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RG100204, A Novel A...
RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis
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- Mohammad, Shireen (författare)
- Queen Mary University
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- O’Riordan, Caroline E. (författare)
- Queen Mary University
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- Verra, Chiara (författare)
- Queen Mary University
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- Aimaretti, Eleonora (författare)
- University of Turin
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- Alves, Gustavo Ferreira (författare)
- University of Turin
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- Dreisch, Klaus (författare)
- Red Glead Discovery AB
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- Evenäs, Johan (författare)
- Red Glead Discovery AB
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- Gena, Patrizia (författare)
- University of Bari Aldo Moro
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- Tesse, Angela (författare)
- University of Nantes
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- Rützler, Michael (författare)
- Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,Apoglyx AB
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- Collino, Massimo (författare)
- University of Turin
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- Calamita, Giuseppe (författare)
- University of Bari Aldo Moro
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- Thiemermann, Christoph (författare)
- Queen Mary University
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(creator_code:org_t)
- 2022-06-14
- 2022
- Engelska.
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- aquaporin (AQP)
- cecal ligation and puncture
- inflammation
- multiple organ failure
- sepsis
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Mohammad, Shiree ...
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O’Riordan, Carol ...
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Verra, Chiara
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Aimaretti, Eleon ...
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Alves, Gustavo F ...
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Dreisch, Klaus
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visa fler...
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Evenäs, Johan
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Gena, Patrizia
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Tesse, Angela
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Rützler, Michael
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Collino, Massimo
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Calamita, Giusep ...
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Thiemermann, Chr ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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Frontiers in Imm ...
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Lunds universitet