Carbon Monoxide Being Hydrogen Sulfide and Nitric Oxide Molecular Sibling, as Endogenous and Exogenous Modulator of Oxidative Stress and Antioxidative Mechanisms in the Digestive System

Table 3

Antioxidative effects of CO donors in various in vitro and in vivo experimental models of liver injury.

Experimental model (publication)	CO donor	Dose	Form of application
Hindlimb I/R-induced systemic inflammation mouse model [85]	CO gas or MC	250 ppm or 5.8 μmol/kg	Inhalation or orally
↓ Lipid peroxidation, ↓ inhibition of NADPH oxidase, and restored GSH/GSSG ratio
Liver transplantation- (LTx-) induced I/R injury rat model/Kupffer cells isolated from the liver [86]	CO gas	20% CO-saturated culture medium	Incubation with medium containing CO
↓ ROS generation, ↑ HSP 70 protein expression
Hemorrhagic shock and resuscitation rat model/Kupffer cells isolated from the liver [87]	CO gas	Gently bubbling CO gas through the RBC resuscitative fluid	Infusion of resuscitative fluids
↓ ROS generation
Hepatic warm I/R injury mouse model [89]	CO gas	250 ppm	Inhalation
↑ ROS-dependent PI3 K/Akt activation, ↓ inhibition of GSK3β through Ser9 phosphorylation
Ethanol-induced liver damage mouse model or primary rat hepatocytes [91]	CORM-2	8 mg/kg or 20 μmol/l	Tail vein injection or incubation with medium containing CO
↓ Lipid peroxidation, restored GSH level, and restored SOD level
APAP-induced liver injury in mice [79]	CORM-1A	20 mg/kg	Intraperitoneal injection
↑ Nrf2 gene upregulation, ↑ ARE gene upregulation, and restored GSH level
HFHF diet-induced hepatic steatosis in mice [92]	CORM-1A	2 mg/kg/day	Intraperitoneal injection
↑ Nrf2 activation, ↑ ARE gene upregulation, and ↑ ATP production
GalN/LPS-induced acute liver mouse model [94]	CO gas	First at a dose of 15 ml/kg, and then 6 h later, 8 ml/kg	Intraperitoneal injection
↓ Lipid peroxidation, restored GSH level, and restored SOD level
Primary rat or mouse hepatocytes and Hep3B cells [96]	CO gas	250 ppm	Incubation with medium containing CO
↓ Apoptosis, ↓ endogenous antioxidant ascorbic acid, ↓ antioxidant power, ↑ ROS generation, ↑ Akt phosphorylation, and ↓ IκB degradation (= ↑ NF-κB activation)
HepG2 cells [95]	CORM-2	80 μM for 6 h	CO-saturated stock solutions
↑ Nrf2 activation, ↑ HO-1 expression
Tert-butyl hydroperoxide- (t-BHP-) treated HepG2 cells [79]	CORM-A1	100 μM	Incubation with medium containing CO
↓ ROS generation, ↑ Nrf2 activation
Rat liver mitochondria [98]	CO gas	50 ppm for 1, 2, or 7 days	Inhalation
↓ GSH/GSSG ratio, ↑ activation of MMP, and ↑ mitochondrial SOD-2
Mouse liver mitochondria [99]	CO solution	10 μM	Swelling buffer
↓ Inhibition of MPP, ↑ mitochondrial ROS generation
PA-treated HepG2 cells [92]	CORM-1A	100 μM	Incubation with medium containing CO
↑ Nrf2 activation, ↑ ARE gene upregulation ↓ mitochondrial ROS generation, and ↑ activation of mitochondrial membrane potential