Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum

Poothong, Juthakorn; Jang, Insook; Kaufman, Randal J.

doi:10.1007/978-3-030-67696-4_6

Cited by 15 publications

(6 citation statements)

References 138 publications

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“…The PERK/eIF2α/ATF4/CHOP pathway is activated in response to ER stress caused by factors such as accumulation of unfolded or misfolded proteins, impaired protein folding, and compromised protein quality control . ER stress is triggered by a variety of factors such as accumulation of unfolded or misfolded proteins, defective protein folding, and impaired protein quality control . Upon activation, PERK phosphorylates eIF2α, leading to a reduction in global protein synthesis .…”

Section: Discussionmentioning

confidence: 99%

“…17 ER stress is triggered by a variety of factors such as accumulation of unfolded or misfolded proteins, defective protein folding, and impaired protein quality control. 18 Upon activation, PERK phosphorylates eIF2α, leading to a reduction in global protein synthesis. 19 ATF4, a downstream transcription factor of PERK, is translated and binds to the promoter region of target genes, including CHOP.…”

Section: Discussionmentioning

confidence: 99%

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Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice

Chen,

Xu,

et al. 2023

ACS Chem. Neurosci.

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Depression is a multifaceted psychiatric disorder that affects a significant number of individuals worldwide, and its pathophysiology encompasses a variety of mechanisms, including the induction of endoplasmic reticulum (ER) stress, which has been correlated with depressive-like behaviors in animal models. Yamogenin, a bioactive compound derived from traditional Chinese medicine Dioscorea species, possesses diverse pharmacological properties. This investigation aimed to explore the antidepressant-like effects of yamogenin and the underlying mechanisms involved. By utilizing a murine model of lipopolysaccharide (LPS)-induced depressive-like behavior, we demonstrated that yamogenin enhanced sucrose preference and reduced immobility time in the forced swimming test. These effects were observed alongside the attenuation of ER stress through modulation of the PERK/eIF2α/ATF4/CHOP signaling pathway in the prefrontal cortex. Moreover, yamogenin augmented the expression of the antiapoptotic protein Bcl-2 while diminishing the expression of the proapoptotic protein caspase-3. Additionally, yamogenin exhibited inhibitory effects on microglial activation but did not elicit the promotion of brain-derived neurotrophic factor (BDNF) signaling. Collectively, our findings propose that yamogenin exerts antidepressant-like effects in LPSinduced mice by inhibiting ER stress and microglial activation. This study contributes novel insights into the potential utilization of yamogenin as a natural antidepressant agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice

Chen,

Xu,

et al. 2023

ACS Chem. Neurosci.

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“…The emerging events are pertinently illustrated by cases of familial neurodegenerative disorders in which ER stress is promoted by mutations that cause changes in the amino acid sequence of proteins [46,47]. It is shown that ER stress contributes to the disruption of ATPase activity of chaperones (foldases) and oxidative protein modification [44,48], caused by an elevated ROS production both in mitochondria [49,50] and in the ER due to the activation of oxidative protein folding [51][52][53][54]. A decrease in Ca 2+ levels in the ER lumen plays an important role in the triggering of ER stress [55][56][57].…”

Section: Mechanisms Of Er Stress and Unfolded Protein Responsementioning

confidence: 99%

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

Voronin

Abramova

Verbovaya

et al. 2023

IJMS

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Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones.

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“…The accumulation of misfolded proteins in the ER to a level that exceeds the ER chaperone folding capacity is a major factor that exacerbates protein aggregation, a phenomenon commonly occurring in neurodegenerative diseases. Alternatively, the perturbation of ER homeostasis also plays critical roles in tumorigenesis, whereas the therapeutic modulation of ER chaperones and/or UPR components presents potential anti-tumor treatments [ 68 ]. Reducing ROS production by antioxidants or chemical chaperones has provided an effective strategy to prevent protein misfolding and aggregation.…”

Section: Isl and Pancreatic Cancermentioning

confidence: 99%

Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator

Zhang

Yung

2022

Antioxidants

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Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant Glycyrrhiza glabra, which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.

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Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum

Cited by 15 publications

References 138 publications

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator

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