Table 1.

Summarized effects and mechanisms of NGR1 on different organs related to ischemia/reperfusion injury in vivo and in vitro studies.

Organs	Model	Objects	Dose/concentration	Tissue sites	Effects	Mechanisms	RF
Brain	Rats MCAO/R model	In vivo	20 mg/kg, i.p.	Ischemic stroke	↓ Infarct size and neurological deficits ↓ Neuronal apoptosis and astrocyte activation ↓ Abnormal accumulation of glucose and citric acid ↑ Glutamate and malate-aspartate shuttle content ↑ ATP metabolism and antioxidant content	Regulate brain small molecule metabolism	35
	Rats MCAO/R model PC12 cells OGD/R model	In vivo In vitro	20 mg/kg, i.p. 25 μM	Ischemic stroke	↓ Infarct volume and neuronal loss ↑ DCX+/EdU+, Nestin+/EdU+, NeuN+/EdU+ and APC+/EdU+ numbers ↑ BDNF, NGF and NT-4 levels ↑ SYN, PSD95, MAP-2 and Tau-1 levels	↑ Neurogenesis via the BDNF/Akt/CREB pathway	40
	Rats BCCAO model	In vivo	100 mg/kg, i.g.	Cerebral I/R injury	↓ Cerebral infarction and neuronal apoptosis	↑ BDNF and Bcl-2 expression ↓ Bax expression	57
	Rats MCAO model PC12 cells OGD/R model	In vivo In vitro	100 mg/kg, p.o. 0.1, 1 and 10 μM	Ischemic stroke	↓ BBB permeability, cerebral infarction volume and neurological impairments ↓ MMPs activity ↑ Zo1 and caludin-5 expressions	Intervene degradation and redistribution of zo1, caludin5 and occludin by cav-1/MMP2/9 pathway	69
	Rats MCAO model Primary cortical neurons OGD/R model	In vivo In vitro	20 mg/kg, i.p. 25 μM	Cerebral I/R injury	↓ MDA, PC and 8-OHdG ↑ ERα, ERβ, phospho-Akt, phospho-GSK3β, nuclear Nrf2 and HO-1 expression	↓ NADPH oxidase activity and mitochondrial dysfunction via ER-dependent activation of Akt/Nrf2 pathways	18
	Rats MCAO model HBMEC cells OGD/R model	In vivo In vitro	20 mg/kg, i.p. 25 μM	Ischemic stroke	↑ Cerebral blood flow, mitochondrial energy metabolism and angiogenesis ↑ Migration, proliferation, and tube formation	↑ NAMPT-NAD+-SIRT1 cascade ↓ Notch signaling ↑ VEGFR-2 expression	39
	Rats HIE model Primary cortical neurons OGD/R model	In vivo In vitro	5, 10 and 15 mg/kg, i.p. 0.5, 1, 2, 5, 10, 20 μmol/L	Neonatal cerebral hypoxic-ischemic injury	↑ GRP78, CHOP, PERK, ERO1-α and IRE1α ↑ Caspase-12 level ↓ BCL-2 level	Estrogen receptor-dependent activation of endoplasmic reticulum stress pathways	33
Heart	IR-induced myocardial injury rat model	In vivo	20, 40 and 60 mg/kg, i.g.	Myocardial I/R injury	↓ LDH, CK, MPO, T-SOD and MDA ↓ IL-1β, IL-8 and TNF-α ↓ p-IκBα, NF-κBP65 and p-NF-κBP65 levels ↑ VDUP1 level	Regulate VDUP1/NF-κB pathway	67
	IR-induced myocardial injury rat model	In vivo	1 mg/kg, femoral vein	Myocardial I/R injury	↓ F-actin and myocardial fiber rupture ↓ Myocardial infarction size ↑ Velocities of RBC in venules ↑ MBF and heart function	↓ Sirt-1/NDUFA10/Complex I ↓ RhoA/ROCK-1 activation ↓ ATP/ATP 5D/Complex V expression	70
	H9c2 cells H/R model	In vitro	20 μM	Myocardial I/R injury	↓ GRP78, P-PERK, ATF6 and IRE ↓ CHOP, caspase-12 and P-JNK ↓ Free radical ↑ Antioxidase activity	Regulate oxidative stress- and endoplasmic reticulum stress-related signaling pathways	66
	IR-induced myocardial injury rabbit model	In vivo	25 mg/kg, i.v.	Acute myocardial infarction	↓ SOD ↑ MDA ↓ Caspase-3, -8 and -9	↑ TGF-β1/TAK1 signaling pathway	38
	H9c2 cells H/R model	In vitro	20 μM	Myocardial I/R injury	↑ Cell viability ↓ Cell apoptosis ↓ LDH and MDA	↑ miR-132 expression ↓ HBEGF expression	71
	IR-induced myocardial injury rat model H9c2 cells H/R model	In vivo In vitro	5 mg/kg, femoral vein 0.1 mM	Myocardial I/R injury	↓ Myocardial infarction, histological injury, and cardiac function ↑ H9c2 cell viability Maintain actin skeleton and mitochondria morphology ↓ Apoptosis and energy abnormity	↓ ROCK expression ↑ Mitochondrial ATP synthase δ-subunits	65
Renal	IR-induced renal injury rat model	In vivo	4.2 mg/kg, i.p.	Transient cerebral ischemia	↓ MDA, PCO and 8-OHdG ↑ SOD, catalase and GSH ↓ TNF-α, TGF-β1, INF-γ and IL-6 ↑ IL-10	↓ Inflammatory cytokines production by suppressing oxidative stress	37
Intestinal	IR-induced intestinal injury rat model	In vivo	10 mg/kg, i.p.	Intestinal I/R injury	↓ Neurological score, infarct volume and cerebral water content ↓ IL-6, IL-1β and TNF-α ↓ ROS, MDA and PARP-1 ↑ SOD, catalase and GSH	↓ Apoptosis signal, NF-κB signaling and microglia	68

RF: reference; I/R: ischemia/reperfusion; MCAO/R: middle cerebral artery occlusion/reperfusion; OGD/R: oxygen-glucose deprivation/reoxygenation; ATP: adenosine triphosphate; BDNF: brain derived neurotrophic factor; CREB: cAMP-responsive element-binding protein; BCCAO: bilateral common carotid artery occlusion; NGF: nerve growth factor; NT-4: neurotrophin-3; SYN: synaptophysin; PSD95: post-synaptic density protein 95; Bax: Bcl-2-associated X protein; BBB: blood brain barrier; MMPs: matrix metalloproteinases; MDA: malondialdehyde; 8-OHdG: 8-hydroxyguanine; ERα: estrogen receptors alpha; ERβ: estrogen receptors beta; GSK3β: glycogen synthase kinase 3β; HO-1: oxygenase-1; NADPH: nicotinamide adenosine dinucleotide phosphate; ER: endoplasmic reticulum; NAMPT: nicotinamide phosphoribosyltransferase; NAD: nicotinamide adenine dinucleotide; SIRT1: Sirtuin 1; HBMEC: human brain microvascular endothelial cells; VEGFR-2: vascular endothelial growth factor receptor-2; HIE: hypoxic-ischemic encephalopathy; GRP78: proteins glucose regulatory protein 78; CHOP: C/EBP homologous protein; PERK: protein kinase R-like endoplasmic reticulum kinase; ERO-1α: ER oxidoreductin-1α; IRE1a: inositol-requiring enzyme-1a; LDH: lactate dehydrogenase; CK: creatine kinase; MPO: myeloperoxidase; MDA: malondialdehyde; IL-1β: Interleukin-1 beta; IL-8: Interleukin-8; TNF-α: tumor necrosis factor-α; p-IκBα: phosphorylation inhibitor of nuclear factor kappa B alpha; NF-κBP65: nuclear factors-κB p65; VDUP1: vitamin D(3) up-regulating protein 1; ROCK-1: Rho associated coiled-coil forming protein kinase 1; PCO: protein carbonyl; SOD: superoxide dismutase; GSH: glutathione; TGF-β1: transforming growth factor-β1; INF-γ: interferon-γ; IL-6: interleukin-6; IL-10: interleukin-10; ROS: reactive oxygen species; PARP-1: poly (ADP-ribose) polymerase 1.

↓: downregulation or inhibition; ↑: upregulation or activation.