scholarly journals ALDH2 protects naturally aged mouse retina via inhibiting oxidative stress-related apoptosis and enhancing unfolded protein response in endoplasmic reticulum

Aging ◽  
2020 ◽  
Author(s):  
Pan Long ◽  
Mengshan He ◽  
Weiming Yan ◽  
Wei Chen ◽  
Dongyu Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Mouse Retina ◽  
Aged Mouse ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress-Induced Endothelial Dysfunction

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Giuseppina Amodio ◽  
Ornella Moltedo ◽  
Raffaella Faraonio ◽  
Paolo Remondelli
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Antioxidant Response ◽  
Unfolded Protein ◽  
Initial Event ◽  
Protein Response

In endothelial cells, the tight control of the redox environment is essential for the maintenance of vascular homeostasis. The imbalance between ROS production and antioxidant response can induce endothelial dysfunction, the initial event of many cardiovascular diseases. Recent studies have revealed that the endoplasmic reticulum could be a new player in the promotion of the pro- or antioxidative pathways and that in such a modulation, the unfolded protein response (UPR) pathways play an essential role. The UPR consists of a set of conserved signalling pathways evolved to restore the proteostasis during protein misfolding within the endoplasmic reticulum. Although the first outcome of the UPR pathways is the promotion of an adaptive response, the persistent activation of UPR leads to increased oxidative stress and cell death. This molecular switch has been correlated to the onset or to the exacerbation of the endothelial dysfunction in cardiovascular diseases. In this review, we highlight the multiple chances of the UPR to induce or ameliorate oxidative disturbances and propose the UPR pathways as a new therapeutic target for the clinical management of endothelial dysfunction.

scholarly journals Calreticulin Ins5 and Del52 Mutations Impair Unfolded Protein and Oxidative Stress Responses in Hematopoietic Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4332-4332 ◽  
Author(s):  
Simona Salati ◽  
Elena Genovese ◽  
Zelia Prudente ◽  
Chiara Carretta ◽  
Niccolò Bartalucci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Oxidative Dna Damage ◽  
K562 Cells ◽  
Unfolded Protein ◽  
Calr Mutations ◽  
Protein Response

Abstract Somatic mutations of calreticulin (CALR) have been described in approximately 30-40% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven't been fully unraveled. In order to assess whether and how CALR mutations could affect the physiological CALR protein functions in the ER and thus contributing through other mechanisms to the development of MPNs, we decided to study the role of mutated CALR in K562 cells, devoid of MPL expression. To this end, K562 cells stably expressing either wt CALR or the two most common CALR mutated variants CALRdel52 and CALRins5 were generated via retroviral mediated gene transfer. To identify common signalling pathways modulated by CALR mutants, GEP analysis was performed. Ingenuity Pathway analysis performed on Differentially Expressed Gene (DEGs) revealed that the categories "Unfolded protein response", "Endoplasmic Reticulum Stress Pathway", and "NRF2-mediated Oxidative Stress Response" were significantly represented in the list of decreased genes in the comparison mutated vs wt K562. Based on these findings, the ability to respond to ER and oxidative stresses were assessed in K562 carrying either wt or mutated CALR. Our data demonstrated that CALR mutants negatively impact on the Unfolded Protein Response (UPR): in particular, CALR mutations appear to reduce the activation of the pro-apoptotic pathway downstream the UPR, therefore allowing the accumulation of misfolded proteins in the ER and conferring resistance to ER stress-induced apoptosis. Moreover, our results showed that CALR mutations also affect the capability to respond to oxidative stress: K562 cells carrying CALR mutants showed decreased SOD activity coupled to increased ROS intracellular levels, suggesting that CALR mutants impair cell ability to counteract ROS accumulation. Furthermore, cells carrying CALR mutants showed increased levels of DNA damage upon oxidative stress exposure and decreased ability to repair the oxidative DNA damage. We also demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. Altogether our data suggest a novel MPL-independent role for CALR mutations in the development of MPNs. On one side, by affecting the ability to respond to the ER stress, CALR mutants confer resistance to ER stress mediated apoptosis. On the other side, by affecting cell sensitivity to oxidative stress and reducing the capability to respond to oxidative DNA damage, CALR mutants might lead to genomic instability and tendency to accumulate further mutations. Disclosures No relevant conflicts of interest to declare.

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