The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies
Abstract
:1. Introduction to Diabetic Retinopathy (DR)
2. Introduction to High-Mobility Group Box 1 (HMGB1)
3. HMGB1 and DR
4. Future Therapeutic Approaches
4.1. Glycyrrhizin (GA)
4.2. Small Interfering RNAs/Short Hairpin RNA (siRNA/shRNA)
4.3. Polygonum Cuspidatum (PCE)
4.4. Paeoniflorin
4.5. Salicin
4.6. Ethyl Pyruvate (EP)
4.7. Bradykinin (BK)
4.8. Kallistatin
4.9. Compound 49b
4.10. Cyclosporine A (CyA)
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
8-OHdG | 8-hydroxydeoxyguanosine |
AGE | advanced glycation end-products |
ARPE-19 | adult retinal pigment epithelial cell line-19 |
BDNF | brain-derived neurotrophic factor |
BK | bradykinin |
BRB | blood–retinal barrier |
COX-2 | cyclooxygenase |
CTGF | connective tissue growth factor |
CyA | cyclosporine A |
DM | diabetes mellitus |
DR | diabetic retinopathy |
EC | endothelial cells |
Egr-1 | early growth response protein 1 |
eNOS | endothelial nitric oxide synthase |
EP | ethyl pyruvate |
ERK | extracellular signal-regulated kinase |
GA | glycyrrhizin |
GSH | reduced glutathione |
HIF-1α | hypoxia induced factor-1α |
HMGB | high-mobility group box |
HO-1 | heme oxygenase-1 |
HRECs | human retinal endothelial cells |
HRMEC | human retinal microvascular endothelial cells |
ICAM-1 | intercellular adhesion molecule-1 |
IFN | interferon |
IGFBP-3 | insulin-like growth factor-binding protein-3 |
IL | interleukin |
iNOS | inducible nitric oxide synthase |
MAPK | mitogen-activated protein kinase |
MMP-9 | metalloproteinases-9 |
NF-κB | nuclear factor-κB |
NOX | nicotinamide adenine dinucleotide phosphate oxidase |
NPDR | non proliferative diabetic retinopathy |
OPN | osteopontin |
PAI-1 | plasminogen activator inhibitor-1 |
PARP | poly ADP-ribose polymerase |
PCE | polygonum cuspidatum |
PDR | proliferative diabetic retinopathy |
PEDF | pigment epithelium-derived factor |
PI3K | phosphatidylinositol 3-kinase |
PK | protein kinase |
PLA-2 | phospholipases A2 |
PVR | proliferative vitreoretinopathy |
RAGE | receptors for AGEs |
RGC | retinal ganglion cells |
ROP | retinopathy of prematurity |
ROS | reactive oxygen species |
RPE | retinal pigmented epithelium |
shRNA | short hairpin RNA |
siRNA | small interfering RNAs |
SIRT | sirtuin |
SOCS3 | suppressor of cytokine signaling 3 |
SOD | superoxide dismutase |
STAT-3 | signal transducer and activator of transcription-3 |
pSTAT-3 | phosphorylated STAT-3 |
STZ | streptozotocin |
TGF-β1 | transforming growth factor-β1 |
TLR | toll like receptor |
TNF-α | tumor necrosis factor-α |
TYK2 | tyrosine kinase 2 |
VAP-1 | vascular adhesion protein-1 |
VCAM-1 | vascular cell adhesion molecule-1 |
VEGF | vascular endothelial growth factor |
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Drug | Target Test | Diabetic Inducement | Mechanism of Action | Results | Reference |
---|---|---|---|---|---|
Glycyrrhizin | HRECs | High glucose concentrations | Inhibition of TLR-4 and TNF-α; cleavage of caspase 3 through inactivation of HMGB1 | Increased insulin receptor signal transduction | [99,100] |
Mice | Ischemia/reperfusion damage | Block of the loss of retinal thickness | Protects GCL and retinal capillaries | [99,100] | |
Mice | STZ | Upregulation of SIRT1, inhibition of inflammatory factors. Attenuates BDNF downregulation, reduces ROS, ICAM-1, NF-κB, and HIF-1α | Reduced vascular permeability, increased retinal thickness. Protection from diabetes-induced retinal damages and inflammation | [101] [67,68,85,90] [93] | |
Retinal Muller Cells | High glucose concentrations | Attenuates p-STAT3 expression | Inhibition of VEGF expression | [69] | |
Small interfering RNAs | Mice | STZ | Intravitreal injection of HMGB1 siRNA | Protected morphological changes, and improved the function of the retina | [105] |
Retinal ganglion cells | High glucose concentrations | Transfection with HMGB1 siRNA reduced the expression of TLR-4 and NF-κB | Increased cell survival rate | [77] | |
HRECs | High glucose concentrations | Transfection with HMGB1 siRNA reduced the expression of caspase 3 | Inhibition the early stage of apoptosis | [105] | |
Short hairpin RNAs | Rat retinas | High glucose concentrations | Transfection with HMGB1 shRNA reduced the expression TNF-α and NF-κB | Increased cell survival rate and vascular permeability | [83] |
Polygonum cuspidatum | Mice | STZ | Reduced RAGE and NF-κB expression | Reduced vascular permeability | [109] |
Paeoniflorin | Mice | STZ | Inhibition of MMP-9 and IL-1β | Alleviated microglial activation | [113] |
BV2 modified microglial cells | High glucose concentrations | Inhibition of NF-κB expression and SOCS3 | Reduced MMP-9 and TLR-4 concentrations | [113] | |
Salicin | HRECs | Incubated with IL-1β (inflammatory response) | Suppression of NF-κB pathway and the release of MMP | Inhibition of IL-1β mediated inflammatory pathways | [118] |
Ethyl pyruvate | Mice | Induction of ROP through exposition to hyperoxia | Reduction of ROS, NF-κB, IL-6, VEGF and TNF-α | Reduction of neoangiogenesis and areas of ischemic retina | [120] |
Bradykinin | HRECs | High glucose concentrations | Suppression of NF-κB, caspase 3, VEGF, TNF-α, IL-1β. Increase in SOD activity | Promotion of retinal cells survival/ inhibition of apoptosis. Reduction of vascular permeability | [122] |
Kallistatin | HRECs | High glucose concentrations | Suppression of VEGF expression | Reduction of neoangiogenesis | [126] |
Compound 49b | HRECs and rat retinal Muller cells | High glucose concentrations | Increase of IGFBP-3 levels and inhibition of TLR-4 pathway | Prevention of cellular apoptosis | [127,129] |
Mice | SZT | Increase of IGFBP-3 levels | Prevention of the decrease in retinal thickness and loss of cells in GCL | [127] | |
Cyclosporine A | Mice | STZ | Reduction of TNF-α and IL-1β | Amelioration of retinal thickness, regression of retinal edema | [131] |
Mice | STZ | Reduction of iNOS, IL-1β and COX-2 | Reduction of BRB permeability | [132] |
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Nebbioso, M.; Lambiase, A.; Armentano, M.; Tucciarone, G.; Bonfiglio, V.; Plateroti, R.; Alisi, L. The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies. Antioxidants 2020, 9, 666. https://doi.org/10.3390/antiox9080666
Nebbioso M, Lambiase A, Armentano M, Tucciarone G, Bonfiglio V, Plateroti R, Alisi L. The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies. Antioxidants. 2020; 9(8):666. https://doi.org/10.3390/antiox9080666
Chicago/Turabian StyleNebbioso, Marcella, Alessandro Lambiase, Marta Armentano, Giosuè Tucciarone, Vincenza Bonfiglio, Rocco Plateroti, and Ludovico Alisi. 2020. "The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies" Antioxidants 9, no. 8: 666. https://doi.org/10.3390/antiox9080666