DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways

Wang, Kun; Fu, Xin; Fu, Xiaoting; Hou, Ya‐Jun; Fang, Jie; Zhang, Shuai; Yang, Mo; Li, Dawei; Mao, Leilei; Sun, Jingyi; Yuan, Hui; Yang, Xiaoyi; Fan, Cundong; Zhang, Zongyong; Sun, Bo

doi:10.1007/s12035-015-9373-1

Cited by 28 publications

(10 citation statements)

References 54 publications

(77 reference statements)

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“…In a recent study, erianin decreased ROS production and p53 expression in HG-treated rat renal tubule cells, implying a role of ROS in p53 activation in this model (60). HG levels also triggered DNA damage through ROS overproduction (61), which may induce p53 activation in diabetes. A thorough investigation will be needed to analyze ROS, the DNA damage response, and p53 expression in DKD.…”

Section: Discussionmentioning

confidence: 82%

p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease

Lin

Livingston

et al. 2020

Journal of Clinical Investigation

128

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Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagyactivating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/ miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.

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Section: Discussionmentioning

confidence: 82%

p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease

Lin

Livingston

et al. 2020

Journal of Clinical Investigation

128

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“…ROS, including hydroxyl radical, hydrogen peroxide, and superoxide anion (Sun et al, 2013 ), all play important roles in mediating cell signaling and maintaining cell homeostasis (Fan et al, 2014 ). The balance of anti-antioxidant and pro-antioxidant system ultimately decides the intracellular ROS level (Li et al, 2015 ; Wang et al, 2016a , b ; Fan et al, 2017a ). Oxidative stress was accepted as a key index in the pathology of human CVD (Castardo-de-Paula et al, 2017 ; Ghosh et al, 2017 ; Paul et al, 2017 ; Ramirez-Lee et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

Fan

Sun

et al. 2017

Front. Physiol.

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Homocysteine (Hcy) as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD). Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX) as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM), TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS). Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

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“…PC12 cells were cultured overnight in a normal glucose medium (25 mM) [ 41 ]. The PC12 cells were treated as follows: Control group (25 mM), CHG group, IHG group (25 mM and high glucose alternating every 12 h), control + ALA group (pretreatment with 100 μΜ ALA for 24 h before incubation with 25 mM glucose), CHG + ALA group (pretreatment with 100 μΜ ALA for 24 h before CHG), and IHG + ALA group (pretreatment with 100 μΜ ALA for 24 h before IHG).…”

Section: Methodsmentioning

confidence: 99%

NGF receptors and PI3K/AKT pathway involved in glucose fluctuation-induced damage to neurons and α-lipoic acid treatment

Yan

Zhang

2020

BMC Neurosci

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Background Glucose fluctuation promotes neuronal apoptosis, which plays a central role in diabetic encephalopathy (DE). Nerve growth factor (NGF), and its interaction with high-affinity (TrkA) and low-affinity (p75NTR) receptors, are involved in neuronal survival. NGF/TrkA contributes to the activation of the PI3K/AKT pathway, which is beneficial for neuronal survival, and α-Lipoic acid (ALA) exerts clinically favorable neuroprotective effects in the periphery. Whether NGF receptors and the PI3K/AKT pathway are involved in glucose fluctuation-induced neuronal damage, as well as the potential molecular mechanism of ALA in protecting glucose fluctuation-induced neuronal damage, remain unclear. Results The results indicated that constant high glucose (CHG) and intermittent high glucose (IHG) significantly increased the expression of Bax and caspase-3, and decreased the expression of TrkA/p75NTR and p-AKT/AKT, while ALA stimulation reversed the above proteins in PC12 cells. IHG stimulates apoptosis more effectively than CHG in PC12 cells, which is related to the PI3K/AKT pathway but not to the TrkA/p75NTR. Furthermore, neuronal apoptosis induced by IHG was aggravated by the TrkA inhibitor K252a or the PI3K/AKT inhibitor LY294002, but this effect was alleviated by the p75NTR inhibitor TAT-pep5. Conclusion Glucose fluctuation induced cell apoptosis by regulating the TrkA/p75NTR and PI3K/AKT pathway, meanwhile ALA exhibited neuroprotective effects in response to IHG and CHG. These observations indicated that the PI3K/AKT pathway and the balance of TrkA/p75NTR are likely to serve as potential therapeutic targets for DE. In addition, ALA could be a possible therapeutic drug for DE.

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DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways

Cited by 28 publications

References 54 publications

p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease

p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

NGF receptors and PI3K/AKT pathway involved in glucose fluctuation-induced damage to neurons and α-lipoic acid treatment

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