NOX as a Therapeutic Target in Liver Disease
Abstract
1. Introduction
2. The NOX Family: From the Respiratory Burst to the Regulation of Metabolic Pathways
- They are dependent on NADPH;
- They are only found in membrane systems (plasma, mitochondrial, etc.);
- NOX consists of a catalytic subunit (gp96phox-like) linked to another subunit (p22phox), in most cases, and some subunits that regulate the activity of this enzyme system (p47phox, p67phox, p40phox, and Rac). The catalytic subunit has six transmembrane domains (seven for DUOX1 and 2), four hemes in transmembrane domains three and five, an NADPH-binding domain, and a FAD-binding domain at the C-terminus in the cytosolic region.
3. Cellular Distribution of NOX in the Liver
4. NOXs and Inflammasomes Activation
5. NOXs and Fibrosis
6. Alcohol and Non-Alcohol Associated Steatohepatitis
7. Hepatitis C Virus (HCV) Induced Hepatocellular Damage
8. Hydrophobic Bile Salts-Induced Liver Injury
9. Role of ROS in Acute and Chronic Liver Damage
10. NOXs and Cancer
10.1. NOX1
10.2. NOX2
10.3. NOX4
10.4. DUOX1
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ROS | reactive oxygen species; |
HCC | hepatic carcinogenesis; |
HBV | hepatitis B virus; |
HCV | hepatitis C virus; |
ALD | alcohol-related liver disease; |
NAFLD | nonalcoholic fatty liver disease; |
NADPH | nicotinamide adenine dinucleotide phosphate hydrogen; |
KC | Kupffer cells; |
HSCs | hepatic stellate cells; |
ECs | endothelial cells; |
PRR | pattern recognition receptor; |
DAMPs | damage-associated molecular patterns; |
PAMPs | pathogen-associated molecular patterns; |
HAMPs | homeostasis-altering molecular processes; |
NOD | nucleotide-binding oligomerization domain; |
NLRC | NOD-like receptor CARD domain containing; |
NLRP | NOD-like receptor Pyrin domain containing; |
TNFR | tumor necrosis factor receptor; |
TLR | Toll-like receptors; |
ECM | extracellular matrix; |
TGF-β1 | transforming growth factor β1; |
αSMA | α-smooth muscle actin; |
BDL | bile duct ligation; |
NASH | non-alcohol associated steatohepatitis; |
HIF-1α | Hypoxia Inducible Factor 1α; |
ET-1 | endothelin-1; |
LSEC | liver sinusoidal endothelial cells; |
DAAs | direct-acting antiviral agents; |
HCC | hepatocellular carcinoma; |
SVR | sustained virologic response; |
FXR or NR1H4 | farnesoid receptor; |
PKCf | Protein kinase C f; |
ERK | Extracellular signal-regulated kinase; |
VSMCs | Vascular Smooth Muscle Cells; |
EGFR | epidermal growth factor receptor; |
VEGF | vascular endothelial growth factor; |
VEGFR2 | vascular endothelial growth factor receptor 2; |
RTK | receptor tyrosine kinase; |
GPCR | G protein-coupled receptors; |
SRC | protooncogene tyrosine-protein kinase; |
RAS | serine-threonine kinase; |
PTEN | lipid tyrosine phosphatase; |
PI3K | phosphoinositol 3-kinase; |
mTOR | target of rapamycin; |
HIF | hypoxia-inducible factors; |
VEGF | vascular endothelial growth factor; |
MMPs | matrix metalloproteinases; |
HIFs | hypoxia-inducible transcription factors; |
AMPK | AMP-activated protein kinase; |
TSG | tumor-suppressor gene. |
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Drug | Nox Inhibited | Pathway Affected | Disease | Study Model | Reference |
---|---|---|---|---|---|
LDC7559 (NA-11) (Indirect action) | NOX2 | Respiratory burst (neutrophils) | Viral infection | Human blood | [163] |
GKT137831 (Setanaxib) (Direct action) | NOX1/NOX4 | Suppressed chemokine production, inhibited hepatic stellate cell (HSC) activation | Hepatic fibrosis | Mouse | [164] |
GKT137831 (Setanaxib) (Direct action) | NOX1/NOX4 | Bile duct ligation-induced hepatic fibrosis (BDL) | Hepatic fibrosis and hepatocyte apoptosis | Mouse | [77] |
GKT137831 (Setanaxib) (Direct action) | NOX1/NOX4 | Decrease in oxidative stress and inflammation | Hepatic fibrosis | Mouse | [165] |
Chlorogenic acid (Indirect action) | NOX | Upregulation of NFE2L2, a transcription factor that regulates the expression of antioxidant enzymes | Hepatic fibrosis | Rats | [166] |
Losartan (Indirect action) | Non-specific inhibition of different NOX | The expression of profibrogenic and NOX genes was reduced | Hypertension and heart failure | Human | [167] |
Catalpol (Indirect action) | NOX4 | AMPK/NOX4/PI3K/AKT | Hepatic insulin resistance in type 2 diabetes | Mouse | [168] |
Apocinin (Direct action) | NOX2 | Inhibits the binding of p47phox to gp91phox | Inflammation and aging | Rats | [169] |
Statinas (Direct action) | NOX1/NOX2 | Inhibit Rac binding to gp91phox | Hepatic fibrosis | Rats | [170] |
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Matuz-Mares, D.; Vázquez-Meza, H.; Vilchis-Landeros, M.M. NOX as a Therapeutic Target in Liver Disease. Antioxidants 2022, 11, 2038. https://doi.org/10.3390/antiox11102038
Matuz-Mares D, Vázquez-Meza H, Vilchis-Landeros MM. NOX as a Therapeutic Target in Liver Disease. Antioxidants. 2022; 11(10):2038. https://doi.org/10.3390/antiox11102038
Chicago/Turabian StyleMatuz-Mares, Deyamira, Héctor Vázquez-Meza, and María Magdalena Vilchis-Landeros. 2022. "NOX as a Therapeutic Target in Liver Disease" Antioxidants 11, no. 10: 2038. https://doi.org/10.3390/antiox11102038
APA StyleMatuz-Mares, D., Vázquez-Meza, H., & Vilchis-Landeros, M. M. (2022). NOX as a Therapeutic Target in Liver Disease. Antioxidants, 11(10), 2038. https://doi.org/10.3390/antiox11102038