Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats : A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis
Copyright © 2021 Youssef, Abd El-Fattah, Abdelhamid, Eissa, El-Ahwany, Amin, Hetta, Mahmoud, Batiha, Gobba, Ahmed Gaafar and Saber..
Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Frontiers in pharmacology - 12(2021) vom: 06., Seite 719984 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Youssef, Mahmoud E [VerfasserIn] |
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| Links: |
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| Themen: |
AMPK |
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| Anmerkungen: |
Date Revised 08.09.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3389/fphar.2021.719984 |
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| Förderinstitution / Projekttitel: |
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NLM330320890 |
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| 245 | 1 | 0 | |a Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats |b A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis |
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| 520 | |a Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a IL-23/1L-17 axis 4 | |
| 650 | 4 | |a NLRP3 | |
| 650 | 4 | |a dextran sulfate sodium | |
| 650 | 4 | |a empagliflozin | |
| 650 | 4 | |a mTOR | |
| 650 | 4 | |a metformin | |
| 650 | 4 | |a ulcerative colitis | |
| 700 | 1 | |a Abd El-Fattah, Eslam E |e verfasserin |4 aut | |
| 700 | 1 | |a Abdelhamid, Amir M |e verfasserin |4 aut | |
| 700 | 1 | |a Eissa, Hanan |e verfasserin |4 aut | |
| 700 | 1 | |a El-Ahwany, Eman |e verfasserin |4 aut | |
| 700 | 1 | |a Amin, Noha A |e verfasserin |4 aut | |
| 700 | 1 | |a Hetta, Helal F |e verfasserin |4 aut | |
| 700 | 1 | |a Mahmoud, Mohamed H |e verfasserin |4 aut | |
| 700 | 1 | |a Batiha, Gaber El-Saber |e verfasserin |4 aut | |
| 700 | 1 | |a Gobba, Naglaa |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmed Gaafar, Ahmed Gaafar |e verfasserin |4 aut | |
| 700 | 1 | |a Saber, Sameh |e verfasserin |4 aut | |
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