scholarly journals Identification of an integrated stress and growth response signaling switch that directs vertebrate intestinal regeneration

BMC Genomics ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Aundrea K. Westfall ◽  
Blair W. Perry ◽  
Abu H. M. Kamal ◽  
Nicole R. Hales ◽  
Jarren C. Kay ◽  
...  
Keyword(s):  
Stress Responses ◽  
Metabolic Stress ◽  
Tissue Growth ◽  
Direct Regeneration ◽  
Molecular Control ◽  
Critical Pathways ◽  
Intestinal Regeneration ◽  
Organ Regeneration ◽  
Pathway Activation ◽  
The Unfolded Protein Response

Abstract Background Snakes exhibit extreme intestinal regeneration following months-long fasts that involves unparalleled increases in metabolism, function, and tissue growth, but the specific molecular control of this process is unknown. Understanding the mechanisms that coordinate these regenerative phenotypes provides valuable opportunities to understand critical pathways that may control vertebrate regeneration and novel perspectives on vertebrate regenerative capacities. Results Here, we integrate a comprehensive set of phenotypic, transcriptomic, proteomic, and phosphoproteomic data from boa constrictors to identify the mechanisms that orchestrate shifts in metabolism, nutrient uptake, and cellular stress to direct phases of the regenerative response. We identify specific temporal patterns of metabolic, stress response, and growth pathway activation that direct regeneration and provide evidence for multiple key central regulatory molecules kinases that integrate these signals, including major conserved pathways like mTOR signaling and the unfolded protein response. Conclusion Collectively, our results identify a novel switch-like role of stress responses in intestinal regeneration that forms a primary regulatory hub facilitating organ regeneration and could point to potential pathways to understand regenerative capacity in vertebrates.

scholarly journals Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance

2018 ◽  
Vol 2018 ◽  
pp. 1-27 ◽  
Author(s):  
Arnold N. Onyango
Keyword(s):  
Insulin Resistance ◽  
Stress Responses ◽  
Environmental Pollutants ◽  
Stress Generation ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Related Factor ◽  
The Metabolic Syndrome ◽  
Cellular Stresses ◽  
The Unfolded Protein Response

Insulin resistance (IR), a key component of the metabolic syndrome, precedes the development of diabetes, cardiovascular disease, and Alzheimer’s disease. Its etiological pathways are not well defined, although many contributory mechanisms have been established. This article summarizes such mechanisms into the hypothesis that factors like nutrient overload, physical inactivity, hypoxia, psychological stress, and environmental pollutants induce a network of cellular stresses, stress responses, and stress response dysregulations that jointly inhibit insulin signaling in insulin target cells including endothelial cells, hepatocytes, myocytes, hypothalamic neurons, and adipocytes. The insulin resistance-inducing cellular stresses include oxidative, nitrosative, carbonyl/electrophilic, genotoxic, and endoplasmic reticulum stresses; the stress responses include the ubiquitin-proteasome pathway, the DNA damage response, the unfolded protein response, apoptosis, inflammasome activation, and pyroptosis, while the dysregulated responses include the heat shock response, autophagy, and nuclear factor erythroid-2-related factor 2 signaling. Insulin target cells also produce metabolites that exacerbate cellular stress generation both locally and systemically, partly through recruitment and activation of myeloid cells which sustain a state of chronic inflammation. Thus, insulin resistance may be prevented or attenuated by multiple approaches targeting the different cellular stresses and stress responses.

MondoA Drives B-ALL Malignancy through Enhanced Adaptation to Metabolic Stress

Blood ◽  
2021 ◽  
Author(s):  
Alexandra Sipol ◽  
Erik Hameister ◽  
Busheng Xue ◽  
Julia Hofstetter ◽  
Maxim Barenboim ◽  
...  
Keyword(s):  
Stress Responses ◽  
Lymphoblastic Leukemia ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
Underlying Mechanism ◽  
Patient Data ◽  
Data Sets ◽  
Dependent Manner

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give a novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.

Emerging roles of endoplasmic reticulum-resident selenoproteins in the regulation of cellular stress responses and the implications for metabolic disease

2018 ◽  
Vol 475 (6) ◽  
pp. 1037-1057 ◽  
Author(s):  
Alex B. Addinsall ◽  
Craig R. Wright ◽  
Sof Andrikopoulos ◽  
Chris van der Poel ◽  
Nicole Stupka
Keyword(s):  
Metabolic Disease ◽  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Cellular Stress ◽  
Metabolic Stress ◽  
Metabolic Dysfunction ◽  
Iodothyronine Deiodinase ◽  
Inflammatory Stress ◽  
Cellular Stress Responses

Chronic metabolic stress leads to cellular dysfunction, characterized by excessive reactive oxygen species, endoplasmic reticulum (ER) stress and inflammation, which has been implicated in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. The ER is gaining recognition as a key organelle in integrating cellular stress responses. ER homeostasis is tightly regulated by a complex antioxidant system, which includes the seven ER-resident selenoproteins — 15 kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins S, N, K, M and T. Here, the findings from biochemical, cell-based and mouse studies investigating the function of ER-resident selenoproteins are reviewed. Human experimental and genetic studies are drawn upon to highlight the relevance of these selenoproteins to the pathogenesis of metabolic disease. ER-resident selenoproteins have discrete roles in the regulation of oxidative, ER and inflammatory stress responses, as well as intracellular calcium homeostasis. To date, only two of these ER-resident selenoproteins, selenoproteins S and N have been implicated in human disease. Nonetheless, the potential of all seven ER-resident selenoproteins to ameliorate metabolic dysfunction warrants further investigation.

Acute Impact of Recovery on the Restoration of Cellular Immunological Homeostasis

2019 ◽  
Vol 41 (01) ◽  
pp. 12-20 ◽  
Author(s):  
Patrick Wahl ◽  
Sebastian Mathes ◽  
Wilhelm Bloch ◽  
Philipp Zimmer
Keyword(s):  
Cell Count ◽  
Stress Responses ◽  
Metabolic Stress ◽  
Interval Training ◽  
Active Recovery ◽  
Mixed Cell ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Passive Recovery ◽  
Quick Recovery

AbstractIn view of the growing amount of (intense) training in competitive sports, quick recovery plays a superior role in performance restoration. The aim of the present study was to compare the effects of active versus passive recovery during high-intensity interval training (HIIT) and sprint interval training (SIT) protocols on acute alterations of circulating blood cells. Twelve male triathletes/cyclists performed 1) a HIIT consisting of 4×4 min intervals, 2) a SIT consisting of 4×30s intervals, separated by either active or passive recovery. Blood samples were collected immediately before and at 0’, 30’, 60’ and 180’ (minutes) post-exercise. Outcomes comprised leukocytes, lymphocytes, neutrophils, mixed cell count, platelets, cellular inflammation markers (neutrophil/lymphocyte-ratio (NLR), platelet/lymphocyte-ratio (PLR)), and the systemic immune-inflammation index (SII). In view of HIIT, passive recovery attenuated the changes in lymphocytes and neutrophils compared to active recovery. In view of SIT, active recovery attenuated the increase in leukocytes, lymphocytes and absolute mixed cell count compared to passive recovery. Both protocols, independent of recovery, significantly increased NLR, PLR and SII up to 3h of recovery compared to pre-exercise values. The mode of recovery influences short-term alterations in the circulating fraction of leukocytes, lymphocytes, neutrophils and the mixed cell count, which might be associated with different hormonal and metabolic stress responses due to the mode of recovery.

scholarly journals Herpesviruses and the Unfolded Protein Response

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 17 ◽  
Author(s):  
Benjamin P. Johnston ◽  
Craig McCormick
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Immune Surveillance ◽  
Lytic Replication ◽  
Glycoprotein Synthesis ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Molecular Events ◽  
The Unfolded Protein Response ◽  
Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

scholarly journals Stressors and Stress Responses in Cystic Fibrosis

2018 ◽  
Vol 5 (1) ◽  
pp. 11-29 ◽  
Author(s):  
Zsuzsa Bebok ◽  
Lianwu Fu
Keyword(s):  
Cystic Fibrosis ◽  
Stress Response ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Bicarbonate Transport ◽  
Persistent Infections ◽  
Human Disorders ◽  
The Unfolded Protein Response

Abstract Cystic fibrosis (CF) is a life-shortening, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The primary cause of CF is reduced CFTR-mediated chloride and bicarbonate transport, due to mutations in CFTR. However, inflammation and persistent infections influence clinical outcome. Cellular stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), referred to here as cellular stress response pathways (SRPs), contribute to the pathology of human disorders. Multiple studies have indicated activation of SRPs in CF tissues. We review our present understanding of how SRPs are activated in CF and their contribution to pathology. We conclude that reduced CFTR function in CF organs establishes a tissue environment in which internal or external insults activate SRPs. SRPs contribute to CF pathogenesis by reducing CFTR expression, enhancing inflammation with consequent tissue remodeling. Understanding the contribution of SRPs to CF pathogenesis is crucial even in the era of CFTR “modulators” that are designed to potentiate, correct or amplify CFTR function, since there is an urgent need for supportive treatments. Importantly, CF patients with established pathology could benefit from the targeted use of drugs that modulate SRPs to reduce the symptoms.

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