Translating endoplasmic reticulum biology into the clinic: a role for ER-targeted natural products?

2015 ◽  
Vol 32 (5) ◽  
pp. 705-722 ◽  
Author(s):  
David M. Pereira ◽  
Patrícia Valentão ◽  
Georgina Correia-da-Silva ◽  
Natércia Teixeira ◽  
Paula B. Andrade
Keyword(s):  
Endoplasmic Reticulum ◽  
Natural Products ◽  
Er Stress ◽  
Current Knowledge ◽  
The Way

In this review, we present the current knowledge of ER biology and the hallmarks of ER stress, thus paving the way for presenting the natural products that have been described as being ER modulators, either stress inducers or ER protectors.

scholarly journals Protein Quality Control in the Endoplasmic Reticulum and Cancer

2018 ◽  
Vol 19 (10) ◽  
pp. 3020 ◽  
Author(s):  
Hye Won Moon ◽  
Hye Gyeong Han ◽  
Young Joo Jeon
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Current Knowledge ◽  
Tumor Development ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
Physiological Relevance ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress. To resolve ER stress and restore proteostasis, cells have evolutionary conserved protein quality-control machineries of the ER, consisting of the unfolded protein response (UPR) of the ER, ER-associated degradation (ERAD), and autophagy. Furthermore, protein quality-control machineries of the ER play pivotal roles in the control of differentiation, progression of cell cycle, inflammation, immunity, and aging. Therefore, severe and non-resolvable ER stress is closely associated with tumor development, aggressiveness, and response to therapies for cancer. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of protein quality control of the ER and discuss new insights into how protein quality control of the ER is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.

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 The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

2022 ◽  
Vol 12 ◽  
Author(s):  
Padmini Sirish ◽  
Daphne A. Diloretto ◽  
Phung N. Thai ◽  
Nipavan Chiamvimonvat
Keyword(s):  
Atrial Fibrillation ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Current Knowledge ◽  
Pressure Overload ◽  
Current Treatment ◽  
Arachidonic Acid Metabolism ◽  
Extrinsic Factors ◽  
Molecule Inhibitor ◽  
Er Homeostasis

Atrial fibrillation (AF) remains the most common arrhythmia seen clinically. The incidence of AF is increasing due to the aging population. AF is associated with a significant increase in morbidity and mortality, yet current treatment paradigms have proven largely inadequate. Therefore, there is an urgent need to develop new effective therapeutic strategies for AF. The endoplasmic reticulum (ER) in the heart plays critical roles in the regulation of excitation-contraction coupling and cardiac function. Perturbation in the ER homeostasis due to intrinsic and extrinsic factors, such as inflammation, oxidative stress, and ischemia, leads to ER stress that has been linked to multiple conditions including diabetes mellitus, neurodegeneration, cancer, heart disease, and cardiac arrhythmias. Recent studies have documented the critical roles of ER stress in the pathophysiological basis of AF. Using an animal model of chronic pressure overload, we demonstrate a significant increase in ER stress in atrial tissues. Moreover, we demonstrate that treatment with a small molecule inhibitor to inhibit the soluble epoxide hydrolase enzyme in the arachidonic acid metabolism significantly reduces ER stress as well as atrial electrical and structural remodeling. The current review article will attempt to provide a perspective on our recent understandings and current knowledge gaps on the critical roles of proteostasis and ER stress in AF progression.

Identification of the Black Tea Polyphenol Theaflavin-3, 3'-Digallate From Screen of Natural Product Inducers of Endoplasmic Reticulum Stress

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5021-5021
Author(s):  
Nicole A Doudican ◽  
Shih Ya Wen ◽  
Amitabha Mazumder ◽  
Seth J Orlow
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Natural Products ◽  
Er Stress ◽  
Natural Product ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Black Tea ◽  
Parp Cleavage ◽  
Tea Polyphenol

Abstract Abstract 5021 Background: A distinguishing characteristic of myeloma plasma cells is the large quantity of paraprotein that they synthesize and secrete, rendering them especially sensitive to the effects of endoplasmic reticulum (ER) stress. Consistent with this notion, the proteasome inhibitor bortezomib disrupts protein equilibrium in the ER by preventing misfolded proteins from being properly degraded. Given the clinically validated importance of targeting ER stress mediated pathways in the treatment of multiple myeloma (MM), we sought to identify natural products that modulate pathways known to be an effective therapeutic target for MM for potential use to inhibit progression of asymptomatic MM to symptomatic MM without the limiting side effects of current targeted therapies. Methods: Using decreased protein processing in the secretory pathway as a measurable hallmark of ER stress, our screen employed the naturally secreted Gaussia luciferase (Gluc) as a reporter that can be easily monitored through extracellular release of luciferase activity in real time. KMS11 and ARP-1 MM cells expressing Gluc were exposed to compounds in our natural products library in order to identify those which potentially induce ER stress as measured by inhibition of Gluc secretion. The growth inhibitory activity of theaflavin-3, 3'–digallate (TF3) was further characterized by MTS assay. Mechanistic studies of ER stress related pathways including the unfolded protein response (UPR) and apoptotic cascades were analyzed by standard Western blotting techniques. Results: Our screen identified the black tea polyphenol TF3 as a significant inhibitor of GLUC secretion in ARP-1 and KMS-11 cells. TF3 at 0. 5 μM inhibits GLUC secretion by 73 and 68% in ARP-1 and KMS-11 cells, respectively. This inhibition observed is on par with that observed for bortezomib and tunacamycin (a well known inducer of ER stress). TF-3 effectively inhibits cellular proliferation and induces apoptosis in a panel of MM cell lines at physiologically achievable concentrations. Apoptotic induction is at least partially mediated by ER stress mediated pathways as upregulation of the protein chaperone HSP90 and phosphorylation of eIF2-a, a key mediator of the UPR pathway, occurs prior to caspase and PARP cleavage. Conclusions: Our results suggest that TF-3 inhibits protein secretion and MM cell growth through promotion of ER stress generating mechanisms. Based upon these promising results, further mechanistic evaluation and characterization of this safe, natural product as a prophylactic agent in the treatment of asymptomatic conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) is warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Heme, Heme Oxygenase, and Endoplasmic Reticulum Stress—A New Insight into the Pathophysiology of Vascular Diseases

2019 ◽  
Vol 20 (15) ◽  
pp. 3675 ◽  
Author(s):  
Gáll ◽  
Balla ◽  
Balla
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Vascular Diseases ◽  
Heme Oxygenase 1 ◽  
Vascular Disorders ◽  
Ferroxidase Activity

The prevalence of vascular disorders continues to rise worldwide. Parallel with that, new pathophysiological pathways have been discovered, providing possible remedies for prevention and therapy in vascular diseases. Growing evidence suggests that endoplasmic reticulum (ER) stress is involved in a number of vasculopathies, including atherosclerosis, vascular brain events, and diabetes. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as ER stress. The potentially toxic free heme is converted by heme oxygenases (HOs) into carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is reduced to bilirubin (BR). Redox-active iron is oxidized and stored by ferritin, an iron sequestering protein which exhibits ferroxidase activity. In recent years, CO, BV, and BR have been shown to control cellular processes such as inflammation, apoptosis, and antioxidant defense. This review covers our current knowledge about how heme induced endoplasmic reticulum stress (HIERS) participates in the pathogenesis of vascular disorders and highlights recent discoveries in the molecular mechanisms of HO-mediated cytoprotection in heme stress and ER stress, as well as crosstalk between ER stress and HO-1. Furthermore, we focus on the translational potential of HIERS and heme oxygenase-1 (HO-1) in atherosclerosis, diabetes mellitus, and brain hemorrhage.

Recent Advances in Characterizing Natural Products that Regulate Autophagy

2020 ◽  
Vol 19 (18) ◽  
pp. 2177-2196 ◽  
Author(s):  
Qian Zhao ◽  
Cheng Peng ◽  
Chuan Zheng ◽  
Xiang-Hong He ◽  
Wei Huang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Natural Products ◽  
Er Stress ◽  
Therapeutic Target ◽  
Living Cells ◽  
Nutrient Deprivation ◽  
Potential Utility ◽  
Cancer Treatments ◽  
Multistep Process ◽  
Potential Activity

Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.

Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces

2008 ◽  
Vol 295 (2) ◽  
pp. F323-F334 ◽  
Author(s):  
Masanori Kitamura
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Current Knowledge ◽  
Renal Diseases ◽  
Unfolded Proteins ◽  
Diverse Range ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A number of pathophysiological insults lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress. In response to accumulation of unfolded/misfolded proteins, cells adapt themselves to the stress condition via the unfolded protein response (UPR). For the cells, UPR is a double-edged sword. It triggers both prosurvival and proapoptotic signals. ER stress and UPR may, therefore, be involved in a diverse range of pathological situations. However, currently, information is limited regarding roles of ER stress and UPR in the renal pathophysiology. This review describes current knowledge on the relationship between ER stress and diseases and summarizes evidence for the link between ER stress/UPR and renal diseases.

scholarly journals The Multifaceted Roles of Plant Hormone Salicylic Acid in Endoplasmic Reticulum Stress and Unfolded Protein Response

2019 ◽  
Vol 20 (23) ◽  
pp. 5842 ◽  
Author(s):  
Péter Poór ◽  
Zalán Czékus ◽  
Irma Tari ◽  
Attila Ördög
Keyword(s):  
Endoplasmic Reticulum ◽  
Salicylic Acid ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Current Knowledge ◽  
Misfolded Proteins ◽  
Full Detail ◽  
Biotic Stresses ◽  
Unfolded Protein ◽  
Protein Response

Different abiotic and biotic stresses lead to the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress. In response to ER stress, cells activate various cytoprotective responses, enhancing chaperon synthesis, protein folding capacity, and degradation of misfolded proteins. These responses of plants are called the unfolded protein response (UPR). ER stress signaling and UPR can be regulated by salicylic acid (SA), but the mode of its action is not known in full detail. In this review, the current knowledge on the multifaceted role of SA in ER stress and UPR is summarized in model plants and crops to gain a better understanding of SA-regulated processes at the physiological, biochemical, and molecular levels.

scholarly journals ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 199
Author(s):  
Kelly Féral ◽  
Manon Jaud ◽  
Céline Philippe ◽  
Doriana Di Bella ◽  
Stéphane Pyronnet ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Current Knowledge ◽  
Leukemic Cells ◽  
Unfolded Protein ◽  
Cell Death Program ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.

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