Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Xinshou Ouyang, Sheng-Na Han, Ji-Yuan Zhang, Evangelos Dioletis, Balazs Tamas Nemeth, Pal Pacher, Dechun Feng, Ramon Bataller, Joaquin Cabezas, Peter Stärkel, Joan Caballeria, Rebecca LePine Pongratz, Shi-Ying Cai, Bernd Schnabl, Rafaz Hoque, Yonglin Chen, Wei-Hong Yang, Irma Garcia-Martinez, Fu-Sheng Wang, Bin Gao, Natalie Julia Torok, Richard Glenn Kibbey, Wajahat Zafar Mehal, Xinshou Ouyang, Sheng-Na Han, Ji-Yuan Zhang, Evangelos Dioletis, Balazs Tamas Nemeth, Pal Pacher, Dechun Feng, Ramon Bataller, Joaquin Cabezas, Peter Stärkel, Joan Caballeria, Rebecca LePine Pongratz, Shi-Ying Cai, Bernd Schnabl, Rafaz Hoque, Yonglin Chen, Wei-Hong Yang, Irma Garcia-Martinez, Fu-Sheng Wang, Bin Gao, Natalie Julia Torok, Richard Glenn Kibbey, Wajahat Zafar Mehal
Abstract
Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.
Keywords: HIF-1α; NASH; ROS; alcohol; digoxin; liver; pyruvate kinase M2; steatohepatitis; sterile inflammation; therapy.
Copyright © 2018 Elsevier Inc. All rights reserved.
Figures
![Figure 1. Digoxin reduces endotoxin-induced hepatic damage](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f1.jpg)
Figure 2. Digoxin prevents chronic hepatic damage…
Figure 2. Digoxin prevents chronic hepatic damage and inflammation in high fat diet model of…
Figure 3. Digoxin reduces hepatitis steatosis and…
Figure 3. Digoxin reduces hepatitis steatosis and inflammation when given therapeutically
( A–H ) Mice…
Figure 4. Digoxin improves cellular redox status…
Figure 4. Digoxin improves cellular redox status from a wide range of stimuli
( A…
Figure 5. Digoxin inhibits the transcription of…
Figure 5. Digoxin inhibits the transcription of HIF-1α signature genes in inflamed liver
Figure 6. Digoxin directly binds to PKM2…
Figure 6. Digoxin directly binds to PKM2 and inhibits PKM2-HIF-1α axis activation
Figure 7. Digoxin disrupts the protein interaction…
Figure 7. Digoxin disrupts the protein interaction of PKM2 to histones in the nucleus
(…
- Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Zhao P, et al. Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1;317(4):G387-G397. doi: 10.1152/ajpgi.00054.2019. Epub 2019 Aug 14. Am J Physiol Gastrointest Liver Physiol. 2019. PMID: 31411894 Free PMC article.
- Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture.Dong T, Yan Y, Chai H, Chen S, Xiong X, Sun D, Yu Y, Deng L, Cheng F. Dong T, et al. Biomed Pharmacother. 2015 Feb;69:277-84. doi: 10.1016/j.biopha.2014.12.010. Epub 2014 Dec 19. Biomed Pharmacother. 2015. PMID: 25661370
- The PKM2 activator TEPP-46 attenuates MCD feeding-induced nonalcoholic steatohepatitis by inhibiting the activation of Kupffer cells.Yang SH, Wu H, Yi ZJ, Lai X. Yang SH, et al. Eur Rev Med Pharmacol Sci. 2021 Jun;25(11):4017-4026. doi: 10.26355/eurrev_202106_26043. Eur Rev Med Pharmacol Sci. 2021. PMID: 34156680
- Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Luo W, et al. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. Cell. 2011. PMID: 21620138 Free PMC article.
- Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer.Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Archer SL, et al. Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H570-8. doi: 10.1152/ajpheart.01324.2007. Epub 2007 Dec 14. Am J Physiol Heart Circ Physiol. 2008. PMID: 18083891 Review.
- The role of hypoxia-inducible factor 1α in hepatic lipid metabolism.Luo M, Li T, Sang H. Luo M, et al. J Mol Med (Berl). 2023 Mar 28. doi: 10.1007/s00109-023-02308-5. Online ahead of print. J Mol Med (Berl). 2023. PMID: 36973503 Review.
- Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators.Yfantis A, Mylonis I, Chachami G, Nikolaidis M, Amoutzias GD, Paraskeva E, Simos G. Yfantis A, et al. Cells. 2023 Mar 3;12(5):798. doi: 10.3390/cells12050798. Cells. 2023. PMID: 36899934 Free PMC article. Review.
- Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Che W, et al. Front Endocrinol (Lausanne). 2022 Nov 29;13:1002916. doi: 10.3389/fendo.2022.1002916. eCollection 2022. Front Endocrinol (Lausanne). 2022. PMID: 36523601 Free PMC article. Review.
- MKK4 Knockdown Plays a Protective Role in Hemorrhagic Shock-Induced Liver Injury through the JNK Pathway.Yao H, Gao Y, Han J, Wang Y, Cai J, Rui Y, Ge X. Yao H, et al. Oxid Med Cell Longev. 2022 Sep 17;2022:5074153. doi: 10.1155/2022/5074153. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 36164393 Free PMC article.
- Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.de Keijzer MJ, de Klerk DJ, de Haan LR, van Kooten RT, Franchi LP, Dias LM, Kleijn TG, van Doorn DJ, Heger M; Photodynamic Therapy Study Group. de Keijzer MJ, et al. Methods Mol Biol. 2022;2451:285-403. doi: 10.1007/978-1-0716-2099-1_19. Methods Mol Biol. 2022. PMID: 35505024
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Amino Acid Sequence
- Animals
- Cell Nucleus / drug effects
- Cell Nucleus / metabolism
- Chromatin / metabolism
- Digoxin / pharmacology*
- Disease Models, Animal
- Endotoxins
- Histones / metabolism
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Inflammation / genetics
- Inflammation / pathology
- Liver / drug effects
- Liver / metabolism
- Liver / pathology
- Non-alcoholic Fatty Liver Disease / genetics*
- Oxidation-Reduction
- Protein Binding / drug effects
- Pyruvate Kinase / chemistry
- Pyruvate Kinase / metabolism*
- THP-1 Cells
- Transcription, Genetic / drug effects
- Transcriptional Activation / drug effects*
- Chromatin
- Endotoxins
- Histones
- Hypoxia-Inducible Factor 1, alpha Subunit
- Digoxin
- Pyruvate Kinase
- U01 AA021912/AA/NIAAA NIH HHS/United States
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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
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Bethesda, MD 20894
![Figure 2. Digoxin prevents chronic hepatic damage…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f2.jpg)
Figure 3. Digoxin reduces hepatitis steatosis and…
Figure 3. Digoxin reduces hepatitis steatosis and inflammation when given therapeutically
( A–H ) Mice…
Figure 4. Digoxin improves cellular redox status…
Figure 4. Digoxin improves cellular redox status from a wide range of stimuli
( A…
Figure 5. Digoxin inhibits the transcription of…
Figure 5. Digoxin inhibits the transcription of HIF-1α signature genes in inflamed liver
Figure 6. Digoxin directly binds to PKM2…
Figure 6. Digoxin directly binds to PKM2 and inhibits PKM2-HIF-1α axis activation
Figure 7. Digoxin disrupts the protein interaction…
Figure 7. Digoxin disrupts the protein interaction of PKM2 to histones in the nucleus
(…
- Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Zhao P, et al. Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1;317(4):G387-G397. doi: 10.1152/ajpgi.00054.2019. Epub 2019 Aug 14. Am J Physiol Gastrointest Liver Physiol. 2019. PMID: 31411894 Free PMC article.
- Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture.Dong T, Yan Y, Chai H, Chen S, Xiong X, Sun D, Yu Y, Deng L, Cheng F. Dong T, et al. Biomed Pharmacother. 2015 Feb;69:277-84. doi: 10.1016/j.biopha.2014.12.010. Epub 2014 Dec 19. Biomed Pharmacother. 2015. PMID: 25661370
- The PKM2 activator TEPP-46 attenuates MCD feeding-induced nonalcoholic steatohepatitis by inhibiting the activation of Kupffer cells.Yang SH, Wu H, Yi ZJ, Lai X. Yang SH, et al. Eur Rev Med Pharmacol Sci. 2021 Jun;25(11):4017-4026. doi: 10.26355/eurrev_202106_26043. Eur Rev Med Pharmacol Sci. 2021. PMID: 34156680
- Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Luo W, et al. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. Cell. 2011. PMID: 21620138 Free PMC article.
- Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer.Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Archer SL, et al. Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H570-8. doi: 10.1152/ajpheart.01324.2007. Epub 2007 Dec 14. Am J Physiol Heart Circ Physiol. 2008. PMID: 18083891 Review.
- The role of hypoxia-inducible factor 1α in hepatic lipid metabolism.Luo M, Li T, Sang H. Luo M, et al. J Mol Med (Berl). 2023 Mar 28. doi: 10.1007/s00109-023-02308-5. Online ahead of print. J Mol Med (Berl). 2023. PMID: 36973503 Review.
- Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators.Yfantis A, Mylonis I, Chachami G, Nikolaidis M, Amoutzias GD, Paraskeva E, Simos G. Yfantis A, et al. Cells. 2023 Mar 3;12(5):798. doi: 10.3390/cells12050798. Cells. 2023. PMID: 36899934 Free PMC article. Review.
- Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Che W, et al. Front Endocrinol (Lausanne). 2022 Nov 29;13:1002916. doi: 10.3389/fendo.2022.1002916. eCollection 2022. Front Endocrinol (Lausanne). 2022. PMID: 36523601 Free PMC article. Review.
- MKK4 Knockdown Plays a Protective Role in Hemorrhagic Shock-Induced Liver Injury through the JNK Pathway.Yao H, Gao Y, Han J, Wang Y, Cai J, Rui Y, Ge X. Yao H, et al. Oxid Med Cell Longev. 2022 Sep 17;2022:5074153. doi: 10.1155/2022/5074153. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 36164393 Free PMC article.
- Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.de Keijzer MJ, de Klerk DJ, de Haan LR, van Kooten RT, Franchi LP, Dias LM, Kleijn TG, van Doorn DJ, Heger M; Photodynamic Therapy Study Group. de Keijzer MJ, et al. Methods Mol Biol. 2022;2451:285-403. doi: 10.1007/978-1-0716-2099-1_19. Methods Mol Biol. 2022. PMID: 35505024
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Amino Acid Sequence
- Animals
- Cell Nucleus / drug effects
- Cell Nucleus / metabolism
- Chromatin / metabolism
- Digoxin / pharmacology*
- Disease Models, Animal
- Endotoxins
- Histones / metabolism
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Inflammation / genetics
- Inflammation / pathology
- Liver / drug effects
- Liver / metabolism
- Liver / pathology
- Non-alcoholic Fatty Liver Disease / genetics*
- Oxidation-Reduction
- Protein Binding / drug effects
- Pyruvate Kinase / chemistry
- Pyruvate Kinase / metabolism*
- THP-1 Cells
- Transcription, Genetic / drug effects
- Transcriptional Activation / drug effects*
- Chromatin
- Endotoxins
- Histones
- Hypoxia-Inducible Factor 1, alpha Subunit
- Digoxin
- Pyruvate Kinase
- U01 AA021912/AA/NIAAA NIH HHS/United States
- UL1 TR001863/TR/NCATS NIH HHS/United States
- U01 AA021908/AA/NIAAA NIH HHS/United States
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- R01 AG060726/AG/NIA NIH HHS/United States
- P30 DK034989/DK/NIDDK NIH HHS/United States
- R56 DK076674/DK/NIDDK NIH HHS/United States
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- R01 DK108283/DK/NIDDK NIH HHS/United States
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- R01 DK083283/DK/NIDDK NIH HHS/United States
- K08 DK092281/DK/NIDDK NIH HHS/United States
- I01 BX003259/BX/BLRD VA/United States
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
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NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3. Digoxin reduces hepatitis steatosis and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f3.jpg)
Figure 4. Digoxin improves cellular redox status…
Figure 4. Digoxin improves cellular redox status from a wide range of stimuli
( A…
Figure 5. Digoxin inhibits the transcription of…
Figure 5. Digoxin inhibits the transcription of HIF-1α signature genes in inflamed liver
Figure 6. Digoxin directly binds to PKM2…
Figure 6. Digoxin directly binds to PKM2 and inhibits PKM2-HIF-1α axis activation
Figure 7. Digoxin disrupts the protein interaction…
Figure 7. Digoxin disrupts the protein interaction of PKM2 to histones in the nucleus
(…
- Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Zhao P, et al. Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1;317(4):G387-G397. doi: 10.1152/ajpgi.00054.2019. Epub 2019 Aug 14. Am J Physiol Gastrointest Liver Physiol. 2019. PMID: 31411894 Free PMC article.
- Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture.Dong T, Yan Y, Chai H, Chen S, Xiong X, Sun D, Yu Y, Deng L, Cheng F. Dong T, et al. Biomed Pharmacother. 2015 Feb;69:277-84. doi: 10.1016/j.biopha.2014.12.010. Epub 2014 Dec 19. Biomed Pharmacother. 2015. PMID: 25661370
- The PKM2 activator TEPP-46 attenuates MCD feeding-induced nonalcoholic steatohepatitis by inhibiting the activation of Kupffer cells.Yang SH, Wu H, Yi ZJ, Lai X. Yang SH, et al. Eur Rev Med Pharmacol Sci. 2021 Jun;25(11):4017-4026. doi: 10.26355/eurrev_202106_26043. Eur Rev Med Pharmacol Sci. 2021. PMID: 34156680
- Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Luo W, et al. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. Cell. 2011. PMID: 21620138 Free PMC article.
- Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer.Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Archer SL, et al. Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H570-8. doi: 10.1152/ajpheart.01324.2007. Epub 2007 Dec 14. Am J Physiol Heart Circ Physiol. 2008. PMID: 18083891 Review.
- The role of hypoxia-inducible factor 1α in hepatic lipid metabolism.Luo M, Li T, Sang H. Luo M, et al. J Mol Med (Berl). 2023 Mar 28. doi: 10.1007/s00109-023-02308-5. Online ahead of print. J Mol Med (Berl). 2023. PMID: 36973503 Review.
- Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators.Yfantis A, Mylonis I, Chachami G, Nikolaidis M, Amoutzias GD, Paraskeva E, Simos G. Yfantis A, et al. Cells. 2023 Mar 3;12(5):798. doi: 10.3390/cells12050798. Cells. 2023. PMID: 36899934 Free PMC article. Review.
- Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Che W, et al. Front Endocrinol (Lausanne). 2022 Nov 29;13:1002916. doi: 10.3389/fendo.2022.1002916. eCollection 2022. Front Endocrinol (Lausanne). 2022. PMID: 36523601 Free PMC article. Review.
- MKK4 Knockdown Plays a Protective Role in Hemorrhagic Shock-Induced Liver Injury through the JNK Pathway.Yao H, Gao Y, Han J, Wang Y, Cai J, Rui Y, Ge X. Yao H, et al. Oxid Med Cell Longev. 2022 Sep 17;2022:5074153. doi: 10.1155/2022/5074153. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 36164393 Free PMC article.
- Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.de Keijzer MJ, de Klerk DJ, de Haan LR, van Kooten RT, Franchi LP, Dias LM, Kleijn TG, van Doorn DJ, Heger M; Photodynamic Therapy Study Group. de Keijzer MJ, et al. Methods Mol Biol. 2022;2451:285-403. doi: 10.1007/978-1-0716-2099-1_19. Methods Mol Biol. 2022. PMID: 35505024
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Amino Acid Sequence
- Animals
- Cell Nucleus / drug effects
- Cell Nucleus / metabolism
- Chromatin / metabolism
- Digoxin / pharmacology*
- Disease Models, Animal
- Endotoxins
- Histones / metabolism
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Inflammation / genetics
- Inflammation / pathology
- Liver / drug effects
- Liver / metabolism
- Liver / pathology
- Non-alcoholic Fatty Liver Disease / genetics*
- Oxidation-Reduction
- Protein Binding / drug effects
- Pyruvate Kinase / chemistry
- Pyruvate Kinase / metabolism*
- THP-1 Cells
- Transcription, Genetic / drug effects
- Transcriptional Activation / drug effects*
- Chromatin
- Endotoxins
- Histones
- Hypoxia-Inducible Factor 1, alpha Subunit
- Digoxin
- Pyruvate Kinase
- U01 AA021912/AA/NIAAA NIH HHS/United States
- UL1 TR001863/TR/NCATS NIH HHS/United States
- U01 AA021908/AA/NIAAA NIH HHS/United States
- R01 DK110181/DK/NIDDK NIH HHS/United States
- R01 DK092606/DK/NIDDK NIH HHS/United States
- R01 AG060726/AG/NIA NIH HHS/United States
- P30 DK034989/DK/NIDDK NIH HHS/United States
- R56 DK076674/DK/NIDDK NIH HHS/United States
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- R01 DK083283/DK/NIDDK NIH HHS/United States
- K08 DK092281/DK/NIDDK NIH HHS/United States
- I01 BX003259/BX/BLRD VA/United States
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
- Miscellaneous
![Figure 4. Digoxin improves cellular redox status…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f4.jpg)
![Figure 5. Digoxin inhibits the transcription of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f5.jpg)
Figure 6. Digoxin directly binds to PKM2…
Figure 6. Digoxin directly binds to PKM2 and inhibits PKM2-HIF-1α axis activation
Figure 7. Digoxin disrupts the protein interaction…
Figure 7. Digoxin disrupts the protein interaction of PKM2 to histones in the nucleus
(…
![Figure 6. Digoxin directly binds to PKM2…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f6.jpg)
![Figure 7. Digoxin disrupts the protein interaction…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5806149/bin/nihms936398f7.jpg)
Source: PubMed