PMID- 37239114
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230530
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 11
IP  - 5
DP  - 2023 May 14
TI  - Inhibition of NADPH Oxidase (NOX) 2 Mitigates Colitis in Mice with Impaired 
      Macrophage AMPK Function.
LID - 10.3390/biomedicines11051443 [doi]
LID - 1443
AB  - Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the 
      development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 
      2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory 
      cytokine secretion in macrophages during inflammation, while increased NOX2 
      expression is reported in experimental models of colitis and inflammatory bowel 
      disease (IBD) patients. Although there are reductions in AMPK activity in IBD, it 
      remains unclear whether targeted inhibition of NOX2 in the presence of defective 
      AMPK can reduce the severity of colitis. Here, we investigate whether the 
      inhibition of NOX2 ameliorates colitis in mice independent of AMPK activation. 
      Our study identified that VAS2870 (a pan-Nox inhibitor) alleviated dextran sodium 
      sulfate (DSS)-induced colitis in macrophage-specific AMPKbeta1-deficient 
      (AMPKbeta1(LysM)) mice. Additionally, VAS2870 blocked LPS-induced TLR-4 and NOX2 
      expression, ROS production, nuclear translocation of NF-kappaB, and pro-inflammatory 
      cytokine secretion in bone marrow-derived macrophages (BMDMs) from AMPKbeta1(LysM) 
      mice, whereas sodium salicylate (SS; AMPK beta1 activator) did not. Both VAS2870 and 
      SS inhibited LPS-induced NOX2 expression, ROS production, and pro-inflammatory 
      cytokine secretions in bone marrow-derived macrophages (BMDMs) from wildtype 
      (AMPKbeta1(fl/fl)) mice but only VAS2870 inhibited these effects of LPSs in 
      AMPKbeta1(LysM) BMDMs. Furthermore, in macrophage cells (RAW 264.7), both SS and 
      VAS2870 inhibited ROS production and the secretion of pro-inflammatory cytokines 
      and reversed the impaired autophagy induced by LPSs. These data suggest that 
      inhibiting NOX2 can reduce inflammation independent of AMPK in colitis.
FAU - Banskota, Suhrid
AU  - Banskota S
AUID- ORCID: 0000-0003-3183-6268
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
FAU - Wang, Huaqing
AU  - Wang H
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
FAU - Kwon, Yun Han
AU  - Kwon YH
AUID- ORCID: 0000-0002-4232-9141
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
FAU - Gautam, Jaya
AU  - Gautam J
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
AD  - Department of Biochemistry and Biomedical Sciences, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
FAU - Haq, Sabah
AU  - Haq S
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
FAU - Grondin, Jensine
AU  - Grondin J
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
FAU - Steinberg, Gregory R
AU  - Steinberg GR
AUID- ORCID: 0000-0001-5425-8275
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
AD  - Department of Biochemistry and Biomedical Sciences, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
FAU - Khan, Waliul I
AU  - Khan WI
AD  - Farncombe Family Digestive Health Research Institute, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
AD  - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 
      L8S 4L8, Canada.
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Hamilton, ON L8S 4L8, Canada.
LA  - eng
GR  - PJT156262/CAPMC/CIHR/Canada
PT  - Journal Article
DEP - 20230514
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC10216132
OTO - NOTNLM
OT  - AMPK
OT  - NOX2
OT  - autophagy
OT  - colitis
OT  - inflammation
OT  - macrophages
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/27 09:43
MHDA- 2023/05/27 09:44
PMCR- 2023/05/14
CRDT- 2023/05/27 01:09
PHST- 2023/04/07 00:00 [received]
PHST- 2023/05/07 00:00 [revised]
PHST- 2023/05/11 00:00 [accepted]
PHST- 2023/05/27 09:44 [medline]
PHST- 2023/05/27 09:43 [pubmed]
PHST- 2023/05/27 01:09 [entrez]
PHST- 2023/05/14 00:00 [pmc-release]
AID - biomedicines11051443 [pii]
AID - biomedicines-11-01443 [pii]
AID - 10.3390/biomedicines11051443 [doi]
PST - epublish
SO  - Biomedicines. 2023 May 14;11(5):1443. doi: 10.3390/biomedicines11051443.