scholarly journals The Role of Oxymatrine in Amelioration of Acute Lung Injury Subjected to Myocardial I/R by Inhibiting Endoplasmic Reticulum Stress in Diabetic Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yongpan Huang ◽  
Xian Long ◽  
Xinliang Li ◽  
Saihua Li ◽  
Jianbin He
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Troponin ◽  
Diabetic Rats ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Expression Levels ◽  
Creatine Kinase Mb

Background. Oxymatrine (OMT) is the primary pharmacological component of Sophora flavescens Aiton., which has been shown to possess potent antifibrotic, antioxidant, and anti-inflammatory activities. The aim of the present study was to clarify the protective mechanism of OMT on acute lung injury (ALI) subjected to myocardial ischemia/reperfusion (I/R). Methods. A myocardial I/R-induced ALI model was achieved in diabetic rats by occluding the left anterior descending coronary artery for 1 h, followed by reperfusion for 1 h. The levels of inflammatory factors (tumor necrosis factor-α, interleukin- (IL-) 6, and IL-17) in bronchoalveolar lavage fluid were assessed using commercially available kits. The index of myocardial injury, including the detection of cardiac troponin I (cTnI), cardiac troponin T (cTnT), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB), was also determined using commercially available kits. Hematoxylin and eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to identify histological changes. The expression levels of endoplasmic reticulum chaperone BiP (GRP78), DNA damage-inducible transcript 3 protein (CHOP), eukaryotic translation initiation factor 2-alpha kinase 3 (PERK), inositol dependent enzyme 1α (IRE1α), ATF6, caspase-3, -9, and-12, Bcl-2, and Bax were determined by Western blotting. The mRNA expression levels of GRP78 and CHOP were detected by reverse transcription-quantitative PCR. Results. Myocardial I/R increased the levels of cTnI, cTnT, LDH, and CK-MB in diabetic rats. Damaged and irregularly arranged myocardial cells were also observed, as well as more serious ALI with higher lung injury scores and WET/DRY ratios and lower PaO2. Moreover, the expression of key proteins of endoplasmic reticulum stress (ERS) was increased by I/R injury, including phosphorylated- (p-) PERK, p-IRE1ɑ, and ATF6, as well as decreased levels of apoptosis. These effects were all significantly reversed by OMT treatment. Conclusions. OMT protects against ALI subjected to myocardial I/R by inhibiting ERS in diabetic rats.

The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia

2017 ◽  
Vol 23 (8) ◽  
pp. 678-686 ◽  
Author(s):  
Jing Huang ◽  
Rui Tian ◽  
Yongqiang Yang ◽  
Rong Jiang ◽  
Jie Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Translation Initiation Factor ◽  
Negative Regulator ◽  
Sirtuin 1 ◽  
Initiation Factor ◽  
Pharmacological Intervention ◽  
Inhibitory Effects ◽  
Plasminogen Activator Inhibitor 1 ◽  
Sirt1 Inhibitor

It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-α and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.

scholarly journals Protein Synthesis and Endoplasmic Reticulum Stress Can Be Modulated by the Hepatitis C Virus Envelope Protein E2 through the Eukaryotic Initiation Factor 2α Kinase PERK

2003 ◽  
Vol 77 (6) ◽  
pp. 3578-3585 ◽  
Author(s):  
Nicole Pavio ◽  
Patrick R. Romano ◽  
Thomas M. Graczyk ◽  
Stephen M. Feinstone ◽  
Deborah R. Taylor
Keyword(s):  
Endoplasmic Reticulum ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Er Stress ◽  
Envelope Protein ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Virus Envelope ◽  
Expression Levels ◽  
Virus Envelope Protein

ABSTRACT The hepatitis C virus envelope protein, E2, is an endoplasmic reticulum (ER)-bound protein that contains a region of sequence homology with the double-stranded RNA-activated protein kinase PKR and its substrate, the eukaryotic translation initiation factor 2 (eIF2). We previously reported that E2 modulates global translation through inhibition of the interferon-induced antiviral protein PKR through its PKR-eIF2α phosphorylation site homology domain (PePHD). Here we show that the PKR-like ER-resident kinase (PERK) binds to and is also inhibited by E2. At low expression levels, E2 induced ER stress, but at high expression levels, and in vitro, E2 inhibited PERK kinase activity. Mammalian cells that stably express E2 were refractory to the translation-inhibitory effects of ER stress inducers, and E2 relieved general translation inhibition induced by PERK. The PePHD of E2 was required for the rescue of translation that was inhibited by activated PERK, similar to our previous findings with PKR. Here we report the inhibition of a second eIF2α kinase by E2, and these results are consistent with a pseudosubstrate mechanism of inhibition of eIF2α kinases. These findings may also explain how the virus promotes persistent infection by overcoming the cellular ER stress response.

scholarly journals Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

2015 ◽  
Vol 195 (10) ◽  
pp. 4802-4809 ◽  
Author(s):  
Rong Hu ◽  
Zhi-Feng Chen ◽  
Jia Yan ◽  
Qi-Fang Li ◽  
Yan Huang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Endoplasmic Reticulum Stress ◽  
Ischemia Reperfusion

scholarly journals Translational Control during Endoplasmic Reticulum Stress beyond Phosphorylation of the Translation Initiation Factor eIF2α

2014 ◽  
Vol 289 (18) ◽  
pp. 12593-12611 ◽  
Author(s):  
Bo-Jhih Guan ◽  
Dawid Krokowski ◽  
Mithu Majumder ◽  
Christine L. Schmotzer ◽  
Scot R. Kimball ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Translation Initiation ◽  
Translational Control ◽  
Translation Initiation Factor ◽  
Initiation Factor

scholarly journals A Melanin-like Nanoenzyme for Acute Lung Injury Therapy via Suppressing Oxidative and Endoplasmic Reticulum Stress Response

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1850
Author(s):  
Xue-Fang Lou ◽  
Chen Wang ◽  
Ju-Cong Zhang ◽  
Yong-Zhong Du ◽  
Xiao-Ling Xu
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Lung Injury ◽  
Stress Response ◽  
Lung Injury ◽  
Endoplasmic Reticulum Stress ◽  
Therapeutic Effect ◽  
Neutrophil Infiltration ◽  
Endoplasmic Reticulum Stress Response ◽  
Ros Scavenging

Nanoenzyme-mediated catalytic activity is emerging as a novel strategy for reactive oxygen species (ROS) scavenging in acute lung injury (ALI) treatment. However, one of the main hurdles for these metal-containing nanoenzymes is their potential toxicity and single therapeutic mechanism. Herein, we uncovered a melanin-like nanoparticles derived from the self-polymerization of 1,8-dihydroxynaphthalene (PDH nanoparticles), showing a significant anti-inflammation therapeutic effect on ALI mice. The prepared PDH nanoparticles rich in phenol groups could not only act as radical scavengers to alleviate oxidative stress but could also chelate calcium overload to suppress the endoplasmic reticulum stress response. As revealed by the therapeutic effect in vivo, PDH nanoparticles significantly prohibited neutrophil infiltration and the secretion of proinflammatory cytokines (TNF-α and IL-6), thus improving the inflammatory cascade in the ALI model. Above all, our work provides an effective anti-inflammatory nanoplatform by using the inherent capability of melanin-like nanoenzymes, proposing the potential application prospects of these melanin-like nanoparticles for acute inflammation-induced injury treatment.

scholarly journals Berberine Reduces Aβ42 Deposition and Tau Hyperphosphorylation via Ameliorating Endoplasmic Reticulum Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Wu ◽  
Qingjie Chen ◽  
Bing Wen ◽  
Ninghua Wu ◽  
Benhong He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Glycogen Synthase ◽  
Senile Plaques ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Pharmacological Intervention ◽  
Eukaryotic Translation ◽  
Main Component

Alzheimer’s disease (AD) is tightly related to endoplasmic reticulum stress (ER stress), which aggravates two dominant pathological manifestations of AD: senile plaques and neurofibrillary tangles. Berberine is widely applied in the clinical treatment of many diseases and is reported to have anti-AD effects. In the present study, berberine was shown to ameliorate ER stress and cognitive impairment in APP/PS1 mice. We found ER stress plays a role as a central hub for signal transduction, which was evidenced by the hyperactivation of glycogen synthase kinase 3β (GSK3β) to phosphorylate tau and the activation of PRKR-like endoplasmic reticulum kinase (PERK) subsequently to phosphorylate eukaryotic translation initiation factor-2 α (eIF2α). Also, eIF2α has regulated the expression of beta-site APP cleaving enzyme-1 (BACE1), which cleaves APP into pro-oligomerized amyloid beta 42 (Aβ42), the main component of senile plaques, proven by using siRNA targeting at eIF2α. Mechanically, berberine can reduce GSK3β activity, contributing to the downregulation of tau phosphorylation. Berberine also suppressed Aβ42 production via inhibiting the PERK/eIF2α/BACE1 signaling pathway. Taken together, these findings indicated that berberine had the potential to ameliorate two major pathological manifestations of AD mainly by suppressing ER stress. Our work provided knowledge on the pharmacological intervention of AD and the possible targets for future drug development.

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