scholarly journals Progranulin protects the mouse retina under hypoxic conditions via inhibition of the Toll‑like receptor‑4‑NADPH oxidase 4 signaling pathway

Author(s):  
Zhi‑Peng You ◽  
Meng‑Jia Yu ◽  
Yu‑Lan Zhang ◽  
Ke Shi
Author(s):  
Huaicheng Chen ◽  
Tao Yan ◽  
Zongming Song ◽  
Shilong Ying ◽  
Beibei Wu ◽  
...  

AbstractModified LDL-induced inflammation and oxidative stress are involved in the pathogenesis of diabetic retinopathy. Recent studies have also shown that modified LDL activates Toll-like receptor 4 (TLR4) to mediate retinal injury. However, the mechanism by which modified LDL activates TLR4 and the potential role of the TLR4 coreceptor myeloid differentiation protein 2 (MD2) are not known. In this study, we inhibited MD2 with the chalcone derivatives L2H17 and L6H21 and showed that MD2 blockade protected retinal Müller cells against highly oxidized glycated-LDL (HOG-LDL)-induced oxidative stress, inflammation, and apoptosis. MD2 inhibition reduced oxidative stress by suppressing NADPH oxidase-4 (NOX4). Importantly, HOG-LDL activated TLR4 and increased the interaction between NOX4 and TLR4. MD2 was required for the activation of these pathways, as inhibiting MD2 prevented the association of NOX4 with TLR4 and reduced NOX4-mediated reactive oxygen species production and TLR4-mediated inflammatory factor production. Furthermore, treatment of diabetic mice with L2H17 significantly reduced LDL extravasation in the retina and prevented retinal dysfunction and apoptosis by suppressing the TLR4/MD2 pathway. Our findings provide evidence that MD2 plays a critical role in mediating modified LDL-induced cell injury in the retina and suggest that targeting MD2 may be a potential therapeutic strategy.


2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Anand Singh ◽  
Bhargav Koduru ◽  
Cameron Carlisle ◽  
Hasina Akhter ◽  
Rui-Ming Liu ◽  
...  

2018 ◽  
Vol 16 ◽  
pp. 1721727X1875675
Author(s):  
Jung-Youn Kim ◽  
Sung-Hyuk Choi ◽  
Young-Duck Cho ◽  
Young-Hoon Yoon ◽  
Jong-Hak Park ◽  
...  

Many patients are admitted to the emergency department due to trauma. Trauma patients suffer from hypoxia due to massive hemorrhage, respiratory failure, and hypovolemic shock. Further damage is caused by reduced immune function and over-expression of inflammatory response. We conducted an experiment to determine the effects of hyperoxia and hypoxia on apoptosis and expression of Toll-like receptor 4 (TLR4) in polymorphonuclear neutrophils (PMNs). Initially, the PMNs were placed in normoxic and hypoxic conditions, and these PMNs were divided into two groups as stimulated or not stimulated with lipopolysaccharide (LPS). Levels of apoptosis and TLR4 expression were measured under normoxic, hypoxic, and hyperoxic conditions. Apoptosis decreased in the hypoxic group than in the normoxic group. With LPS stimulation, apoptosis was decreased in all three treatment groups and even more reduced in the hypoxic group. TLR4 expression increased in all three treatment groups with LPS stimulation, increased further in the hypoxic group, and to a lesser degree in the hyperoxic group. Unlike the cells exposed to hypoxic conditions, the cells exposed to the hyperoxic condition reacted similarly to the cells in the control (normoxic) group. Therefore, the inflammatory reactions can be stronger in the hypoxic group than in the other two groups.


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