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      1. Author :
        Zschiebsch, Katja; Fischer, Caroline; Pickert, Geethanjali; Häeussler, Annett; Radeke, Heinfried; Grösch, Sabine; Ferreirós, Nerea; Geisslinger, Gerd; Werner, Ernst R; Tegeder, Irmgard
      2. Title :
        Tetrahydrobiopterin attenuates DSS-evoked colitis in mice by rebalancing redox and lipid signaling
      3. Type :
        Journal Article
      4. Year :
      5. Publication :
        Journal of Crohn's and Colitis
      6. Products :
      7. Volume :
      8. Issue :
      9. Page Numbers :
      10. Research Area :
      11. Keywords :
        Tetrahydrobiopterin,; nitric oxide,; inflammatory bowel disease,; glycerophospholipids,; redox stress,; lipid signaling molecules,; AGMO; IVIS; IVIS BLI in vivo
      12. Abstract :
        Background and aims: GTP cyclohydrolase (GCH1) governs the production of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine synthesis, lipid metabolism via alkylglycerol monooxygenase (AGMO) and redox coupling of nitric oxide synthases (NOSs). Inflammation-evoked unequal regulations of GCH1 and NOS or AGMO may cause redox stress and lipid imbalances. Methods: The present study assessed potential therapeutic effects of rebalancing these systems with BH4 in experimental colitis in mice. Results: Oral treatment with BH4 as suspension of crushed tablets attenuated colitis whereas inhibition of its production had opposite effects i.e. aggravated weight loss, epithelial hemorrhages and ulcers, neutrophil infiltrates, production of reactive oxygen species and unfavorable profile changes of endocannabinoids, ceramides and lysophosphatidic acids. Oppositely, oral BH4 normalized biopterin, reduced in vivo activity of oxidases and peroxidases in the inflamed gut, favoured nitric oxide over hydrogen peroxide and maintained normal levels of lipid signalling molecules. BH4 favoured thereby resident CD3+CD8+ and regulatory CD3+CD25+ intraepithelial T-cells that are important for epithelial integrity. Conclusions: BH4 protected against colitis in mice via two major pathways: (i) by reduction of oxidative stress and (ii) by re-orchestration of alkyl- and acylglycerolipid signaling via AGMO. Oral treatment with BH4 is a safe approved supplementary therapy for genetic BH4 deficiency and did not excessively increase systemic BH4 levels. Therefore, one may consider repurposing of oral BH4 as an adjunctive treatment for colitis.
      13. URL :
      14. Call Number :
        PKI @ user @ 11187
      15. Serial :