Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury
Aim. Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively at...
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| Format: | Article |
| Language: | English |
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Palacký University Olomouc, Faculty of Medicine and Dentistry
2023-03-01
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| Series: | Biomedical Papers |
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| Online Access: | https://biomed.papers.upol.cz/artkey/bio-202301-0008_differentiated-modulation-of-signaling-molecules-ampk-and-sirt1-in-experimentally-drug-induced-hepatocyte-injur.php |
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| author | Lea Njeka Wojnarova Nikolina Kutinova Canova Mahak Arora Hassan Farghali |
| author_facet | Lea Njeka Wojnarova Nikolina Kutinova Canova Mahak Arora Hassan Farghali |
| author_sort | Lea Njeka Wojnarova |
| collection | DOAJ |
| description | Aim. Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively attenuate acute liver injury. The aim of this experimental study was to elucidate whether modulation of AMPK and SIRT1 activity can modify drug/paracetamol (APAP)-induced hepatocyte damage in vitro. Methods. Primary rat hepatocytes were pretreated with mutual combinations of specific synthetic activators and inhibitors of SIRT1 and AMPK and followed by a toxic dose of APAP. At the end of cultivation, medium samples were collected for biochemical analysis of alanine-aminotransferase and nitrite levels. Hepatocyte viability, thiobarbituric reactive substances, SIRT1 and AMPK activity and protein expression were also assessed. Results. The harmful effect of APAP was associated with decreased AMPK and SIRT1 activity and protein expression alongside enhanced oxidative stress in hepatocytes. The addition of AMPK activator (AICAR) or SIRT1 activator (CAY10591) significantly attenuated the deleterious effects of AMPK inhibitor (Compound C) on the hepatotoxicity of APAP. Furthermore, CAY10591 but not AICAR markedly decreased the deleterious effect of APAP in combination with SIRT1 inhibitor (EX-527). Conclusion. Our findings demonstrate that decreased AMPK activity is associated with the hepatotoxic effect of APAP which can be significantly attenuated by the administration of a SIRT1 activator. These findings suggest that differentiated modulation of AMPK and SIRT1 activity could therefore provide an interesting and novel therapeutic opportunity in the future to combat hepatocyte injury. |
| first_indexed | 2024-04-09T14:54:17Z |
| format | Article |
| id | doaj.art-75c26e92418c48a6a65aab408d99f02b |
| institution | Directory Open Access Journal |
| issn | 1213-8118 1804-7521 |
| language | English |
| last_indexed | 2024-04-09T14:54:17Z |
| publishDate | 2023-03-01 |
| publisher | Palacký University Olomouc, Faculty of Medicine and Dentistry |
| record_format | Article |
| series | Biomedical Papers |
| spelling | doaj.art-75c26e92418c48a6a65aab408d99f02b2023-05-02T08:04:03ZengPalacký University Olomouc, Faculty of Medicine and DentistryBiomedical Papers1213-81181804-75212023-03-011671506010.5507/bp.2022.018bio-202301-0008Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injuryLea Njeka Wojnarova0Nikolina Kutinova Canova1Mahak Arora2Hassan Farghali3Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech RepublicAim. Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively attenuate acute liver injury. The aim of this experimental study was to elucidate whether modulation of AMPK and SIRT1 activity can modify drug/paracetamol (APAP)-induced hepatocyte damage in vitro. Methods. Primary rat hepatocytes were pretreated with mutual combinations of specific synthetic activators and inhibitors of SIRT1 and AMPK and followed by a toxic dose of APAP. At the end of cultivation, medium samples were collected for biochemical analysis of alanine-aminotransferase and nitrite levels. Hepatocyte viability, thiobarbituric reactive substances, SIRT1 and AMPK activity and protein expression were also assessed. Results. The harmful effect of APAP was associated with decreased AMPK and SIRT1 activity and protein expression alongside enhanced oxidative stress in hepatocytes. The addition of AMPK activator (AICAR) or SIRT1 activator (CAY10591) significantly attenuated the deleterious effects of AMPK inhibitor (Compound C) on the hepatotoxicity of APAP. Furthermore, CAY10591 but not AICAR markedly decreased the deleterious effect of APAP in combination with SIRT1 inhibitor (EX-527). Conclusion. Our findings demonstrate that decreased AMPK activity is associated with the hepatotoxic effect of APAP which can be significantly attenuated by the administration of a SIRT1 activator. These findings suggest that differentiated modulation of AMPK and SIRT1 activity could therefore provide an interesting and novel therapeutic opportunity in the future to combat hepatocyte injury.https://biomed.papers.upol.cz/artkey/bio-202301-0008_differentiated-modulation-of-signaling-molecules-ampk-and-sirt1-in-experimentally-drug-induced-hepatocyte-injur.php5-aminoimidazole-4-carboxamide ribonucleotide (aicar)adenosine monophosphate protein kinase (ampk)cay10591enzyme activationhepatocyte protectionsirtuin 1 (sirt1) |
| spellingShingle | Lea Njeka Wojnarova Nikolina Kutinova Canova Mahak Arora Hassan Farghali Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury Biomedical Papers 5-aminoimidazole-4-carboxamide ribonucleotide (aicar) adenosine monophosphate protein kinase (ampk) cay10591 enzyme activation hepatocyte protection sirtuin 1 (sirt1) |
| title | Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury |
| title_full | Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury |
| title_fullStr | Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury |
| title_full_unstemmed | Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury |
| title_short | Differentiated modulation of signaling molecules AMPK and SIRT1 in experimentally drug-induced hepatocyte injury |
| title_sort | differentiated modulation of signaling molecules ampk and sirt1 in experimentally drug induced hepatocyte injury |
| topic | 5-aminoimidazole-4-carboxamide ribonucleotide (aicar) adenosine monophosphate protein kinase (ampk) cay10591 enzyme activation hepatocyte protection sirtuin 1 (sirt1) |
| url | https://biomed.papers.upol.cz/artkey/bio-202301-0008_differentiated-modulation-of-signaling-molecules-ampk-and-sirt1-in-experimentally-drug-induced-hepatocyte-injur.php |
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