title: AMPK Serves as a Therapeutic Target Against Anemia of Inflammation.
abstract: Anemia of inflammation (AI), the second prevalent anemia, is associated with worse prognosis and increased mortality in numerous chronic diseases. We recently reported that the gasotransmitter hydrogen sulfide (H2S) suppressed the inflammatory activation of signal transducer and activator of transcription 3 (STAT3) and hepcidin, the critical mediators of AI. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a novel inflammatory regulator and might be activated by H2S. In this study, we determined whether AMPK played a role in H2S-mediated anti-inflammatory response in AI and evaluated the therapeutic potential of AMPK against AI by pharmacological and clinical approaches.
  
  
  
  We showed that AMPK mediated the inhibition of STAT3, hepcidin, and AI by H2S during inflammation. Moreover, pharmacological and genetic activation of AMPK ameliorated hepcidin production, corrected iron dysregulation, and relieved hypoferremia and anemia in both acute and chronic inflammation models in mice. Mechanistic studies indicated that AMPK suppressed STAT3/hepcidin activation by promoting proteasome-mediated Janus kinase 2 (JAK2) degradation, which was dependent on the intact function of suppressor of cytokine signaling 1 (SOCS1) and increased interactions between SOCS1 and JAK2. Most importantly, the AMPK activator metformin was associated with decreased serum hepcidin content and anemia morbidity in Chinese type 2 diabetes mellitus patients.
  
  
  
  This is the first study to demonstrate the inhibition of inflammatory hepcidin and AI by AMPK-induced JAK2 degradation. Our work uncovered AMPK as a novel therapeutic target, and metformin as a potential therapy against AI.
  
  
  
  The present work demonstrated that AMPK mediated the therapeutic effects of H2S and relieved AI by promoting SOCS1-mediated JAK2 degradation. Antioxid. Redox Signal. 27, 251-268.
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .|2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China .
authors.forename: Minjun
authors.initials: M
authors.lastname: Wang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.affiliation: 3 Department of Oncology, School of Medicine, Fudan University , Shanghai, China .
authors.forename: Wenbo
authors.initials: W
authors.lastname: Tang
authors.affiliation: 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China .
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China .
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China .
authors.forename: Linling
authors.initials: L
authors.lastname: Fan
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: 5 Department of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, China .
authors.forename: Bo
authors.initials: B
authors.lastname: Tan
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Xiling
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .|2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China .
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism; D014425:Turpentine / Q000633:toxicity; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D064451:Hepcidins; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D053614:Janus Kinase 2; D014425:Turpentine; D006862:Hydrogen Sulfide
keywords: AMPK; anemia of inflammation; hepcidin; hydrogen sulfide; metformin