scholarly journals Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy

2017 ◽  
Vol 42 (2) ◽  
pp. 824-837 ◽  
Author(s):  
Zhiwei Dong ◽  
Jian Zhou ◽  
Ying Zhang ◽  
Yajie Chen ◽  
Zichen Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Inflammatory Responses ◽  
Fluorescence Emission ◽  
Inhalation Injury ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Astragaloside Iv ◽  
Imaging Results ◽  
Tnf Α

Background: Thermal injury is the main cause of pulmonary disease in stroke after burn and can be life threatening. Heat-induced inflammation is an important factor that triggers a series of induces pathological changes. However, this mechanism underlying heat-induced inflammation in thermal inhalation injury remains unclear. Studies have revealed that astragaloside-IV (AS-IV), a natural compound extracted from Astragalus membranaceus, has protective effects in inflammatory diseases. Here, we investigated whether the protective effects of AS-IV occur because of the suppression of heat-induced endoplasmic reticulum (ER) stress and excessive autophagy Methods: AS-IV was administered to Wistar rats after thermal inhalation injury and 16HBE140-cells were treated with AS-IV. TNF-α, IL-6, and IL-8 levels were determined by ELISA and real-time PCR. ER stress and autophagy were determined by western blot. Autophagic flux was measured by recording the fluorescence emission of the fusion protein mRFP-GFP-LC3 by dynamic live-cell imaging. Results: AS-IV had protective effects against heat-induced reactive oxygen species production and attenuated ER stress. AS IV alleviated heat-induced excessive autophagy in vitro and in vivo. Excessive autophagy was attenuated by the PERK inhibitor GSK2656157 and eIF2α siRNA, suggesting that heat stress-induced autophagy can activate the PERK-eIF2α pathway. Beclin 1 and Atg5 siRNAs inhibited the upregulation of the inflammatory cytokines TNF-α, IL-6, and IL-8 after heat exposure. Conclusions: Thus, AS-IV may attenuate inflammatory responses by disrupting the crosstalk between autophagy and the PERK-eIF2α pathway and may be an ideal agent for treating inflammatory pulmonary diseases.

scholarly journals Oxytocin Suppresses Inflammatory Responses Induced by Lipopolysaccharide through Inhibition of the eIF-2α–ATF4 Pathway in Mouse Microglia

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 527 ◽  
Author(s):  
Takayuki Inoue ◽  
Hajime Yamakage ◽  
Masashi Tanaka ◽  
Toru Kusakabe ◽  
Akira Shimatsu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
The Novel ◽  
Activated Microglia ◽  
Effective Strategies ◽  
Tnf Α ◽  
Brain Homeostasis

Microglia maintain brain homeostasis and modulate neuroinflammation and are implicated in the pathogenesis of various neurological diseases such as Alzheimer’s disease. In this study, we found that in lipopolysaccharide (LPS)-stimulated microglia, the endoplasmic reticulum (ER) stress-related eIF-2α–ATF4 pathway plays significant roles in TNF-α and IL-6 production, as well as in the inflammasome-mediated production of IL-1β. Furthermore, our analysis revealed that oxytocin (OT), a nonapeptide synthesized in the hypothalamus, suppressed the production of these proinflammatory cytokines by inhibiting activation of the eIF-2α–ATF4 pathway. Our findings therefore suggest a novel anti-inflammatory axis of OT in activated microglia, which would be helpful for developing the novel effective strategies for regulating microglia-associated neuroinflammation.

scholarly journals Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4210
Author(s):  
Yan Zhou ◽  
Chunxiu Zhou ◽  
Xutao Zhang ◽  
Chi Teng Vong ◽  
Yitao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Mice ◽  
And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

scholarly journals Contrasting effects of stored allogeneic red blood cells and their supernatants on permeability and inflammatory responses in human pulmonary endothelial cells

2020 ◽  
Vol 318 (3) ◽  
pp. L533-L548
Author(s):  
Junghyun Kim ◽  
Trang T. T. Nguyen ◽  
Yue Li ◽  
Chen-Ou Zhang ◽  
Boyoung Cha ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Map Kinases ◽  
Inflammatory Responses ◽  
Intercellular Junctions ◽  
Protective Effects ◽  
Pyrin Domain ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Rbc Transfusion

Transfusion of red blood cells (RBCs) is a common life-saving clinical practice in severely anemic or hemorrhagic patients; however, it may result in serious pathological complications such as transfusion-related acute lung injury. The factors mediating the deleterious effects of RBC transfusion remain unclear. In this study, we tested the effects of washed long-term (RBC-O; >28 days) versus short-term (RBC-F; <14 days) stored RBCs and their supernatants on lung endothelial (EC) permeability under control and inflammatory conditions. RBCs enhanced basal EC barrier function as evidenced by an increase in transendothelial electrical resistance and decrease in permeability for macromolecules. RBCs also attenuated EC hyperpermeability and suppressed secretion of EC adhesion molecule ICAM-1 and proinflammatory cytokine IL-8 in response to LPS or TNF-α. In both settings, RBC-F had slightly higher barrier protective effects as compared with RBC-O. In contrast, supernatants from both RBC-F and RBC-O disrupted the EC barrier. The early phase of EC permeability response caused by RBC supernatants was partially suppressed by antioxidant N-acetyl cysteine and inhibitor of Src kinase family PP2, while addition of heme blocker and inhibition of NOD-like receptor family pyrin domain containing protein 3 (NLRP3), stress MAP kinases, receptor for advanced glycation end-products (RAGE), or Toll-like receptor-4 (TLR4) signaling were without effect. Morphological analysis revealed that RBC supernatants increased LPS- and TNF-α-induced breakdown of intercellular junctions and formation of paracellular gaps. RBC supernatants augmented LPS- and TNF-α-induced EC inflammation reflected by increased production of IL-6, IL-8, and soluble ICAM-1. These findings demonstrate the deleterious effects of RBC supernatants on EC function, which may have a major impact in pathological consequences associated with RBC transfusion.

scholarly journals Development of a pH-responsive polymersome inducing endoplasmic reticulum stress and autophagy blockade

2020 ◽  
Vol 6 (31) ◽  
pp. eabb8725 ◽  
Author(s):  
Funeng Xu ◽  
Xilin Li ◽  
Xuehui Huang ◽  
Jingmei Pan ◽  
Yi Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Tumor Metastasis ◽  
Focal Adhesions ◽  
Matrix Metalloproteinase 2 ◽  
Autophagic Flux ◽  
Ph Responsive ◽  
Ph Response ◽  
Function Mechanism ◽  
Inhibit Tumor Metastasis

Autophagy is involved in the occurrence and development of tumors. Here, a pH-responsive polymersome codelivering hydroxychloroquine (HCQ) and tunicamycin (Tuni) drugs is developed to simultaneously induce endoplasmic reticulum (ER) stress and autophagic flux blockade for achieving an antitumor effect and inhibiting tumor metastasis. The pH response of poly(β-amino ester) and HCQ synergistically deacidifies the lysosomes, thereby blocking the fusion of autophagosomes and lysosomes and lastly blocking autophagic flux. The function mechanism of regulating autophagy was systematically investigated on orthotopic luciferase gene–transfected, 4T1 tumor–bearing BALB/c mice through Western blot and immunohistochemistry analyses. The Tuni triggers ER stress to regulate the PERK/Akt signaling pathway to increase the autophagic level. The “autophagic stress” generated by triggering ER stress–induced autophagy and blocking autophagic flux is effective against tumors. The reduced expression of matrix metalloproteinase-2 due to ER stress and reduced focal adhesions turnover due to the blockade of autophagic flux synergistically inhibit tumor metastasis.

scholarly journals Endoplasmic Reticulum Stress Is Involved in Baicalin Protection on Chondrocytes From Patients With Osteoarthritis

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581881063 ◽  
Author(s):  
Jiangang Cao ◽  
Yu Zhang ◽  
Tianyi Wang ◽  
Bo Li
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cell Viability ◽  
Er Stress ◽  
Messenger Rna ◽  
Cell Counting ◽  
Protective Effects ◽  
Gene Expressions ◽  
Protein Levels

Osteoarthritis (OA) affects elderly population worldwide and endoplasmic reticulum (ER) stress is known to be positively correlated with OA development. Previous reports prove the cytoprotective effects of baicalin on chondrocytes, whereas the mechanisms are hardly reported. Hence, we aimed to investigate the links between OA, ER stress, and baicalin. Chondrocytes from patients with OA were subjected to H2O2 treatment with or without baicalin pretreatment, and cell viability was assessed via Cell Counting Kit-8. Messenger RNA (mRNA) amounts of apoptosis-related genes (Bax, Bcl-2, and Caspase-3), extracellular matrix (ECM)-related genes (Collange I, Collange II, Aggrecan, and Sox9) and ER stress hallmarks (binding immunoglobulin protein [BiP] C/EBP homologous protein [CHOP]) were evaluated via quantitative real-time PCR. Bax, Bcl-2, BiP, and CHOP protein levels were analyzed via Western blot. Baicalin suppressed the changes in cell viability and apoptosis-related gene expressions caused by H2O2. Reactive oxygen species and glutathione/oxidized glutathione assay showed that H2O2 enhanced oxidative stress. Baicalin suppressed H2O2-induced downregulation of mRNA expression of ECM-related genes. Moreover, baicalin reduced H2O2-stimulated increase in oxidative stress and the expression of ER stress hallmarks. Endoplasmic reticulum stress inducer abolished the protective activities, whereas ER stress inhibitor did not exhibit extra protective effects. Baicalin pretreatment protected patient-derived chondrocytes from H2O2 through ER stress inhibition.

Enteroids Derived From Inflammatory Bowel Disease Patients Display Dysregulated Endoplasmic Reticulum Stress Pathways, Leading to Differential Inflammatory Responses and Dendritic Cell Maturation

2019 ◽  
Vol 14 (7) ◽  
pp. 948-961 ◽  
Author(s):  
William D Rees ◽  
Martin Stahl ◽  
Kevan Jacobson ◽  
Brian Bressler ◽  
Laura M Sly ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Bowel Disease ◽  
Inflammatory Responses ◽  
Human Colon ◽  
Intestinal Epithelial ◽  
Stress Changes ◽  
Inflammatory Bowel ◽  
Stress Pathway

Abstract Background and Aims Endoplasmic reticulum [ER] stress in intestinal epithelial cells [IECs] contributes to the pathogenesis of inflammatory bowel disease [IBD]. We hypothesized that ER stress changes innate signalling in human IECs, augmenting toll-like receptor [TLR] responses and inducing pro-inflammatory changes in underlying dendritic cells [DCs]. Methods Caco-2 cells and primary human colon-derived enteroid monolayers were exposed to ATP [control stressor] or thapsigargin [Tg] [ER stress inducer], and were stimulated with the TLR5 agonist flagellin. Cytokine release was measured by an enzyme immunoassay. ER stress markers CHOP, GRP78 and XBP1s/u were measured via quantitative PCR and Western blot. Monocyte-derived DCs [moDCs] were cultured with the IEC supernatants and their activation state was measured. Responses from enteroids derived from IBD patients and healthy control participants were compared. Results ER stress enhanced flagellin-induced IL-8 release from Caco-2 cells and enteroids. Moreover, conditioned media activated DCs to become pro-inflammatory, with increased expression of CD80, CD86, MHCII, IL-6, IL-15 and IL-12p70 and decreased expression of CD103 and IL-10. Flagellin-induced IL-8 production correlated with DC activation, suggesting a common stress pathway. Moreover, there were distinct differences in cytokine expression and basal ER stress between IBD and healthy subject-derived enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. Conclusions Cellular stress enhances TLR5 responses in IECs, leading to increased DC activation, indicating a previously unknown mechanistic link between epithelial ER stress and immune activation in IBD. Furthermore, dysregulated ER stress may be propagated from the intestinal epithelial stem cell niche in IBD patients.

Fish oil supplementation inhibits endoplasmic reticulum stress and improves insulin resistance: involvement of AMP-activated protein kinase

2017 ◽  
Vol 8 (4) ◽  
pp. 1481-1493 ◽  
Author(s):  
Wenqi Yang ◽  
Xu Chen ◽  
Ming Chen ◽  
Yanping Li ◽  
Qing Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Endoplasmic Reticulum Stress ◽  
Fish Oil ◽  
Er Stress ◽  
Protective Effects ◽  
Ampk Activation ◽  
Amp Activated Protein Kinase ◽  
Fish Oil Supplementation

ER stress inhibition through AMPK activation may explain the protective effects of fish oil against HFD-induced insulin resistance.

scholarly journals Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression

2006 ◽  
Vol 26 (8) ◽  
pp. 3071-3084 ◽  
Author(s):  
Ping Hu ◽  
Zhang Han ◽  
Anthony D. Couvillon ◽  
Randal J. Kaufman ◽  
John H. Exton
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Tumor Necrosis ◽  
Death Receptor ◽  
Down Regulation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT NF-κB is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-κB and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1α through the adapter protein TRAF2. ER stress-induced NF-κB activation is impaired in IRE1α knockdown cells and IRE1α−/− MEFs. We found, however, that inhibiting NF-κB significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-α) was IRE1α and NF-κB dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-α-induced activation of NF-κB and c-Jun N-terminal kinase and turns TNF-α from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-α induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.

scholarly journals MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycaemia-Induced Endoplasmic Reticulum Stress

2020 ◽  
Author(s):  
Ada Admin ◽  
Xiaochuan Wang ◽  
Weina Li ◽  
Qingjun Zhou ◽  
Jing Li ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nerve Regeneration ◽  
Neurotrophic Factor ◽  
Therapeutic Modality ◽  
Subconjunctival Injection ◽  
Protective Effects ◽  
Corneal Epithelial ◽  
Epithelial Wound Healing

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues and exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. <a>Here, we demonstrated</a> that MANF is abundantly expressed in normal corneal epithelial cells, however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in STZ-induced type 1 diabetic C57BL/6 mice. Recombinant MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycaemia-induced endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific siRNA. Finally, we revealed that the subconjunctival injection of MANF-specific siRNA prevented corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycaemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK.

scholarly journals Diesel exhaust particulates induce neutrophilic lung inflammation by modulating endoplasmic reticulum stress-mediated CXCL1/KC expression in alveolar macrophages

2020 ◽  
Author(s):  
Dong Im Kim ◽  
Mi-Kyung Song ◽  
Kyuhong Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Alveolar Macrophages ◽  
Diesel Exhaust ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Cell Damage ◽  
Interferon Γ ◽  
Mouse Lung ◽  
Lung Weight

Abstract Background Exposure to particular matter (PM)2.5, including diesel exhaust particulates (DEP), has adverse effects on the respiratory system. Endoplasmic reticulum (ER) abnormalities contribute to respiratory disease pathogenesis such as lung inflammation. However, there is little published research on the relationship between DEP exposure and ER stress in the respiratory immune system and especially the alveolar macrophages (AM). Here, we examined ER stress and inflammatory responses in a DEP-induced murine lung inflammation model and in DEP-stimulated AM.Results DEP treatment increased relative lung weight and the number of total cells, neutrophils, and lymphocytes in mouse BALF. Histological examinations also showed that DEP exposure induced neutrophilic lung inflammation and increased the number of DEP-pigmented AM. Western blot analysis showed that BiP and CHOP were relatively upregulated in DEP-induced mouse lung tissues. DEP caused cell damage, increased intracellular reactive oxygen species (ROS), and upregulated the genes associated with inflammation (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, interferon-γ, and toll-like receptor 4) and with ER stress (bound immunoglobulin protein [BiP], CCAAT/enhancer binding protein-homologous protein [CHOP], sXBP-1, and activating transcription factor 4) in AM. Furthermore, DEP stimulation upregulated the gene encoding the chemokine CXCL1/KC in AM.Conclusions DEP may contribute to neutrophilic lung inflammation pathogenesis by modulating ER stress-mediated CXCL1/KC expression in alveolar macrophages.

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