scholarly journals Prolyl Hydroxylase Inhibition Mitigates Pouchitis

2019 ◽  
Author(s):  
Jonathan M Harnoss ◽  
Jasper M Gebhardt ◽  
Praveen Radhakrishnan ◽  
Christine Leowardi ◽  
Julius Burmeister ◽  
...  
Keyword(s):  
Small Molecule ◽  
Intestinal Inflammation ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Intestinal Epithelial ◽  
Epithelial Barrier Function ◽  
Molecule Inhibitor ◽  
Epithelial Cell Apoptosis ◽  
Zona Occludens ◽  
The Impact

Abstract Background Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase–containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis. Methods PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)–induced pouchitis was studied. Clinical and molecular parameters were investigated. Results PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation. Conclusions Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.

scholarly journals Evaluation of the Carcinogenic Potential of Roxadustat (FG-4592), a Small Molecule Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase in CD-1 Mice and Sprague Dawley Rats

2017 ◽  
Vol 36 (6) ◽  
pp. 427-439 ◽  
Author(s):  
James Beck ◽  
Carroll Henschel ◽  
James Chou ◽  
Al Lin ◽  
Ughetta del Balzo
Keyword(s):  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Small Molecule Inhibitor ◽  
Prolyl Hydroxylase ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Distribution Width ◽  
Sprague Dawley Rats ◽  
Molecule Inhibitor ◽  
Carcinogenic Potential

The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-α concentrations, followed by translocation of HIF-α to the nucleus and upregulation of HIF-responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2.5, 5, and 10 mg/kg. Treatment-associated changes in hematology parameters were consistent with the pharmacologic activity of roxadustat and included elevations in hematocrit in mice at 30 and 60 mg/kg TIW and elevations in erythrocyte count, hemoglobin, hematocrit, and red cell distribution width in rats at 10 mg/kg TIW. No increase in mortality or neoplastic effects compared with vehicle controls was observed after roxadustat treatment in either species. No treatment-related nonneoplastic findings were observed in mice, whereas nonneoplastic microscopic findings in rats were limited to atrial/aortic thromboses at 10 mg/kg TIW males and bone marrow hypercellularity in all treated male and female groups, consistent with the pharmacology of roxadustat. In conclusion, roxadustat administered by oral gavage to mice and rats TIW for up to 104 weeks resulted in dose-dependent exposure and hematologic effects with no effect on survival or development of neoplastic lesions at up to 60 mg/kg in mice and up to 10 mg/kg in rats.

scholarly journals The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis

2020 ◽  
Vol 31 (20) ◽  
pp. 2249-2258
Author(s):  
Alexander S. Dowdell ◽  
Ian M. Cartwright ◽  
Matthew S. Goldberg ◽  
Rachael Kostelecky ◽  
Tyler Ross ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Epithelial Barrier ◽  
Adaptation To Hypoxia ◽  
Intestinal Epithelial ◽  
Hypoxia Response ◽  
Epithelial Barrier Function

The transcription factor hypoxia-inducible factor (HIF) mediates adaptation to hypoxia. We found that HIF regulates the autophagy protein ATG9A in intestinal epithelial cells. Subsequent knockdown of ATG9A resulted in tight junction mislocalization and cytoskeletal defects. These results suggest a link among the hypoxia response, autophagy, and junctional biogenesis.

PGE2promotes Ca2+-mediated epithelial barrier disruption through EP1and EP4receptors in Caco-2 cell monolayers

2010 ◽  
Vol 299 (2) ◽  
pp. C324-C334 ◽  
Author(s):  
M. José Rodríguez-Lagunas ◽  
Raquel Martín-Venegas ◽  
Juan José Moreno ◽  
Ruth Ferrer
Keyword(s):  
Signaling Pathways ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Epithelial Barrier Function ◽  
Cell Monolayers ◽  
Intracellular Ca ◽  
Inflammatory Processes ◽  
Zona Occludens

We recently demonstrated that PGE2induces the disruption of the intestinal epithelial barrier function. In the present study, our objectives were to study the role of PGE2receptors (EP1–EP4) and the signaling pathways involved in this event. Paracellular permeability (PP) was assessed in differentiated Caco-2 cell cultures from d-mannitol fluxes and transepithelial electrical resistance (TER) in the presence of different PGE2receptor agonists (carbacyclin, sulprostone, butaprost, ONO-AE1-259, ONO-AE-248, GR63799, and ONO-AE1-329) and antagonists (ONO-8711, SC-19220, AH-6809, ONO-AE3-240, ONO-AE3-208, and AH-23848). The results indicate that EP1and EP4but not EP2and EP3might be involved in PP regulation. These effects were mediated through PLC-inositol trisphosphate (IP3)-Ca2+and cAMP-PKA signaling pathways, respectively. We also observed an increase in intracellular Ca2+concentration ([Ca2+]i) strengthened by cAMP formation indicating a cross talk interaction of these two pathways. Moreover, the participation of a conventional PKC isoform was shown. The results also indicate that the increase in PP may be correlated with the redistribution of occludin, zona occludens 1 (ZO-1), and the perijunctional actin ring together with an increase in myosin light chain kinase activity. Although the disruption of epithelial barrier function observed in inflammatory bowel disease (IBD) patients has been traditionally attributed to cytokines, the present study focused on the role of PGE2in PP regulation, as mucosal levels of this eicosanoid are also increased in these inflammatory processes.

scholarly journals The NLRP3 inflammasome mediates DSS-induced intestinal inflammation in Nod2 knockout mice

2019 ◽  
Vol 25 (2) ◽  
pp. 132-143 ◽  
Author(s):  
Benjamin Umiker ◽  
Hyun-Hee Lee ◽  
Julia Cope ◽  
Nadim J. Ajami ◽  
Jean-Philippe Laine ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Chronic Disorder ◽  
Molecule Inhibitor ◽  
Pathway Inhibition

Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2−/− mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1β secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1β secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.

scholarly journals Activation of HIF-1α does not increase intestinal tumorigenesis

2014 ◽  
Vol 307 (2) ◽  
pp. G187-G195 ◽  
Author(s):  
Xiang Xue ◽  
Sadeesh K. Ramakrishnan ◽  
Yatrik M. Shah
Keyword(s):  
Colon Cancer ◽  
Transcription Factors ◽  
Cancer Progression ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Cell Metabolism ◽  
Tumor Biology ◽  
Hypoxia Inducible Factor ◽  
Pharmacological Agents ◽  
Epithelial Barrier Function

The hypoxic response is mediated by two transcription factors, hypoxia-inducible factor (HIF)-1α and HIF-2α. These highly homologous transcription factors are induced in hypoxic foci and regulate cell metabolism, angiogenesis, cell proliferation, and cell survival. HIF-1α and HIF-2α are activated early in cancer progression and are important in several aspects of tumor biology. HIF-1α and HIF-2α have overlapping and distinct functions. In the intestine, activation of HIF-2α increases inflammation and colon carcinogenesis in mouse models. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1α is beneficial and can reduce intestinal inflammation. HIF-1α is a critical transcription factor regulating epithelial barrier function following inflammation. The beneficial value of pharmacological agents that chronically activate HIF-1α is decreased due to the tumorigenic potential of HIFs. The present study tested the hypothesis that chronic activation of HIF-1α may enhance colon tumorigenesis. Two models of colon cancer were assessed, a sporadic and a colitis-associated colon cancer model. Activation of HIF-1α in intestinal epithelial cells does not increase carcinogenesis or progression of colon cancer. Together, the data provide proof of principle that pharmacological activation of HIF-1α could be a safe therapeutic strategy for inflammatory bowel disease.

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