PMID- 37569823
OWN - NLM
STAT- MEDLINE
DCOM- 20230814
LR  - 20230814
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 15
DP  - 2023 Aug 4
TI  - Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse 
      Model by Suppressing Glycolysis.
LID - 10.3390/ijms241512448 [doi]
LID - 12448
AB  - Sepsis is a life-threatening medical emergency triggered by excessive 
      inflammation in response to an infection. High mortality rates and limited 
      therapeutic options pose significant challenges in sepsis treatment. Histone 
      deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), 
      have been proposed as potent anti-inflammatory agents for treating inflammatory 
      diseases. However, the underlying mechanisms of sepsis treatment remain poorly 
      understood. In this study, we investigated the effects of SAHA treatment in the 
      lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the 
      early stages of the systemic inflammation of sepsis. Our results demonstrate a 
      reduced inflammatory mediator secretion and improved survival rates in mice. 
      Using quantitative acetylomics, we found that SAHA administration increases the 
      acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA 
      activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate 
      of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages 
      (BMDMs) show that SAHA administration reduced oxidative stress and extracellular 
      ATP concentrations, ultimately blunting inflammasome activation. Overall, our 
      study provides insights into the mechanism underlying SAHA's therapeutic effects 
      in sepsis treatment and highlights LDHA as a potential target for developing 
      novel sepsis treatment.
FAU - Wu, Yunchen
AU  - Wu Y
AD  - School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
AD  - Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, 
      Friedrich Schiller University Jena, 07745 Jena, Germany.
FAU - He, Yudan
AU  - He Y
AD  - School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
FAU - Liu, Chen
AU  - Liu C
AD  - School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
FAU - Ehle, Charlotte
AU  - Ehle C
AD  - Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, 
      Friedrich Schiller University Jena, 07745 Jena, Germany.
FAU - Iyer-Bierhoff, Aishwarya
AU  - Iyer-Bierhoff A
AD  - Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, 
      Friedrich Schiller University Jena, 07745 Jena, Germany.
FAU - Liu, Bing
AU  - Liu B
AD  - School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
FAU - Heinzel, Thorsten
AU  - Heinzel T
AUID- ORCID: 0009-0003-8937-6089
AD  - Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, 
      Friedrich Schiller University Jena, 07745 Jena, Germany.
FAU - Xing, Shaojun
AU  - Xing S
AUID- ORCID: 0000-0003-0777-2196
AD  - School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
AD  - The First Affiliated Hospital of Shenzhen University, Shenzhen University, 
      Shenzhen 518055, China.
LA  - eng
GR  - KQTD20190929172538530/Marshall Laboratory of Biomedical Engineering, and Shenzhen 
      Science and Technology Program/
GR  - 81971492/National Natural Science Foundation of China/
GR  - XXXX/Jena School of Molecular Medicine (JSMM), Germany/
PT  - Journal Article
DEP - 20230804
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 58IFB293JI (Vorinostat)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Vorinostat/pharmacology/therapeutic use
MH  - Histone Deacetylase Inhibitors/pharmacology/therapeutic use
MH  - *Endotoxemia/drug therapy
MH  - Hydroxamic Acids/pharmacology/therapeutic use
MH  - *Sepsis/drug therapy
PMC - PMC10418975
OTO - NOTNLM
OT  - SAHA
OT  - glycolysis
OT  - liver
OT  - macrophage
OT  - sepsis
COIS- The authors declare no conflict of interest.
EDAT- 2023/08/12 10:49
MHDA- 2023/08/14 06:41
PMCR- 2023/08/04
CRDT- 2023/08/12 01:12
PHST- 2023/07/11 00:00 [received]
PHST- 2023/07/28 00:00 [revised]
PHST- 2023/08/02 00:00 [accepted]
PHST- 2023/08/14 06:41 [medline]
PHST- 2023/08/12 10:49 [pubmed]
PHST- 2023/08/12 01:12 [entrez]
PHST- 2023/08/04 00:00 [pmc-release]
AID - ijms241512448 [pii]
AID - ijms-24-12448 [pii]
AID - 10.3390/ijms241512448 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Aug 4;24(15):12448. doi: 10.3390/ijms241512448.