scholarly journals The Cell Protective Effect of Adenine on Hypoxia–Reoxygenation Injury through PPAR Delta Activation

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1408
Author(s):  
Jyh-Gang Leu ◽  
Chien-Mei Wang ◽  
Chao-Yi Chen ◽  
Yi-Feng Yang ◽  
Chin-Yu Shih ◽  
...  
Keyword(s):  
Protective Effect ◽  
Adenosine Monophosphate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Delta ◽  
Activating Transcription Factor 4 ◽  
Reoxygenation Injury ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Hypoxia Reoxygenation

Ischemia followed by blood supply reperfusion in cardiomyocytes leads to an overproduction of free radicals and a rapid decrease of adenosine triphosphate concentration. The cardioprotective effect of a potential drug, adenine, was evaluated using H9c2 rat cardiomyoblasts. After hypoxia–reoxygenation (HR) treatment consisting of hypoxia for 21 h followed by reoxygenation for 6 h, it was revealed that pretreatment with 200 µM adenine for 2 h effectively prevented HR-induced cell death. Adenine also significantly decreased the production of reactive oxygen species and reduced cell apoptosis after HR injury. The antioxidant effect of adenine was also revealed in this study. Adenine pretreatment significantly reduced the expression of activating transcription factor 4 (ATF4) and glucose-regulated protein 78 (GRP78) proteins, and protein disulfide isomerase induced a protective effect on mitochondria after HR stimulation. Intracellular adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor delta (PPARδ), and perilipin levels were increased by adenine after HR stimulation. Adenine had a protective effect in HR-damaged H9c2 cells. It may be used in multiple preventive medicines in the future.

scholarly journals Two New Compounds From the Heartwood of Dalbergia melanoxylon and Their Protective Effect on Hypoxia/Reoxygenation Injury in H9c2

2021 ◽  
Vol 16 (1) ◽  
pp. 1934578X2098777
Author(s):  
Yang Liu ◽  
Ni Zhang ◽  
Jun-wei He ◽  
Lan-ying Chen ◽  
Li Yang ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Lactate Dehydrogenase ◽  
Protective Effect ◽  
Superoxide Dismutase Activity ◽  
Spectral Evidence ◽  
Reoxygenation Injury ◽  
Dalbergia Melanoxylon ◽  
New Compounds ◽  
Hypoxia Reoxygenation

A new neoflavonoid, named as (7 R)-(-)-3′,5-dihydroxy-4′,2,4-trimethoxy-dalbergiquinol (1) and a new phenanthrenedione, named as 3′,7-dihydroxy-3,6- dimethoxy-9-phenyl-1,4-phenanthrenedione (2), together with 4 known compounds, 5- O-methyldalbergiphenol (3), 3′,7-dihydroxy-4′,3,6-trimethoxy-9-phenyl-1,4-phenanthrenedione (4), (+)-obtusafuran (5), and melanoxin (6) were isolated from the heartwood of Dalbergia melanoxylon. Their structures were elucidated on the basis of chemical and spectral evidence, as well as by comparison with literature data. Moreover, compound 1 showed a protective effect on hypoxia/reoxygenation injury in H9c2 at 10.0 μM by decreasing lactate dehydrogenase and malondialdehyde activity and enhancing superoxide dismutase activity.

scholarly journals Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

2004 ◽  
Vol 24 (17) ◽  
pp. 7469-7482 ◽  
Author(s):  
Jaime D. Blais ◽  
Vasilisa Filipenko ◽  
Meixia Bi ◽  
Heather P. Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Microarray Analysis ◽  
Initiation Factor ◽  
Hypoxic Stress ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Transcription Factor 4

ABSTRACT Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.

scholarly journals Role of Activating Transcription Factor 4 in Murine Choroidal Neovascularization Model

2021 ◽  
Vol 22 (16) ◽  
pp. 8890
Author(s):  
Hiroto Yasuda ◽  
Miruto Tanaka ◽  
Anri Nishinaka ◽  
Shinsuke Nakamura ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Er Stress ◽  
Choroidal Neovascularization ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Activating Transcription Factor 4 ◽  
Age Related ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

Neovascular age-related macular degeneration (nAMD) featuring choroidal neovascularization (CNV) is the principal cause of irreversible blindness in elderly people in the world. Integrated stress response (ISR) is one of the intracellular signals to be adapted to various stress conditions including endoplasmic reticulum (ER) stress. ISR signaling results in the upregulation of activating transcription factor 4 (ATF4), which is a mediator of ISR. Although recent studies have suggested ISR contributes to the progression of some age-related disorders, the effects of ATF4 on the development of CNV remain unclear. Here, we performed a murine model of laser-induced CNV and found that ATF4 was highly expressed in endothelial cells of the blood vessels of the CNV lesion site. Exposure to integrated stress inhibitor (ISRIB) reduced CNV formation, vascular leakage, and the upregulation of vascular endothelial growth factor (VEGF) in retinal pigment epithelium (RPE)-choroid-sclera complex. In human retinal microvascular endothelial cells (HRMECs), ISRIB reduced the level of ATF4 and VEGF induced by an ER stress inducer, thapsigargin, and recombinant human VEGF. Moreover, ISRIB decreased the VEGF-induced cell proliferation and migration of HRMECs. Collectively, our findings showed that pro-angiogenic effects of ATF4 in endothelial cells may be a potentially therapeutic target for patients with nAMD.

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