The Effects of Bergamot Polyphenolic Fraction, Cynara cardunculus, and Olea europea L. Extract on Doxorubicin-Induced Cardiotoxicity

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.

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Cu, Zn Superoxide Dismutase and NADP(H) Homeostasis Are Required for Tolerance of Endoplasmic Reticulum Stress inSaccharomyces cerevisiae

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0697 ◽

2009 ◽

Vol 20 (5) ◽

pp. 1493-1508 ◽

Cited By ~ 44

Author(s):

Shi-Xiong Tan ◽

Mariati Teo ◽

Yuen T. Lam ◽

Ian W. Dawes ◽

Gabriel G. Perrone

Keyword(s):

Endoplasmic Reticulum ◽

Superoxide Dismutase ◽

Er Stress ◽

Stress Sensitivity ◽

Pentose Phosphate ◽

Unfolded Protein ◽

Genome Wide ◽

The Unfolded Protein Response ◽

Protein Response

Genome-wide screening for sensitivity to chronic endoplasmic reticulum (ER) stress induced by dithiothreitol and tunicamycin (TM) identified mutants deleted for Cu, Zn superoxide dismutase (SOD) function (SOD1, CCS1) or affected in NADPH generation via the pentose phosphate pathway (TKL1, RPE1). TM-induced ER stress led to an increase in cellular superoxide accumulation and an increase in SOD1 expression and Sod1p activity. Prior adaptation of the hac1 mutant deficient in the unfolded protein response (UPR) to the superoxide-generating agent paraquat reduced cell death under ER stress. Overexpression of the ER oxidoreductase Ero1p known to generate hydrogen peroxide in vitro, did not lead to increased superoxide levels in cells subjected to ER stress. The mutants lacking SOD1, TKL1, or RPE1 exhibited decreased UPR induction under ER stress. Sensitivity of the sod1 mutant to ER stress and decreased UPR induction was partially rescued by overexpression of TKL1 encoding transketolase. These data indicate an important role for SOD and cellular NADP(H) in cell survival during ER stress, and it is proposed that accumulation of superoxide affects NADP(H) homeostasis, leading to reduced UPR induction during ER stress.

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Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress

eLife ◽

10.7554/elife.47084 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 6

Author(s):

Anna Shemorry ◽

Jonathan M Harnoss ◽

Ofer Guttman ◽

Scot A Marsters ◽

László G Kőműves ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Unfolded Protein ◽

Proapoptotic Protein ◽

Stress Sensing ◽

The Unfolded Protein Response ◽

Cell Commitment ◽

Protein Response

Upon detecting endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) orchestrates adaptive cellular changes to reestablish homeostasis. If stress resolution fails, the UPR commits the cell to apoptotic death. Here we show that in hematopoietic cells, including multiple myeloma (MM), lymphoma, and leukemia cell lines, ER stress leads to caspase-mediated cleavage of the key UPR sensor IRE1 within its cytoplasmic linker region, generating a stable IRE1 fragment comprising the ER-lumenal domain and transmembrane segment (LDTM). This cleavage uncouples the stress-sensing and signaling domains of IRE1, attenuating its activation upon ER perturbation. Surprisingly, LDTM exerts negative feedback over apoptotic signaling by inhibiting recruitment of the key proapoptotic protein BAX to mitochondria. Furthermore, ectopic LDTM expression enhances xenograft growth of MM tumors in mice. These results uncover an unexpected mechanism of cross-regulation between the apoptotic caspase machinery and the UPR, which has biologically significant consequences for cell survival under ER stress.

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Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms21218177 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8177

Author(s):

Nataša Pavlović ◽

Maria Kopsida ◽

Pär Gerwins ◽

Femke Heindryckx

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Adenosine Diphosphate ◽

In Vitro Methods ◽

Unfolded Protein ◽

Key Players ◽

The Unfolded Protein Response ◽

Protein Response ◽

G Protein Coupled

The P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 is expressed by macrophages in the liver. Using in vitro methods, we show that inhibition of P2Y12 with ticagrelor enhances tumor cell phagocytosis by macrophages and induces an anti-tumoral phenotype. Treatment with ticagrelor also increases the expression of several actors of the endoplasmic reticulum (ER) stress pathways, suggesting activation of the unfolded protein response (UPR). Inhibiting the UPR with tauroursodeoxycholic acid (Tudca) diminishes the pro-phagocytotic effect of ticagrelor, thereby indicating that P2Y12 mediates macrophage function through activation of ER stress pathways. This could be relevant in the pathogenesis of chronic liver disease and cancer, as macrophages are considered key players in these inflammation-driven pathologies.

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3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitro

Food & Function ◽

10.1039/c5fo00562k ◽

2015 ◽

Vol 6 (10) ◽

pp. 3275-3281 ◽

Cited By ~ 23

Author(s):

Elena Giordano ◽

Olivier Dangles ◽

Njara Rakotomanomana ◽

Silvia Baracchini ◽

Francesco Visioli

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

Atherosclerosis Development ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress is important for atherosclerosis development and is mediated by the unfolded protein response (UPR).

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Pathogenic tau does not drive activation of the unfolded protein response

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.008263 ◽

2019 ◽

Vol 294 (25) ◽

pp. 9679-9688 ◽

Cited By ~ 5

Author(s):

Aleksandra P. Pitera ◽

Ayodeji A. Asuni ◽

Vincent O'Connor ◽

Katrin Deinhardt

Keyword(s):

Endoplasmic Reticulum ◽

Mouse Model ◽

Neurodegenerative Diseases ◽

Unfolded Protein Response ◽

Neuronal Cultures ◽

Critical Determinant ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is commonly associated with a range of neurodegenerative diseases, and targeting UPR components has been suggested as a therapeutic strategy. The UPR surveys protein folding within the endoplasmic reticulum. However, many of the misfolded proteins that accumulate in neurodegeneration are localized so that they do not directly cause endoplasmic reticulum triggers that activate this pathway. Here, using a transgenic mouse model and primary cell cultures along with quantitative PCR, immunoblotting, and immunohistochemistry, we tested whether the UPR is induced in in vivo and in vitro murine models of tauopathy that are based on expression of mutant tauP301L. We found no evidence for the UPR in the rTg4510 mouse model, in which mutant tau is transgenically expressed under the control of tetracycline-controlled transactivator protein. This observation was supported by results from acute experiments in which neuronal cultures expressed mutant tau and accumulated misfolded cytoplasmic tau aggregates but exhibited no UPR activation. These results suggest that the UPR is not induced as a response to tau misfolding and aggregation despite clear evidence for progressive cellular dysfunction and degeneration. We propose that caution is needed when evaluating the implied significance of the UPR as a critical determinant across major neurodegenerative diseases.

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Endoplasmic Reticulum Stress: Signaling the Unfolded Protein Response

Physiology ◽

10.1152/physiol.00050.2006 ◽

2007 ◽

Vol 22 (3) ◽

pp. 193-201 ◽

Cited By ~ 276

Author(s):

Elida Lai ◽

Tracy Teodoro ◽

Allen Volchuk

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Apoptotic Cell ◽

Signaling Cascades ◽

Stress Signaling ◽

Apoptosis Induction ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

The endoplasmic reticulum (ER) is the cellular site of newly synthesized secretory and membrane proteins. Such proteins must be properly folded and posttranslationally modified before exit from the organelle. Proper protein folding and modification requires molecular chaperone proteins as well as an ER environment conducive for these reactions. When ER lumenal conditions are altered or chaperone capacity is overwhelmed, the cell activates signaling cascades that attempt to deal with the altered conditions and restore a favorable folding environment. Such alterations are referred to as ER stress, and the response activated is the unfolded protein response (UPR). When the UPR is perturbed or not sufficient to deal with the stress conditions, apoptotic cell death is initiated. This review will examine UPR signaling that results in cell protective responses, as well as the mechanisms leading to apoptosis induction, which can lead to pathological states due to chronic ER stress.

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The Endoplasmic Reticulum Stress/Unfolded Protein Response and Their Contributions to Parkinson’s Disease Physiopathology

Cells ◽

10.3390/cells9112495 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2495

Author(s):

Cristine Alves da Costa ◽

Wejdane El Manaa ◽

Eric Duplan ◽

Frédéric Checler

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endoplasmic Reticulum ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

Age Related ◽

The Unfolded Protein Response ◽

Protein Response

Parkinson’s disease (PD) is a multifactorial age-related movement disorder in which defects of both mitochondria and the endoplasmic reticulum (ER) have been reported. The unfolded protein response (UPR) has emerged as a key cellular dysfunction associated with the etiology of the disease. The UPR involves a coordinated response initiated in the endoplasmic reticulum that grants the correct folding of proteins. This review gives insights on the ER and its functioning; the UPR signaling cascades; and the link between ER stress, UPR activation, and physiopathology of PD. Thus, post-mortem studies and data obtained by either in vitro and in vivo pharmacological approaches or by genetic modulation of PD causative genes are described. Further, we discuss the relevance and impact of the UPR to sporadic and genetic PD pathology.

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In vitro FRET analysis of IRE1 and BiP association and dissociation upon endoplasmic reticulum stress

eLife ◽

10.7554/elife.30257 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 19

Author(s):

Megan C Kopp ◽

Piotr R Nowak ◽

Natacha Larburu ◽

Christopher J Adams ◽

Maruf MU Ali

Keyword(s):

Endoplasmic Reticulum ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Misfolded Proteins ◽

Protein Substrates ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Substrate Binding Domain

The unfolded protein response (UPR) is a key signaling system that regulates protein homeostasis within the endoplasmic reticulum (ER). The primary step in UPR activation is the detection of misfolded proteins, the mechanism of which is unclear. We have previously suggested an allosteric mechanism for UPR induction (<xref ref-type="bibr" rid="bib3">Carrara et al., 2015</xref>) based on qualitative pull-down assays. Here, we develop an in vitro Förster resonance energy transfer (FRET) UPR induction assay that quantifies IRE1 luminal domain and BiP association and dissociation upon addition of misfolded proteins. Using this technique, we reassess our previous observations and extend mechanistic insight to cover other general ER misfolded protein substrates and their folded native state. Moreover, we evaluate the key BiP substrate-binding domain mutant V461F. The new experimental approach significantly enhances the evidence suggesting an allosteric model for UPR induction upon ER stress.

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Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways

Molecular Biology of the Cell ◽

10.1091/mbc.e11-04-0295 ◽

2011 ◽

Vol 22 (18) ◽

pp. 3520-3532 ◽

Cited By ~ 148

Author(s):

Thanyarat Promlek ◽

Yuki Ishiwata-Kimata ◽

Masahiro Shido ◽

Mitsuru Sakuramoto ◽

Kenji Kohno ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transmembrane Domain ◽

Membrane Lipid ◽

Yeast Cells ◽

Wild Type ◽

Unfolded Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Eukaryotic cells activate the unfolded-protein response (UPR) upon endoplasmic reticulum (ER) stress, where the stress is assumed to be the accumulation of unfolded proteins in the ER. Consistent with previous in vitro studies of the ER-luminal domain of the mutant UPR initiator Ire1, our study show its association with a model unfolded protein in yeast cells. An Ire1 luminal domain mutation that compromises Ire1's unfolded-protein–associating ability weakens its ability to respond to stress stimuli, likely resulting in the accumulation of unfolded proteins in the ER. In contrast, this mutant was activated like wild-type Ire1 by depletion of the membrane lipid component inositol or by deletion of genes involved in lipid homeostasis. Another Ire1 mutant lacking the authentic luminal domain was up-regulated by inositol depletion as strongly as wild-type Ire1. We therefore conclude that the cytosolic (or transmembrane) domain of Ire1 senses membrane aberrancy, while, as proposed previously, unfolded proteins accumulating in the ER interact with and activate Ire1.

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Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

Nature Communications ◽

10.1038/s41467-021-27597-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Adrien Le Thomas ◽

Elena Ferri ◽

Scot Marsters ◽

Jonathan M. Harnoss ◽

David A. Lawrence ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Stem Loop ◽

Unfolded Protein ◽

Cellular Mrnas ◽

The Unfolded Protein Response ◽

Protein Response

AbstractInositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.

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