However, although the actions of PHD3 in the suppression of angiogenesis, growth and differentiation of tumor cells have previously been reported (20), the detailed molecular mechanisms implicating PHD3 in gastric cancer have yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

PHD3 affects gastric cancer progression by negatively regulating HIF1A

Xia

Jiang

et al. 2017

Molecular Medicine Reports

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Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent non‑cancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of well‑differentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxia‑inducible factor‑1α and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer.

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PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function

Cited by 56 publications

References 51 publications

Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction

Hypoxia-dependent regulation of inflammatory pathways in immune cells

PHD3 affects gastric cancer progression by negatively regulating HIF1A

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