scholarly journals A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”

2019 ◽  
Vol 20 (3) ◽  
pp. 713 ◽  
Author(s):  
Jae Seok Jeong ◽  
So Ri Kim ◽  
Seong Ho Cho ◽  
Yong Chul Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Severe Asthma ◽  
Current Knowledge ◽  
Current System ◽  
Clinical Syndrome ◽  
Eosinophilic Inflammation ◽  
Corticosteroid Resistance ◽  
Asthma Patients

Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma

scholarly journals Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

2019 ◽  
Vol 8 (9) ◽  
pp. 1385 ◽  
Author(s):  
Burgos-Morón ◽  
Abad-Jiménez ◽  
Marañón ◽  
Iannantuoni ◽  
Escribano-López ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Current Knowledge ◽  
Β Cells ◽  
The Relationship ◽  
And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

scholarly journals Treatment options in type-2 low asthma

2020 ◽  
pp. 2000528 ◽  
Author(s):  
Timothy SC Hinks ◽  
Stewart J Levine ◽  
Guy G Brusselle
Keyword(s):  
Severe Asthma ◽  
Bacterial Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Occupational Exposures ◽  
Evidence Base ◽  
Type I ◽  
Eosinophilic Asthma ◽  
Ongoing Research

Monoclonal antibodies targeting IgE or the type-2 cytokines IL-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma respectively. However, these therapies are not appropriate for 30–50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, “type-2 low” asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, though poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity, occupational exposures and may be driven by persistent bacterial infections and by activation of a recently-described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits which can be identified and addressed. We particularly focus on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally we review ongoing research into other pathways including TNF, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems and is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.

Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6

2011 ◽  
Vol 300 (4) ◽  
pp. E640-E649 ◽  
Author(s):  
Christopher D. Green ◽  
L. Karl Olson
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Neutral Lipids ◽  
Saturated Fatty Acids ◽  
Mrna Levels ◽  
Β Cells ◽  
Fatty Acid Elongase ◽  
Stearoyl Coa Desaturase

Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of β-cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of β-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS-1 β-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect β-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering β-cells more susceptible to saturated FA-induced ER stress and apoptosis.

scholarly journals Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress

2020 ◽  
Author(s):  
Shubham Khetan ◽  
Susan Kales ◽  
Romy Kursawe ◽  
Alexandria Jillette ◽  
Steven K. Reilly ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Steady State ◽  
Er Stress ◽  
Transcriptional Activity ◽  
Chromatin Accessibility ◽  
Stress Conditions ◽  
Gwas Snps

AbstractA major goal in functional genomics and complex disease genetics is to identify functional cis-regulatory elements (CREs) and single nucleotide polymorphisms (SNPs) altering CRE activity in disease-relevant cell types and environmental conditions. We tested >13,000 sequences containing each allele of 6,628 SNPs associated with altered in vivo chromatin accessibility in human islets and/or type 2 diabetes risk (T2D GWAS SNPs) for transcriptional activity in ß cell under steady state and endoplasmic reticulum (ER) stress conditions using the massively parallel reporter assay (MPRA). Approximately 30% (n=1,983) of putative CREs were active in at least one condition. SNP allelic effects on in vitro MPRA activity strongly correlated with their effects on in vivo islet chromatin accessibility (Pearson r=0.52), i.e., alleles associated with increased chromatin accessibility exhibited higher MPRA activity. Importantly, MPRA identified 220/2500 T2D GWAS SNPs, representing 104 distinct association signals, that significantly altered transcriptional activity in ß cells. This study has thus identified functional ß cell transcription-activating sequences with in vivo relevance, uncovered regulatory features that modulate transcriptional activity in ß cells under steady state and ER stress conditions, and substantially expanded the set of putative functional variants that modulate transcriptional activity in ß cells from thousands of genetically-linked T2D GWAS SNPs.

scholarly journals Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Hariharan Subramanian ◽  
Tanwir Hashem ◽  
Devika Bahal ◽  
Ananth K. Kammala ◽  
Kanedra Thaxton ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Murine Model ◽  
Airway Hyperresponsiveness ◽  
Lung Inflammation ◽  
Janus Kinase ◽  
Asthma Prevalence ◽  
Asthma Patients ◽  
Antibody Titers ◽  
Model Treatment

Asthma prevalence has increased considerably over the decades and it is now considered as one of the most common chronic disorders in the world. While the current anti-asthmatic therapies are effective for most asthma patients, there are 5-10% subjects whose disease is not controlled by such agents and they account for about 50% of the asthma-associated healthcare costs. Such patients develop severe asthma (SA), a condition characterized by a dominant Th1/Th17 cytokine response that is accompanied by Type 2 (T2)-low endotype. As JAK (Janus Kinase) signaling is very important for the activation of several cytokine pathways, we examined whether inhibition of JAKs might lessen the clinical and laboratory manifestations of SA. To that end, we employed a recently described murine model that recapitulates the complex immune response identified in the airways of human SA patients. To induce SA, mice were sensitized with house dust mite extract (HDME) and cyclic (c)-di-GMP and then subsequently challenged with HDME and a lower dose of c-di-GMP. In this model, treatment with the JAK inhibitor, Ruxolitinib, significantly ameliorated all the features of SA, including airway hyperresponsiveness and lung inflammation as well as total IgE antibody titers. Thus, these studies highlight JAKs as critical targets for mitigating the hyper-inflammation that occurs in SA and provide the framework for their incorporation into future clinical trials for patients that have severe or difficult-to manage asthma.

scholarly journals Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Feng Liao ◽  
Yang Zheng ◽  
Junyan Cai ◽  
Jinghui Fan ◽  
Jing Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Receptor Antagonist ◽  
Acetylcholine Receptor ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Protective Effects ◽  
Muscarinic Acetylcholine

Abstract Catestatin (CST) is a catecholamine secretion inhibiting peptide as non-competitive inhibitor of nicotinic acetylcholine receptor. CST play a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. Cardiomyocytes endogenously produced CST and its expression was reduced after I/R. CST pretreatment decreased apoptosis especially endoplasmic reticulum (ER) stress response during I/R. The protection of CST was confirmed in H9c2 cardiomyoblasts under Anoxia/reoxygenation (A/R). In contrast, siRNA-mediated knockdown of CST exaggerated ER stress induced apoptosis. The protective effects of CST were blocked by extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor PD90895 and phosphoinositide 3-kinase (PI3 K) inhibitor wortmannin. CST also increased ERK1/2 and protein kinase B (Akt) phosphorylation and which was blocked by atropine and selective type 2 muscarinic acetylcholine (M2) receptor, but not type 1 muscarinic acetylcholine (M1) receptor antagonist. Receptor binding assay revealed that CST competitively bound to the M2 receptor with a 50% inhibitory concentration of 25.7 nM. Accordingly, CST inhibited cellular cAMP stimulated by isoproterenol or forskolin and which was blocked by selective M2 receptor antagonist. Our findings revealed that CST binds to M2 receptor, then activates ERK1/2 and PI3 K/Akt pathway to inhibit ER stress-induced cell apoptosis resulting in attenuation cardiac I/R injury.

scholarly journals Porcine Circovirus Type 2 Induces ORF3-Independent Mitochondrial Apoptosis via PERK Activation and Elevation of Cytosolic Calcium

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Yikai Zhang ◽  
Renjie Sun ◽  
Shichao Geng ◽  
Ying Shan ◽  
Xiaoliang Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Porcine Circovirus Type ◽  
Porcine Circovirus Type 2 ◽  
Pcv2 Infection ◽  
Initiation Factor ◽  
Porcine Circovirus ◽  
Mitochondrial Apoptosis ◽  
Infected Cells

ABSTRACT Our previous studies demonstrated that porcine circovirus type 2 (PCV2) triggers an unfolded protein response (UPR) in porcine kidney PK-15 cells by activating the protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α) pathway of endoplasmic reticulum (ER) stress, which in turn facilitates viral replication (Y. Zhou et al., Viruses 8:e56, 2016, https://doi.org/10.3390/v8020056; Y. Zhou et al., J Zhejiang Univ Sci B 18:316–323, 2017, https://doi.org/10.1631/jzus.B1600208). PCV2 is found to cause oxidative stress and upregulation of cytoplasmic Ca2+ levels. The virus is reported to employ its open reading frame 3 (ORF3) to induce apoptosis. We wondered whether and how PCV2-induced UPR would lead to apoptosis independent of ORF3. Using an ORF3-deficient PCV2 mutant (ΔORF3), apoptotic responses in infected PK-15 and porcine alveolar macrophage (PAM) cells were still apparent, although lower than in the parental PCV2 strain. We hypothesized that apoptosis induced by ΔORF3 might result from the UPR. We found that ΔORF3-induced apoptosis was significantly reduced when the infected cells were treated with the selective PERK blocker GSK2606414 (GSK) or the general ER stress attenuator 4-phenylbutyrate (4-PBA). Such treatments also ameliorated elevation of cytoplasmic Ca2+ and reactive oxygen species (ROS) levels in PK-15 and PAM cells, two predisposing factors for apoptosis via disruption of the ER-mitochondrion units. Treatment of ΔORF3-infected cells with GSK and 4-PBA also decreased the mitochondrial Ca2+ load and increased the mitochondrial membrane potential (MMP). With transient expression of the structural protein capsid (Cap) in combination with PERK silencing, we found that Cap induced MMP collapse and mitochondrial apoptosis could result from the UPR and elevation of Ca2+ and ROS levels, which were inhibitable by downregulation of PERK. We propose that PCV2-driven ER stress is Cap dependent and could lead to mitochondrial apoptotic responses independent of ORF3 via perturbation of intracellular Ca2+ homeostasis and accumulation of ROS. IMPORTANCE PCV2 encodes protein ORF3, a putative protein with proapoptotic activity. Our early studies showed that PCV2 infection triggers ER stress via selective activation of the PERK pathway, a branch of the ER stress pathways, in permissive cells for enhanced replication and infection increased cytosolic Ca2+ and ROS levels. Here we clearly show that PCV2 infection or Cap expression induces ORF3-independent apoptosis via increased cytosolic and mitochondrial Ca2+ levels and cellular ROS levels as a result of activation of the PERK pathway.

scholarly journals Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes

2015 ◽  
Vol 98 (4) ◽  
pp. 615-622 ◽  
Author(s):  
R. Lenin ◽  
A. Sankaramoorthy ◽  
V. Mohan ◽  
M. Balasubramanyam
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress

scholarly journals Maternal Obesity-Induced Endoplasmic Reticulum Stress Causes Metabolic Alterations and Abnormal Hypothalamic Development in the Offspring

2019 ◽  
Author(s):  
Soyoung Park ◽  
Alice Jang ◽  
Sebastien G. Bouret
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Maternal Obesity ◽  
Leptin Resistance ◽  
Health Concern ◽  
Steady Increase ◽  
Major Health ◽  
Stress Relieving ◽  
Stress Related Genes

AbstractThe steady increase in the prevalence obesity and associated type II diabetes is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of metabolic disease. Offspring of obese dams displayed increased body weight, adiposity, food intake and developed glucose intolerance. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were upregulated in the hypothalamus of neonates born to obese mothers and neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reverses leptin resistance in neonates born to obese dams.

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