Hany H Arab1, Ahmed M Ashour2, Amany M Gad3, Ayman M Mahmoud4, Ahmed M Kabel5. 1. Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia. Electronic address: h.arab@tu.edu.sa. 2. Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia. 3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, El Ismailia, Egypt; Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt. 4. Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt; Biotechnology Department, Research Institute of Medicinal and Aromatic Plants, Beni-Suef University, Beni-Suef, Egypt. 5. Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt.
Abstract
AIMS: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1β levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.
AIMS: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1β levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.
Authors: Hany H Arab; Sarah A Abd El-Aal; Ahmed M Ashour; Azza A K El-Sheikh; Hana J Al Khabbaz; El-Shaimaa A Arafa; Ayman M Mahmoud; Ahmed M Kabel Journal: Inflammopharmacology Date: 2022-06-28 Impact factor: 5.093
Authors: Hany H Arab; Alzahraa A Elhemiely; Azza A K El-Sheikh; Hana J Al Khabbaz; El-Shaimaa A Arafa; Ahmed M Ashour; Ahmed M Kabel; Ahmed H Eid Journal: Pharmaceuticals (Basel) Date: 2022-07-11