Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abdelhady R.; Mohammed O.A.; Doghish A.S.; Hamad R.S.; Abdel-Reheim M.A.; Alamri M.M.S.; Alharthi M.H.; Alfaifi J.; Adam M.I.E.; Alhalafi A.; Mohammed N.A.; Isa A.I.; Abdel-Ghany S.; Attia M.A.; Elmorsy E.A.; AL-Noshokaty T.; Nomier Y.; El-Dakroury W.A.; Saber S.

Journal: FASEB Journal

Publisher: John Wiley and Sons Inc

Publication Date: 14 February 2024

Volume / Issue: Volume 38 / Issue 4

Article No.: e23480

ISSN: 8926638

DOI: 10.1096/fj.202302461RR

Scopus: View on Scopus

PubMed: 38354025

Document Type: Article

Access: All Open Access; Hybrid Gold Open Access

Authors and Affiliations

Abdelhady R., Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt; Mohammed O.A., Department of Pharmacology, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Doghish A.S., Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Egypt; Hamad R.S., Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia, Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt; Abdel-Reheim M.A., Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Aldawadmi, Saudi Arabia, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt; Alamri M.M.S., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Alharthi M.H., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Alfaifi J., Department of Child Health, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Adam M.I.E., Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Alhalafi A., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Mohammed N.A., Department of Physiology Unit, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Isa A.I., Department of Physiology Unit, College of Medicine, University of Bisha, Bisha, Saudi Arabia; Abdel-Ghany S., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Attia M.A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Elmorsy E.A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraydah, Saudi Arabia; AL-Noshokaty T., Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt; Nomier Y., Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al-khod, Oman; El-Dakroury W.A., Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage. © 2024 Federation of American Societies for Experimental Biology.

Keywords

AMPK; diethylnitrosamine; FOXO3a; Linagliptin; liver damage; NFκB; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antiviral Agents; Carcinoma, Hepatocellular; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Liver Neoplasms; Protease Inhibitors; Rats; alanine aminotransferase; alpha fetoprotein; angiogenesis inhibitor; antiinflammatory agent; antineoplastic agent; aspartate aminotransferase; beclin 1; caspase 3; complementary DNA; cytosolic pro microtubule associated protein 1 light chain 3; gamma glutamyltransferase; gelatinase B; glyceraldehyde 3 phosphate dehydrogenase; hydroxymethylglutaryl coenzyme A reductase kinase kinase; immunoglobulin enhancer binding protein; interleukin 6; Ki 67 antigen; lactate dehydrogenase; liver protective agent; microtubule associated protein; myeloperoxidase; protein bcl 2; reactive oxygen metabolite; secobarbital; sequestosome 1; transcription factor FKHRL1; transcription factor RelA; tumor necrosis factor; unclassified drug; vasculotropin; dipeptidyl peptidase IV inhibitor; anesthesia; animal experiment; animal model; animal tissue; antiangiogenic activity; antigen retrieval; antiinflammatory activity; antiproliferative activity; apoptosis; Article; autophagy (cellular); biochemical analysis; blood; cell proliferation; cell viability; colorimetry; comparative study; controlled study; correlational study; cytosolic fraction; cytotoxicity; drug mechanism; drug repositioning; enzyme activity; exposure; fluorescence intensity; gene expression; gene expression profiling; Huh-7 cell line; human; human cell; IC50; indirect ELISA; liver cell; liver histology; liver injury; liver protection; liver tissue; male; nonhuman; pathogenesis; protein blood level; rat; real time polymerase chain reaction; signal transduction; Sprague Dawley rat; animal cell; carcinogenesis; in vivo study; inflammation; liver; liver cell carcinoma; liver function

Citation Information

Scopus Citations: 6

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