M S Abdel-Bakky1,2, G K Helal3,4, E M El-Sayed3, A H Alhowail5, A M Mansour3, K S Alharbi6, Elham Amin7,8, S Allam9, S A Salama10,11, A S Saad12. 1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt. M.AbdelBakky@qu.edu.sa. 2. Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Kingdom of Saudi Arabia. M.AbdelBakky@qu.edu.sa. 3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt. 4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt. 5. Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Kingdom of Saudi Arabia. 6. Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, 72341, Kingdom of Saudi Arabia. 7. Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. 8. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, 52471, Kingdom of Saudi Arabia. 9. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafralsheikh University, Kafralsheikh, Egypt. 10. Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt. 11. Division of Biochemistry, Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Taif, 21974, Saudi Arabia. 12. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
Abstract
BACKGROUND: Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation. PURPOSE: We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury. METHODS: Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated. RESULTS: Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.
BACKGROUND:Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation. PURPOSE: We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury. METHODS:Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated. RESULTS: Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.
Authors: Mohamed S Abdel-Bakky; Elham Amin; Mohamed G Ewees; Nesreen I Mahmoud; Hamdoon A Mohammed; Waleed M Altowayan; Ahmed A H Abdellatif Journal: Viruses Date: 2022-01-24 Impact factor: 5.048