PMID- 26718771
OWN - NLM
STAT- MEDLINE
DCOM- 20170530
LR  - 20190115
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 310
IP  - 7
DP  - 2016 Apr 1
TI  - Sparstolonin B attenuates early liver inflammation in experimental NASH by 
      modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation.
PG  - G510-25
LID - 10.1152/ajpgi.00259.2015 [doi]
AB  - Although significant research data exist on the pathophysiology of nonalcoholic 
      steatohepatitis (NASH), finding an efficient treatment regimen for it remains 
      elusive. The present study used sparstolonin B (SsnB), a novel TLR4 antagonist 
      derived from the Chinese herb Sparganium stoloniferum, as a possible drug to 
      mitigate early inflammation in NASH. This study used an early steatohepatitic 
      injury model in high-fat-fed mice with CYP2E1-mediated oxidative stress as a 
      second hit. SsnB was administered for 1 wk along with bromodichloromethane 
      (BDCM), an inducer of CYP2E1-mediated oxidative stress. Results showed that SsnB 
      administration attenuated inflammatory morphology and decreased elevation of the 
      liver enzyme alanine aminotransferase (ALT). Mice administered SsnB also showed 
      decreased mRNA expression of proinflammatory cytokines TNF-alpha, IFN-gamma, IL-1beta, and 
      IL-23, while protein levels of both TNF-alpha and IL-1beta were significantly decreased. 
      SsnB significantly decreased Kupffer cell activation as evidenced by reduction in 
      CD68 and monocyte chemoattractant protein-1 (MCP1) mRNA and protein levels with 
      concomitant inhibition of macrophage infiltration in the injured liver. 
      Mechanistically, SsnB decreased TLR4 trafficking to the lipid rafts, a phenomenon 
      described by the colocalization of TLR4 and lipid raft marker flotillin in 
      tissues and immortalized Kupffer cells. Since we have shown previously that NADPH 
      oxidase drives TLR4 trafficking in NASH, we studied the role of SsnB in 
      modulating this pathway. SsnB prevented NADPH oxidase activation in vivo and in 
      vitro as indicated by decreased peroxynitrite formation. In summary, the present 
      study reports a novel use of the TLR4 antagonist SsnB in mitigating inflammation 
      in NASH and in parallel shows a unique molecular mechanism of decreasing 
      nitrative stress.
CI  - Copyright (c) 2016 the American Physiological Society.
FAU - Dattaroy, Diptadip
AU  - Dattaroy D
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina;
FAU - Seth, Ratanesh Kumar
AU  - Seth RK
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina;
FAU - Das, Suvarthi
AU  - Das S
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina;
FAU - Alhasson, Firas
AU  - Alhasson F
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina;
FAU - Chandrashekaran, Varun
AU  - Chandrashekaran V
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina;
FAU - Michelotti, Gregory
AU  - Michelotti G
AD  - Division of Gastroenterology, Duke University, Durham, North Carolina;
FAU - Fan, Daping
AU  - Fan D
AD  - Department of Cell Biology and Anatomy, University of South Carolina School of 
      Medicine, Columbia, South Carolina; and.
FAU - Nagarkatti, Mitzi
AU  - Nagarkatti M
AD  - Department of Pathology, Microbiology and Immunology, University of South 
      Carolina School of Medicine, Columbia, South Carolina.
FAU - Nagarkatti, Prakash
AU  - Nagarkatti P
AD  - Department of Pathology, Microbiology and Immunology, University of South 
      Carolina School of Medicine, Columbia, South Carolina.
FAU - Diehl, Anna Mae
AU  - Diehl AM
AD  - Division of Gastroenterology, Duke University, Durham, North Carolina;
FAU - Chatterjee, Saurabh
AU  - Chatterjee S
AD  - Environmental Health and Disease Laboratory, Department of Environmental Health 
      Sciences, Arnold School of Public Health, University of South Carolina, Columbia, 
      South Carolina; schatt@mailbox.sc.edu.
LA  - eng
GR  - R00 ES019875/ES/NIEHS NIH HHS/United States
GR  - P20 GM103641/GM/NIGMS NIH HHS/United States
GR  - P01 AT003961/AT/NCCIH NIH HHS/United States
GR  - R01 AT006888/AT/NCCIH NIH HHS/United States
GR  - R01 MH094755/MH/NIMH NIH HHS/United States
GR  - R01 ES019313/ES/NIEHS NIH HHS/United States
GR  - R01 DK053792/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20151230
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cytokines)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Inflammation Mediators)
RN  - 0 (MIRN21 microRNA, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (MicroRNAs)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (flotillins)
RN  - 0 (sparstolonin B)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Cell Line
MH  - Cytochrome P-450 CYP2E1/biosynthesis
MH  - Cytokines/genetics/metabolism
MH  - Disease Models, Animal
MH  - Enzyme Activation
MH  - Enzyme Induction
MH  - Hepatitis/enzymology/genetics/pathology/*prevention & control
MH  - Heterocyclic Compounds, 4 or More Rings/*pharmacology
MH  - Inflammation Mediators/metabolism
MH  - Kupffer Cells/drug effects/metabolism/pathology
MH  - Liver/*drug effects/enzymology/pathology
MH  - Macrophages/drug effects/enzymology
MH  - Male
MH  - Membrane Microdomains/*drug effects/enzymology
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics/metabolism
MH  - NADPH Oxidases/*metabolism
MH  - Non-alcoholic Fatty Liver Disease/enzymology/genetics/pathology/*prevention & 
      control
MH  - Oxidative Stress/drug effects
MH  - PTEN Phosphohydrolase/metabolism
MH  - Peroxynitrous Acid/metabolism
MH  - Protein Transport
MH  - Signal Transduction/drug effects
MH  - Toll-Like Receptor 4/*antagonists & inhibitors/genetics/metabolism
PMC - PMC4824178
OTO - NOTNLM
OT  - NADPH oxidase
OT  - SsnB
OT  - inflammation
OT  - p47phox
OT  - peroxynitrite
EDAT- 2016/01/01 06:00
MHDA- 2017/05/31 06:00
PMCR- 2017/04/01
CRDT- 2016/01/01 06:00
PHST- 2015/07/31 00:00 [received]
PHST- 2015/12/28 00:00 [accepted]
PHST- 2016/01/01 06:00 [entrez]
PHST- 2016/01/01 06:00 [pubmed]
PHST- 2017/05/31 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - ajpgi.00259.2015 [pii]
AID - GI-00259-2015 [pii]
AID - 10.1152/ajpgi.00259.2015 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2016 Apr 1;310(7):G510-25. doi: 
      10.1152/ajpgi.00259.2015. Epub 2015 Dec 30.