New progress in understanding roles of nitric oxide during hepatic ischemia-reperfusion injury

Table 1 Roles of nitric oxide, inducible nitric oxide synthase, and endothelial nitric oxide synthase in various conditions and pharmacological protection against hepatic ischemia-reperfusion injury

Pretreatment	NO/ iNOS/ eNOS levels	Animals	Experimental cells	Mechanism	Liver cell necrosis and liver damage	Ref.
NMP, BMMSCs, and liver CDC	eNOS↑, iNOS↓	SPF rats	Liver tissue	Macrophage activation, ICAM-1, VCAM-1, vWF↓	↓	[5]
L-NAME and BDL	iNOS mRNA↓	Male Wistar rats	Liver tissue	TGF-β, NOx, HA↓; AMDA↑		[6]
Simvastatin and WIR	NO↑	Male Wistar rats	Primary LSEC	Nitrotyrosines, O2-↓; Nrf2, HO-1↑	↓	[14]
Simvastatin and WIR	NO, eNOS↑	Male Wistar rats	LSEC	KLF2, p-eNOS, cGMP↑; O2−, VCAM-1↓	↓	[16]
Obestatin and HIRI	eNOS↑, iNOS↓	Adult Wistar albino male rats	Liver tissue samples	Reducing oxidative stress and inflammatory process	↓	[17]
HIRI	NO↑	Male Sprague-Dawley rats	Liver	Decrease synthesis of LTC4S, NF-κB↓	↓	[18,19]
V-PYRRO/NO and HIRI	NO↑	Male Sprague-Dawley rats	Liver	Decrease synthesis of LTC4S, NF-κB↓	↓	[20]
AMPK–caspase-6 axis and nonalcoholic steatohepatitis	-	LAKO mice	Hepatocyte	Caspases-6 activation	↓	[21]
Cd-Induced Apoptosis	NO↑ iNOS↑	Hy-Line Brown laying hen	Liver	Mitochondrial apoptotic pathway	↓	[23]
Punicalagin and cyclophosphamide	NO, iNOS↓	Sprague-Dawley male rats	Liver	Reduce cell apoptosis	↓	[25]
Emblica officinalisGaertn and NAP	NO↓	Male Wistar rats	Liver	Apoptosis, autophagy, inflammation↓	↓	[28]
Tormentic acid and LPS/ D-GalN	NO, iNOS↓	Male C57BL/6 mice	Liver samples	TNF-α, NF-κB↓; imbalanced Bax/Bcl-2 ratio	↓	[30]
Selenocysteine-containing 7-mer peptide	NO↓	Adult male Wistar rats	Liver tissue	Inhibit oxidant peroxynitrite, Bax↓; Bcl-2↑	↓	[34]
IPC and HIRI	NO↑	Male C57BL/6 mice	Liver tissue	p38 MAPK↑; autophagy↑	↓	[35]
Simvastatin and hepatic transplantation	NO↑	Male rats	Liver	Autophagy↑	↓	[36]
IPC	NO↑	Male Sprague-Dawley rats	Liver	Oxygen species liberation and proinflammatory cytokine↓; microcirculation↑	↓	[37]
Oxytocin and HIRI	NO↑	Adult male albino (Sprague Dawley strain)	Liver	NO bioavailability↑	↓	[38]
TELL and HIRI	eNOS↑	Male Wistar rats	Liver	Activate PI3K/Akt pathway, suppress TLR4, p-PI3K, p-Akt, Nrf2, p-NF-κB p65, p-MAPK p38, TNF-α, GSH, MyD88, HMGB-1, TBARS↑; NF-κB↓	↓	[42]
Apelin preconditioning and HIRI	eNOS↑	Male albino rats	Liver tissue	Activate PI3K/Akt pathway, suppress AT1R, counteract Ang II/AT1R system	↓	[43]
Simvastatin and WIR	eNOS↑	Male inbred Sprague Dawley rats	Liver tissue	Activate KLF2 pathway, TM, p-eNOS↑, TGF-β, TNF-α, IL- 1β↓	↓	[44]
HMP and liver DCD	NO, eNOS↑	Adult male Sprague-dawley rat	Liver	KLF2↑; NF-κB p65, IL-1β, TNF-α↓	↓	[45]
TMZ and WIR	eNOS↑	Male Wistar rats	Liver tissue	p-MAPK↑; activate MAPK pathway	↓	[46]
IGL-1 and Fatty Liver Graft Cold Storage	eNOS↑	Homozygous (obese) Zücker rats	Liver	Activate MAPK pathway, ATP↑	↓	[48]
SEW2871 and WIR	eNOS↑	Male C57BL/6 mice	SECs	VE-cadherin, p-Akt↑; IFN-γ, TNF-α, IL-6, VCAM-1↓	↓	[49]
EPO and liver transplantation	eNOS↑	Female landrace pigs	Liver tissue	Activate JAK2/PI3/AKT pathway, AMPK↑; βcR2-VEGFR-2 complex	↓	[51]
HIRI	-	Female domestic (Landrace) pigs	Liver tissue	IL-6, STAT-3 and E-selectin mRNA↑	-	[52]
TDF and HIRI	eNOS, iNOS↓	Female Wistar albino rats	Liver tissue	cGMP↑, activate mitochondrial K-ATP channels, mitochondrial Ca2+↓	↓	[53]
PTX and HIRI	eNOS, iNOS↓			cAMP↑ TNF-α, IL-1, IL-6, IL-12, TGF-β, IFN-γ, procollagen-I mRNA↓	↓
L-NNA and HIRI	iNOS↑, eNOS, NO↓	Male Wistar rats	Liver	TNF-α, NF-κB↑, Bcl-2↓	↑	[54]
L-Arginine/CDN and HIRI	NO, eNOS↑, iNOS↓			TNF-α, NF-κB↓, Bcl-2↑	↓
iNOS knockout and WIR	iNOS↓	C57BL/6 male rats	293 T cells	PUMA↓	↑	[55]
NAC and HIRI	eNOS↑, iNOS↓	Male Wister albino rats	Liver	NOSTRIN, MDA, MPO activity↓	↓	[56]
TQ and HIRI	eNOS↑, iNOS↓			NOSTRIN, MDA, oxidative stress, nitrosative stress↓, GSH↑	↓
LA and HIRI	iNOS mRNA↓	Male Wistar rats	Liver	NF-κB p65, MIP-2 mRNA, GSH↓	↓	[57]
V and HIRI	NO, iNOS mRNA↓	Male Wistar rats	Lung and Liver tissue	Inhibit HIF-α/HGF/iNOS pathway	↓	[58]
Eupatilin and HIRI	iNOS↓	Male C57BL/6 mice	Embryonic liver BNL CL.2 cell	TLR2/4, p-IκB-a↓, Bcl-2↑	↓	[59]
N-SMase inhibitor and HIRI	iNOS	Male Wistar rats	Liver tissue	Protein nitration, nitrite/nitrate levels, HNE		[60]
Ad-eNOS and small-for-size liver transplatation	NO, eNOS↑	-	Human normal liver cell line L02	TNF-α↓, inhibit macrophage activation	↓	[61]
Ad-eNOS and HIRI	eNOS↑	Male inbred C57BL6 lean mice	Liver	ATP↓, bax, p53↑	↓	[62]

L-NAME: Nomega-nitro-L-arginine methyl ester; BDL: Bile duct ligation; WIR: Warm ischemia and reperfusion; LSEC: Rat liver sinusoidal endothelial cells; KLF2: Kruppel-like factor 2; VCAM-1: Vascular cell adhesion molecule-1; HIRI: Hepatic ischemia reperfusion injury; NF-κB: nuclear factor-kappaB; LTC4S: Leukotriene C4 synthase; AMPK: Adenosine monophosphate activated protein kinase; NAP:N-nitrosodiethylamine; LPS: Lipopolysaccharide; D-GalN: D-galactosamine; TNF-α: Tumor necrosis factor-α; Bax: BCL2-Associated X; Bcl-2: B-cell lymphoma-2; MAPK: Mitogen-activated protein kinase; IPC: Ischemic preconditioning; TM: Thrombomodulin; PI3K: Phosphoinositide 3-kinase; TLR4: Toll like receptor-4; Nrf2: Nuclear erythroid-related factor 2; MyD88: Myeloid differentiation primary-response protein 88; TBARS: Thiobarbituric acid reactive substances; AT1R: Angiotensin type 1 receptor; VE-cadherin: Vascular endothelial cadherin; JAK: Janus activated kinase 2; DCD: Donated after circulatory death; HMP: Hypothermic machine perfusion; TMZ: Trimetazidine; IGL-1: Institut georges lopez-1; SECs: Sinusoidal endothelial cells; EPO: Erythropoietin; TDF: Tadalafil; PTX: Pentoxifylline; SPF: Pathogen-free; BMMSCs: Bone marrow mesenchymal stem cells; NMP: Normothermic machine perfusion; L-NNA: Nomega-nitro-L-arginine; CDN: Cardamonin; PUMA: p53 up-regulated modulator of apoptosis; HIF-α: Hypoxia inducible factor 1α; HGF: Hepatocyte growth factor; MIP-2: Macrophage inflammatory protein-2, LA: Alpha-lipoic acid; V: Vildagliptin; MPO: Myeloperoxidase, MDA: Malondialdehyde; NAC: N-acetylcysteine; TQ: Thymoquinone; Ad-eNOS: Adenovirus-eNOS; N-SMase: Neutral sphingomyelinase; HNE: 4-hydroxynonenal; VEGFR: Vascular endothelial growth factor receptor; ICAM-1: Intracellular cell adhesion molecule-1; βcR: Common β receptor; NOSTRIN: Nitric oxide synthase trafficking.