The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Aghaei, Mahmoud; Dastghaib, Sanaz; Aftabi, Sajjad; Aghanoori, Mohamad‐Reza; Alizadeh, Javad; Mokarram, Pooneh; Mehrbod, Parvaneh; Ashrafizadeh, Milad; Zarrabi, Ali; McAlinden, Kielan Darcy; Eapen, Mathew Suji; Sohal, Sukhwinder Singh; Sharma, Pawan; Zeki, Amir A.; Ghavami, Saeid

doi:10.3390/life11010001

Cited by 32 publications

(24 citation statements)

References 288 publications

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“…In a diseased state, the cell would be under a heavy burden of oxidative stress and inflammation that damages cell organelles [84] , [85] . Indeed, oxidative stress-induced endoplasmic reticulum (ER) stress is implicated in the unfolded protein response (UPR) pathophysiology in COPD, where protein translation and synthesis are downregulated to alleviate ER stress [86] , [87] . Analyzing lung fibroblasts of COPD patients has revealed deficient and disorganized ER and Golgi apparatus, which cannot heal despite being cultured for several weeks in the absence of cigarette smoke [88] .…”

Section: Hypothesismentioning

confidence: 99%

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Yong

2021

Medical Hypotheses

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Presently, it remains unclear why the prevalence of lung diseases, namely chronic obstructive pulmonary disease (COPD), is much lower than other medical comorbidities and the general population among patients with coronavirus disease 2019 (COVID-19). If COVID-19 is a respiratory disease, why is COPD not the leading risk factor for contracting COVID-19? The same odd phenomenon was also observed with other pathogenic human coronaviruses causing severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS), but not other respiratory viral infections such as influenza and respiratory syncytial viruses. One commonly proposed reason for the low COPD rates among COVID-19 patients is the usage of inhaled corticosteroids or bronchodilators that may protect against COVID-19. However, another possible reason not discussed elsewhere is that lungs in a diseased state may not be conducive for the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) to establish COVID-19. For one, COPD causes mucous plugging in large and small airways, which may hinder SARS-CoV-2 from reaching deeper parts of the lungs (i.e., alveoli). Thus, SARS-CoV-2 may only localize to the upper respiratory tract of persons with COPD, causing mild or asymptomatic infections requiring no hospital attention. Even if SARS-CoV-2 reaches the alveoli, cells therein are probably under a heavy burden of endoplasmic reticulum (ER) stress and extensively damaged where it may not support efficient viral replication. As a result, limited SARS-CoV-2 virions would be produced in diseased lungs, preventing the development of COVID-19.

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Section: Hypothesismentioning

confidence: 99%

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Yong

2021

Medical Hypotheses

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“…Under normal cell conditions, it is a passive monomer that binds to GRP78. In contrast, GRP78 dissociates and PERK becomes oligomerized and activated during stress [ 22 ]. Activated PERK has two specific functions, activating eIF2α-ATF4, which inhibits protein synthesis as well as activating CHOP protein (C/EBP homologous protein), which activates cell death receptor 5 (DR5), and growth arrest- and DNA damage-inducible gene 153 (GADD153) which leads to cell growth arrest.…”

Section: Introductionmentioning

confidence: 99%

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

Siri

Dastghaib

Zamani

et al. 2021

IJMS

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The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.

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“…The three branches are composed of protein kinase R (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), orchestrate the major regulatory circuits to ensure ER homeostasis [5]. A growing number of studies indicate that ER stress involves numerous diseases including but not limited to neurodegenerative disease [6] like Alzheimer's Ivyspring International Publisher disease [7], Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis [8], disease of immune system [2], diabetes [9], cardiovascular disease [10], as well as various cancer. Digestive cancer is one of the common malignant tumors with very poor overall survival worldwide, including esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer and liver cancer.…”

Section: Introductionmentioning

confidence: 99%

The Role of miRNAs during Endoplasmic Reticulum Stress Induced Apoptosis in Digestive Cancer

et al. 2021

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Digestive cancer is one of the leading causes of cancer mortality in the world. Despite a number of studies being conducted, the exact mechanism for treating digestive cancer has not yet been fully understood. To survive, digestive cancer cells are subjected to various internal and external adverse factors, such as hypoxia, nutritional deficiencies or drug toxicity, resulting in accumulation of misfolded and unfolded protein in endoplasmic reticulum (ER) lumen further leading to ER stress and the unfolded protein response (UPR). During the last years, studies on the relationship between ER stress and microRNAs (miRNAs) has burst on the scene. miRNAs are non-coding RNAs with a length of 21~22nucleotides involved in post-transcriptional regulation of gene expression, which could be regarded as oncomiRs (tumor inducers) and tumor suppressors regulating cancer cell proliferation, invasion, and apoptosis by differently affecting the expression of genes related to cancer cell signaling. Therefore, investigating the interaction between ER stress and miRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we mainly discuss miRNAs focusing on its regulation, role in ER stress induced apoptosis in Digestive cancer, expound the underlying mechanism, thus provides a theoretical foundation for finding new therapeutic targets of digestive cancer.

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The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Cited by 32 publications

References 288 publications

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

The Role of miRNAs during Endoplasmic Reticulum Stress Induced Apoptosis in Digestive Cancer

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