InterfERing with endoplasmic reticulum stress

Kraskiewicz, Honorata; FitzGerald, Una

doi:10.1016/j.tips.2011.10.002

Cited by 86 publications

(66 citation statements)

References 62 publications

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“…The evidence presented above in conjunction with previous results showing that restoring or improving ER function alleviates atherosclerosis (14,17,47) suggest that inhibiting IRE1 may impair atherosclerosis progression. Therefore, we postulated that administration of IRE1 modulators might have beneficial effects by limiting the inflammatory signaling associated with elevated ER stress in a mouse model of atherosclerosis.…”

Section: Resultssupporting

confidence: 71%

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

174

195

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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.endoplasmic reticulum stress | unfolded protein response | metaflammation | lipotoxicity | atherosclerosis C omplex molecular interactions between environment, diet, and genetics that take place at the metabolic and immune interface provoke a low-grade, chronic inflammatory responsemetaflammation-that engages cells of the immune system (macrophages, neutrophils, and lymphocytes) and metabolic tissues (adipocytes, hepatocytes, and pancreatic cells) (1). An important primer for metaflammation is chronic metabolic overloading of organelles, such as the endoplasmic reticulum (ER) and mitochondria, which results in impairment of their functions (2).The ER serves essential cellular functions that include the synthesis and folding of secreted and transmembrane proteins, calcium storage, and lipid synthesis for membrane biogenesis or energy storage. Disruption of any of these functions leads to ER stress and the subsequent activation of an elaborate network of adaptive responses, collectively known as the unfolded protein response (UPR) (3). The UPR reestablishes homeostasis through both transcriptional and translational layers of control. The UPR signals through three mechanistically distinct branches that are initiated by the ER-resident protein folding sensors inositolrequiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (3).IRE1 controls the phylogenetically most conserved branch of the UPR found from fungi to metazoans. It has an ER-lumenal sensor domain that recognizes unfolded peptides and cytosolic kinase and endoribonuclease (RNase) domains that relay the information to downstrea...

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Section: Resultssupporting

confidence: 71%

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

174

195

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“…The most studied chemical chaperones are 4-phenylbutyrate (4-PBA), tauroursodeoxycholic acid (TUDCA) and trimethylamine oxide. TUDCA and 4-PBA have been extensively used to alleviate disease signs in several animal models (reviewed in [85]). Importantly, these chemical chaperones have been evaluated in different clinical trials, and approved by regulatory authorities for primary biliary cirrhosis (4-BPA) and urea cycle disorders (TUDCA).…”

Section: Chemical Chaperonesmentioning

confidence: 99%

“…Importantly; trehalose administration has a potent neuroprotective effect in preclinical models of several neurodegenerative diseases through oral delivery. For example, trehalose protects against experimental HD [93], ALS [94,95], Parkinson [96] and tauopathies [97], among other conditions [18,85]. However, only a few studies have correlated the impact on protein aggregation and protection of chemical chaperones with the attenuation of ER stress levels after their administration in vivo (see examples in [43,[88][89][90]92]).…”

Section: Chemical Chaperonesmentioning

confidence: 99%

Targeting the unfolded protein response for disease intervention

Rivas

Vidal

Hetz

2015

Expert Opinion on Therapeutic Targets

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Therapeutic strategies directed to regulate the activity of different UPR signaling arms may reduce stress levels with a therapeutic gain. Recent drug discovery efforts have identified small molecules that target specific UPR components, providing protection on various disease models. However, important side effects are predicted in the chronic administration due to the fundamental role of the UPR in highly secretory organs such as liver and pancreas. To overcome these problems, we propose the use of combinatorial treatments of selected drugs with natural compounds that are known to modulate the ER proteostasis network.

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“…The stressed ER exhibits an imbalance between unfolded proteins and mature proteins, activating a series of compensatory responses, collectively termed as "unfolded protein response" [23][24][25]. Three ER membrane-localized proteins are considered as 'sensors' of ER stress: inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-activated (PKR)-like ER kinase (PERK) [26]. ER stress may occur before apoptotic cell death and glutathione (GSH) depletion.…”

Section: Endoplasmic Reticulum (Er) Stressmentioning

confidence: 99%

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

Erkekoğlu¹

2015

MOJT

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Despite recent advances in drug development technologies, some drugs continue to be withdrawn from the market because of their late hepatotoxic effects. Drugs can cause liver toxicity through several molecular mechanisms, most of which need to be clarified by further research. Newly found drug-induced liver injury (DILI)-mechanisms like endoplasmic reticulum stress should also be considered while evaluating drug toxicity. New drugs launched in the market should be tested particularly for hepatotoxicity by using hepatic cell cultures and animal models continuously. Future research should target patients in the post-marketing phase in order to provide more evidence grounds to the clinical safety of potential drugs of high propensity of DILI. This review aims to draw the attention to the issue of cellular and molecular aspects of liver toxicity induced by drugs and address DILI as a potential clinical problem that needs further investigation.

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InterfERing with endoplasmic reticulum stress

Cited by 86 publications

References 62 publications

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Targeting the unfolded protein response for disease intervention

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

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