RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice
Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.701275/full |
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| author | Shireen Mohammad Sura Al Zoubi Sura Al Zoubi Debora Collotta Nadine Krieg Nadine Krieg Bianka Wissuwa Bianka Wissuwa Gustavo Ferreira Alves Gareth S. D. Purvis Gareth S. D. Purvis Giuseppe Danilo Norata Giuseppe Danilo Norata Giuseppe Danilo Norata Andrea Baragetti Andrea Baragetti Alberico Luigi Catapano Alberico Luigi Catapano Alberico Luigi Catapano Egle Solito Egle Solito Elisabeth Zechendorf Tobias Schürholz Wilmar Correa-Vargas Klaus Brandenburg Sina M. Coldewey Sina M. Coldewey Massimo Collino Muhammad M. Yaqoob Lukas Martin Lukas Martin Christoph Thiemermann |
| author_facet | Shireen Mohammad Sura Al Zoubi Sura Al Zoubi Debora Collotta Nadine Krieg Nadine Krieg Bianka Wissuwa Bianka Wissuwa Gustavo Ferreira Alves Gareth S. D. Purvis Gareth S. D. Purvis Giuseppe Danilo Norata Giuseppe Danilo Norata Giuseppe Danilo Norata Andrea Baragetti Andrea Baragetti Alberico Luigi Catapano Alberico Luigi Catapano Alberico Luigi Catapano Egle Solito Egle Solito Elisabeth Zechendorf Tobias Schürholz Wilmar Correa-Vargas Klaus Brandenburg Sina M. Coldewey Sina M. Coldewey Massimo Collino Muhammad M. Yaqoob Lukas Martin Lukas Martin Christoph Thiemermann |
| author_sort | Shireen Mohammad |
| collection | DOAJ |
| description | Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease. |
| format | Article |
| id | doaj-art-2157c8300608458ca1bb4ae7bd4a0d60 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-2157c8300608458ca1bb4ae7bd4a0d602025-01-28T06:05:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.701275701275RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in MiceShireen Mohammad0Sura Al Zoubi1Sura Al Zoubi2Debora Collotta3Nadine Krieg4Nadine Krieg5Bianka Wissuwa6Bianka Wissuwa7Gustavo Ferreira Alves8Gareth S. D. Purvis9Gareth S. D. Purvis10Giuseppe Danilo Norata11Giuseppe Danilo Norata12Giuseppe Danilo Norata13Andrea Baragetti14Andrea Baragetti15Alberico Luigi Catapano16Alberico Luigi Catapano17Alberico Luigi Catapano18Egle Solito19Egle Solito20Elisabeth Zechendorf21Tobias Schürholz22Wilmar Correa-Vargas23Klaus Brandenburg24Sina M. Coldewey25Sina M. Coldewey26Massimo Collino27Muhammad M. Yaqoob28Lukas Martin29Lukas Martin30Christoph Thiemermann31William Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDepartment of Basic Medical Sciences, School of Medicine, Al-Balqa Applied University, As-Salt, JordanDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanySeptomics Research Center, Jena University Hospital, Jena, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanySeptomics Research Center, Jena University Hospital, Jena, GermanyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomSir William Dunn School Pathology, University of Oxford, Oxford, United KingdomDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan, ItalyIRCCS Multimedica, Sesto San Giovanni, Milan, ItalySocietà Italiana per lo Studio della Aterosclerosi (S.I.S.A.) Centre for the Study of Atherosclerosis, Bassini Hospital, Milan, ItalyDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan, ItalyIRCCS Multimedica, Sesto San Giovanni, Milan, ItalyDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan, ItalyIRCCS Multimedica, Sesto San Giovanni, Milan, ItalySocietà Italiana per lo Studio della Aterosclerosi (S.I.S.A.) Centre for the Study of Atherosclerosis, Bassini Hospital, Milan, ItalyWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom0Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá degli Studi di Napoli “Federico II”, Napoli, Italy1Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany1Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany2Forschungszentrum Borstel, Department of Biophysics, Borstel, Germany3Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, Borstel, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanySeptomics Research Center, Jena University Hospital, Jena, Germany4Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, ItalyWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom1Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, GermanyWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomMetabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.https://www.frontiersin.org/articles/10.3389/fimmu.2021.701275/fullpeptide 19-2.5high-fat diettype-2 diabetesantimicrobial peptideinsulin resistancesteatohepatitis |
| spellingShingle | Shireen Mohammad Sura Al Zoubi Sura Al Zoubi Debora Collotta Nadine Krieg Nadine Krieg Bianka Wissuwa Bianka Wissuwa Gustavo Ferreira Alves Gareth S. D. Purvis Gareth S. D. Purvis Giuseppe Danilo Norata Giuseppe Danilo Norata Giuseppe Danilo Norata Andrea Baragetti Andrea Baragetti Alberico Luigi Catapano Alberico Luigi Catapano Alberico Luigi Catapano Egle Solito Egle Solito Elisabeth Zechendorf Tobias Schürholz Wilmar Correa-Vargas Klaus Brandenburg Sina M. Coldewey Sina M. Coldewey Massimo Collino Muhammad M. Yaqoob Lukas Martin Lukas Martin Christoph Thiemermann RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice Frontiers in Immunology peptide 19-2.5 high-fat diet type-2 diabetes antimicrobial peptide insulin resistance steatohepatitis |
| title | RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice |
| title_full | RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice |
| title_fullStr | RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice |
| title_full_unstemmed | RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice |
| title_short | RETRACTED: A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice |
| title_sort | retracted a synthetic peptide designed to neutralize lipopolysaccharides attenuates metaflammation and diet induced metabolic derangements in mice |
| topic | peptide 19-2.5 high-fat diet type-2 diabetes antimicrobial peptide insulin resistance steatohepatitis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.701275/full |
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