Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abdelhamid A.M.; Youssef M.E.; Abd El-Fattah E.E.; Gobba N.A.; Gaafar A.G.A.; Girgis S.; Shata A.; Hafez A.-M.; El-Ahwany E.; Amin N.A.; Shahien M.A.; Abd-Eldayem M.A.; Abou-Elrous M.; Saber S.

Journal: Life Sciences

Publisher: Elsevier Inc.

Publication Date: December 2021

Volume / Issue: Volume 286

Article No.: 120070

ISSN: 243205

DOI: 10.1016/j.lfs.2021.120070

Scopus: View on Scopus

PubMed: 34688695

Document Type: Article

Access: All Open Access; Hybrid Gold Open Access

Authors and Affiliations

Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Abd El-Fattah E.E., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Gobba N.A., Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Egypt; Gaafar A.G.A., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt; Girgis S., Department of Pharmaceutics, Faculty of Pharmacy, Alsalam University, Egypt; Shata A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Hafez A.-M., Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt, Department of Physiology, College of Medicine, Qassim University, Saudi Arabia; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt; Shahien M.A., Department of Clinical Pharmacology, Faculty of Medicine, Damietta University, Damietta, Egypt; Abd-Eldayem M.A., Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt; Abou-Elrous M., Department of Biochemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Aim: Metformin and empagliflozin combined therapy may have complementary effects that go beyond the well-recognized targets of their monotherapy through AMPK activation. Therefore, the current study was designed to investigate for the first time the hepatoprotective effects of such combination therapy in the carbon tetrachloride (CCl4)-induced hepatic fibrosis model in mice. Materials and methods: Determination of liver enzymes and the liver content of oxidative stress parameters, and hydroxyproline were performed biochemically. ELISA was performed to measure PDGF-BB, TNF-α, TGF-β, TIMP-1, AMPK, p-mTOR, NF-κB P65 binding activity, p38 MAPKα, JNK1/2 and ERK1/2. Real-time qPCR was conducted to determine Col1a1 and α-SMA. In addition, histopathological examination using H&E and Masson's trichrome stain were performed for determination of histopathological changes. Key findings: Empagliflozin inhibited the activation of p38 MAPK and ERK1/2 and exhibited a weak AMPKα stimulation. On the other hand, metformin exerted a more robust stimulatory action on the AMPKα that was accompanied by a notable decrease in the NF-κB nuclear binding activity and a decline in the p-mTOR levels. Nevertheless, the effect of metformin on MAPK kinases was insignificant. Our results revealed that blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhanced the antifibrotic effect of metformin and augmented its AMPK-induced NF-κB inactivation. Significance: As diabetes is one of the most common risk factors for liver fibrosis, the use of antidiabetic drugs is expected to improve therapeutic outcome. Therefore, metformin/empagliflozin combined therapy could be promising in preventing hepatic inflammation and fibrosis via exhibiting complementary effects particularly in diabetic patients. © 2021 Elsevier Inc.

Keywords

AMPKα; ERK1/2; Liver fibrosis; Metformin/empagliflozin; NF-κB; p38 MAPK; Adenylate Kinase; AMP-Activated Protein Kinases; Animals; Benzhydryl Compounds; Carbon Tetrachloride; Drug Therapy, Combination; Female; Glucosides; Hepatocytes; Liver; Liver Cirrhosis; Male; MAP Kinase Signaling System; Metformin; Mice; Mice, Inbred BALB C; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture; Signal Transduction; Transcription Factor RelA; empagliflozin; eosin; hematoxylin; hydroxymethylglutaryl coenzyme A reductase kinase; hydroxyproline; Janus kinase 1; Janus kinase 2; mammalian target of rapamycin; mitogen activated protein kinase 1; mitogen activated protein kinase 14; mitogen activated protein kinase 3; platelet derived growth factor; tissue inhibitor of metalloproteinase 1; transforming growth factor beta; tumor necrosis factor; benzhydryl derivative; glucoside; immunoglobulin enhancer binding protein; mitogen activated protein kinase p38; a SMA gene; animal cell; animal experiment; animal model; animal tissue; antifibrotic activity; Article; biochemistry; col1a1 gene; controlled study; drug potentiation; enzyme inactivation; enzyme linked immunosorbent assay; histopathology; intoxication; liver protection; Masson staining; mouse; nonhuman; oxidative stress; quantitative analysis; real time polymerase chain reaction; animal; Bagg albino mouse; combination drug therapy; drug effect; liver cell; MAPK signaling; metabolism; pathophysiology; physiology; procedures

Citation Information

Scopus Citations: 44

For comprehensive information about the Theodor Bilharz Research Institute (TBRI), its institutional activities, scientific and research achievements, clinical and hospital services, and the diverse expertise offered through its 22 specialized research and clinical departments, as well as opportunities for professional training, specialized workshops, and scientific conferences, readers are invited to visit the Institute’s official website.

The website provides regularly updated information on the Institute’s latest news, research activities, scientific initiatives, clinical services, institutional programs, and academic and professional opportunities.

English Website: https://www.tbri.sci.eg/en/

Arabic Website: https://www.tbri.sci.eg/ar/

Prepared and Uploaded by:

Abdalla F. Abdalla

Electronic Portal Unit

Electronic Portal Unit

Popular Posts

A cost-performance index for nano-optical biosensor evaluation: Systematic evaluation of europium–salicylate luminescent platforms for GPC3-targeted early HCC diagnosis

Image
Bibliographic Information Authors: Hassan Y.M.; El-Tantawi H.; Ali I.R.; Attia M.S. Journal: Talanta Publisher: Elsevier B.V. Publication Date: January 2027 Volume / Issue: Volume 311 Article No.: 130103 ISSN: 399140 DOI: 10.1016/j.talanta.2026.130103 Scopus: View on Scopus PubMed: 42391698 Document Type: Review Authors and Affiliations Hassan Y.M., Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt; El-Tantawi H., Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Ali I.R., Department of Immunology and Treatment Evaluation, Theodore Bilharz Research Institute, Giza, Egypt; Attia M.S., Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia Abstract Comparative evaluation of nano-optical biosensor platforms lacks a standardised, multi-parameter quantitative framework that integrates analytical performance...
Read more

Interpretation of liver stiffness measurement in patients with mixed liver disease etiologies

Image
Bibliographic Information Authors: El Ray A.; El Ghannam M.; Rautou P.E. Journal: Arab Journal of Gastroenterology Publisher: Elsevier Ltd Publication Date: August 2026 ISSN: 16871979 DOI: 10.1016/j.ajg.2026.05.002 Scopus: View on Scopus PubMed: 42362465 Document Type: Letter Authors and Affiliations El Ray A., Theodor Bilharz Research Institute, Hepatogastroenterology Department, Giza, Egypt, Faculty of Medicine, October 6 University, Egypt; El Ghannam M., Theodor Bilharz Research Institute, Hepatogastroenterology Department, Giza, Egypt; Rautou P.E., Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France, AP-HP, Hôpital Beaujon, Service d’Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France Abstract Vibration-controlled transient elastography (VCTE)–based liver stiffness measurement (LSM) is widely used for non-invasive assessment of liver fibrosis and p...
Read more

Variable clinical presentations of pulmonary hydatid cysts: a four-case series from a single center in United Arab Emirates, non-endemic region

Image
Bibliographic Information Authors: Yehya M.; Abdallah M.F.H.; Ajeka S.; Al-Masalmeh F.H.; Albaghdadi M.O.J. Journal: Journal of Surgical Case Reports Publisher: Oxford University Press Publication Date: 29 July 2026 Volume / Issue: Volume 2026 / Issue 7 Article No.: rjag658 ISSN: 20428812 DOI: 10.1093/jscr/rjag658 Scopus: View on Scopus Document Type: Article Access: All Open Access; Gold Open Access; Green Open Access Authors and Affiliations Yehya M., Department of Thoracic Surgery, SAQR Hospital, Al Juwais Al Kadi St, Ras Al-Khaimah, United Arab Emirates; Abdallah M.F.H., Department of Radiology, SAQR Hospital, Al Juwais Al Kadi St, Ras Al-Khaimah, United Arab Emirates, Theodor Bilharz Research Institute, Mahad Al Abhas Al bahari St, Kornish Al Nile, Warraq Al Arab, Al Warak, Governorate, Giza, 3863341, Egypt; Ajeka S., Department of General Surgery, SAQR Hospital, Al Juwais Al Kadi St, Ras Al-Khaimah, United Arab Emirates; Al-Masalmeh F.H., Department of ...
Read more

Mytilus edulis-mediated green synthesis of selenium nanoparticles with antimicrobial and molluscicidal applications

Image
Bibliographic Information Authors: Dokmak H.-A.A.; AlSedawy M.; Ramadan M.A.; Amin B.H.; Faid A.H.; Abdelmaksoud H.F.; El-Sayed S.M. Journal: Scientific Reports Publisher: Nature Research Publication Date: 7 September 2026 Volume / Issue: Volume 16 / Issue 1 Article No.: 27918 ISSN: 20452322 DOI: 10.1038/s41598-026-65860-3 Scopus: View on Scopus PubMed: 42706305 Document Type: Article Access: All Open Access; Gold Open Access; Green Open Access Authors and Affiliations Dokmak H.-A.A., Department of Medical Malacology, Theodor Bilharz Research Institute, Giza, Egypt; AlSedawy M., Microbiology and Immunology Department, Faculty of Pharmacy (For Boys), Al-Azhar University, Cairo, Egypt; Ramadan M.A., Department of Laser Application in Metrology, Photochemistry and Agriculture, National Institute of Laser Enhanced Science (NILES) Cairo University (CU), Giza, Egypt; Amin B.H., The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, 11787,...
Read more

Holothuria arenicola Extract-Loaded Polycaprolactone Nanocapsules Attenuate Bile Duct Ligation-Induced Acute Liver Injury

Image
Bibliographic Information Authors: Mansour E.M.; Shemis M.; Fahmy S.R.; Amer M.A.; Mohamed A.S. Journal: Current Nanomedicine Publisher: Bentham Science Publishers Publication Date: September 2026 Volume / Issue: Volume 16 / Issue 5 Pages: 771–786 ISSN: 24681873 DOI: 10.2174/0124681873401484250924125945 Scopus: View on Scopus Document Type: Article Authors and Affiliations Mansour E.M., Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, Egypt; Shemis M., Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, Egypt; Fahmy S.R., Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt; Amer M.A., Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt; Mohamed A.S., Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt Abstract Introduction: Cholestatic liver diseases are characterized by jaundice and cholestasis with various conseq...
Read more

Microbial levan potentiates hepatic retention and antitumor activity of a PEGylated benzimidazole–curcumin nanocomplex through TLR2–FXR/FGF15-associated immunometabolic remodeling in experimental liver cancer

Image
Bibliographic Information Authors: Shawky H.; Ibrahim N.E.; Amer M.N.; Al-Ashmawy A.A.K.; Hammam O.A.; Fayed D.B.; Maghraby A.S. Journal: Scientific Reports Publisher: Nature Research Publication Date: 12 August 2026 Volume / Issue: Volume 16 / Issue 1 Article No.: 25094 ISSN: 20452322 DOI: 10.1038/s41598-026-64576-8 Scopus: View on Scopus PubMed: 42581056 Document Type: Article Access: All Open Access; Gold Open Access; Green Open Access Authors and Affiliations Shawky H., Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt; Ibrahim N.E., Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt; Amer M.N., Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt; Al-Ashmawy A.A.K., Therapeutic Chem...
Read more

Corrigendum to ‘Eco-friendly approach for the removal and simultaneous detection of cyanide toxins from drinking and wastewater sources’ [Environ. Pollut. 385 (2025) 127094]

Image
Bibliographic Information Authors: El-Sewify I.M.; Shenashen M.A.; Gomaa H.; Selim M.S.; Akhtar N.; Azzam A.; Mekawy M.; Emran M.Y.; Khairy M.; Shahat A.; Hasan M.; Elmarakbi A.; El-Safty S.A. Journal: Environmental Pollution Publisher: Elsevier Ltd Publication Date: September 2026 Volume / Issue: Volume 405 Article No.: 128412 ISSN: 2697491 DOI: 10.1016/j.envpol.2026.128412 Scopus: View on Scopus PubMed: 42259729 Document Type: Erratum Authors and Affiliations El-Sewify I.M., Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), 1–2-1 Sengen, Ibaraki-ken, Tsukubashi, 305–0047, Japan, Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo, 11566, Egypt; Shenashen M.A., Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), 1–2-1 Sengen, Ibaraki-ken, Tsukubashi, 305–0047, Japan; Gomaa H., Research Center for Macromolecules and Biomaterials, Na...
Read more