The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

Takasugi, Nobumasa; Hiraoka, Hideki; Nakahara, Kengo; Akiyama, Shiori; Fujikawa, Kana; Furuichi, Moeka; Uehara, Takashi

doi:10.3390/ijms20071783

Cited by 13 publications

(8 citation statements)

References 138 publications

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“…It has been reported that NO may regulate the ER stress through modifications of its chaperon proteins [41] however, lacunae exist. Among numerous chaperon the protein disulfide isomerase is most studied [46]. Besides this, NO could also nitrosylate the ER membrane located sensors of ER stress (PERK1, IRE1 and ATF6) [47,48].…”

Section: Discussionmentioning

confidence: 99%

“…In AD pathology, the correlation of NO and PDI has well suggested through complexities of unfolded protein responses [49]. In 2019, the emerging role of various electrophiles including NO has also been suggested as regulator of ER stress in various diseases [46]. Oxidative stress is correlated with impairment of mitochondrial functions and thus afflicted cellular physiology which could lead to the activation of chaperons and may subsequently initiate the ER stress and decide the cellular fate.…”

Section: Discussionmentioning

confidence: 99%

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Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

Gupta

Tiwari

Singh

et al. 2021

Biochemical Journal

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Rivastigmine is clinical drug for patients of Alzheimer’s disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Further the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

Gupta

Tiwari

Singh

et al. 2021

Biochemical Journal

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“…This can increase the exposure of hidden residues, rendering the protein more vulnerable to further modification [ 31 ]. As a result, the unfolded protein response (UPR) may be activated [ 67 , 68 , 69 , 70 ]. In addition, cross-linking or aggregation of proteins prevents their degradation via the 20S proteasome; inhibition of proteasome function may then occur, which directly affects cell viability and commonly results in cell death [ 71 , 72 ].…”

Section: Functional Consequences Of Lipoxidationmentioning

confidence: 99%

Protein Lipoxidation: Basic Concepts and Emerging Roles

et al. 2021

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Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process.

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“…Recently, an emerging role of reactive electrophilic species (RES) as key regulators for the UPR, more specifically the IRE1 pathway, have been described [123]. Furthermore, RES have been reported to be involved in ER-stress related diseases, including neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), and cancer [124,125,126].…”

Section: Therapeutic Approaches To Restore Protein Balancementioning

confidence: 99%

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

Faber

Roepman

2019

Genes

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The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines.

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The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

Cited by 13 publications

References 138 publications

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling

Protein Lipoxidation: Basic Concepts and Emerging Roles

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

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