Up-Regulation Thioredoxin Inhibits Advanced Glycation End Products-Induced Neurodegeneration

Abstract

Background/Aims: Diabetic retinopathy (DR) is one of the most serious complications of diabetes and is the leading cause of adult blindness in developed countries. Advanced glycation end products (AGEs) accumulation in diabetes is associated with its complications. Thioredoxin (Trx) is a small molecule (12kDa) antioxidant protein widely distributed in mammalian tissues, which has important biological functions including anti-apoptosis and transcriptional regulation. In a previous study, we found that Trx plays a key role in retinal neurodegeneration prior to the occurrence of endothelial damage in diabetic mice. In this study, our aim is to determine the effect of Trx on neurodegeneration induced by AGEs in order to identify new therapeutic targets for the clinical treatment and prevention of DR. Methods: In vivo, a high-fat diet and Streptozotocin (STZ) injection were used to generate a mouse model of diabetes. Histology was utilized to examine tissue morphology and measure the outer nuclear layer (ONL) thickness. Electroretinography (ERG) was used to assess retinal function and Western blot was used to examine protein expression. In vitro, three methods of Trx up-regulation were used, including a stable cell line that overexpresses Trx, treatment with Sulforaphane, and shRNA down-regulation Txnip. Cells were treated with AGEs, and level of apoptosis was performed to quantify this by flow cytometry and TUNEL. Quantitative Reverse Transcription PCR (qRT-PCR), Western blotting and immunofluorescence were used to measure gene and protein expression. Transmission electron microscopy (TEM) was used to observe autophagosomes. Results: We found that diabetic mice display decreased retinal function and reduced ONL thickness with AGEs accumulation and a reduction of Trx expression. Up-regulation Trx can prevent the ONL thickness decrease in diabetic mice, as observed by H&E staining. In vitro, up-regulation Trx resulted in decreased intracellular ROS generation, reduced apoptosis by inhibited autophagy. Conclusion: Up-regulating Trx inhibited neurodegeneration induced by AGEs. The underlying mechanism may be related to inhibit Txnip/mTOR pathway-mediated autophagy.

Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

“…This brought, as a consequence, a loss in anti-apoptotic and antioxidant function as well as a reduced cardiac protection function in a mice model of diabetic myocardial ischemia-reperfusion injury. It has also been shown that upregulation of thioredoxin is able to inhibit the expression of RAGE, suggesting crosstalk between RAGE and thioredoxin [93,94].…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…Finally, among the nitrogen-containing group of phytochemicals, examples of potentially beneficial compounds in neurodegeneration/neurotoxicity here taken into account are sulforaphane (belonging to the glucosinolates group and found in cruciferous vegetables such as broccoli, cabbage, brussels sprouts, and cauliflower) [ 64 , 122 , 123 , 124 ] and spermine/spermidine (a polyamine found in soybean seeds) [ 68 , 125 , 126 , 127 ].…”

“…In the last decades, the search for an effective and potentially safe strategy to combat oxidative stress-mediated neuronal damage has increasingly prompted the investigation of naturally occurring compounds as antioxidant agents. The attenuation of oxidative stress by bioactive compounds belonging to different classes of phytochemicals including (i) flavonoids (quercetin, kaempferol and myricetin, scutellarin, baicalin, apigenin, catechins, epigallocatechin, and genistein) [ 52 , 61 , 81 , 82 , 83 , 88 , 94 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]; (ii) phenolic acids (syringic, gallic, caffeic, chlorogenic and salvianolic acids, and curcumin) [ 70 , 103 , 104 , 105 , 138 , 139 , 140 , 141 , 142 , 143 ]; (iii) flavonolignans (silymarin) [ 96 ]; (iv) stilbenes (resveratrol) [ 59 , 65 , 97 , 98 , 144 ]; (v) terpenes (bacosides/bacopasides, withanolides, and the carotenoids lutein and zeaxanthin) [ 7 , 110 , 113 , 115 , 145 , 146 , 147 ]; (vi) alkaloids (berberine and caffeine) [ 148 , 149 ]; (vii) glucosinolates (sulforaphane) and polyamines (spermine/spermidine) [ 123 , 124 ,…”

The neuroprotective mechanisms and effects of sulforaphane

“…AGEs are well-known neurotoxins that form due to high glucose concentrations as seen in diabetes mellitus (DM) and can cause peripheral neuropathy, cognitive dysfunction, and retinal damage. [122863] In cultured peripheral neurons, SFN improves multiple parameters of AGE-induced neuronal damage, including the normalization of conduction velocity and blood flow. [28] In animal models of DM-induced neuropathy, pain behavior is lessened with SFN administration.…”