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- salubrinal / Soochow University
PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_5393;
Taken together, our study suggests that targeting PPP1R15B-PP1c complex or maintaining eIF2? hyperphosphorylation may serve as a new therapeutic approach in MM, which warrants further investigation.
- | Journal: Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2? phosphorylation. (Pubmed Central) - Mar 5, 2024
- | salubrinal / Soochow University
Journal: African swine fever virus maintains de novo global cellular protein synthesis and inhibits stress granules formation via dephosphorylating eIF2?. (Pubmed Central) - Feb 21, 2024
dephosphorylation and inhibit viral replication. Our results provide new insights into the areas of ASFV`s escape from host immunity and hijacking of the host protein translation system.
- | Journal: The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation. (Pubmed Central) - Jan 14, 2024
Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the integrated stress response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.
- | 5-fluorouracil / Generic mfg.
Journal: Inhibition of EIF2? Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma. (Pubmed Central) - Nov 25, 2023
Our results indicate that pharmacological inhibition of EIF2? dephosphorylation is a potential therapeutic strategy for HNSCC.
- icerguastat (IFB-088) / InFlectis
Integrated Stress Response in alpha synucleinopathy (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_11540;
pathway is an important pathological axis for ?-synucleinopathy and different phosphatases are differentially involved in various neurodegenerative conditions. Moreover, we show that ISR components, particularly inhibition of CReP, is a therapeutic target for ?-synucleinopathy.
- || salubrinal / Soochow University
Review, Journal: ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review. (Pubmed Central) - Aug 2, 2023
expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts...In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.
- Targeting the Integrated Stress Response Pathway in T Cells Ameliorates Crescentic Glomerulonephritis in Mice (W414, Orange County Convention Center, West Building) - Oct 15, 2022 - Abstract #KIDNEYWEEK2022KIDNEY_WEEK_4091;
Targeting ISR by Raphin1 suppresses cytokine production from activated Trm cells and autoimmune kidney disease progression in mice. Our study identifies a novel mechanism of how ISR regulates rapid cytokine production of poised Trm cells in health and disease.
- Gadd34 mediates bdnf-induced increases in neuronal de novo protein synthesis and memory (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_10939;
In summary, our results provide evidence of a novel GADD34-eIF2α pathway to increase neuronal protein synthesis in response to activity and learning. This work was supported by NIH grants NS034007 and NS122316 (E.K.)
- | Zolinza (vorinostat) / Merck (MSD), salubrinal / Soochow University
Journal, PARP Biomarker: Pediatric glioblastoma cells are sensitive to drugs that inhibit eIF2α dephosphorylation and its phosphomimetic S51D variant. (Pubmed Central) - Sep 14, 2022
Finally, PED-GBM was more sensitive than normal human astrocytes to salubrinal, raphin-1, and the treatment combinations described herein. Our results indicate that combinations of histone deacetylase inhibitors and PARP-1 inhibitors should be evaluated for their toxicity and efficacy in PED-GBM patients and point to drugs that increase P-eIF2α or modulate its downstream effectors as a novel means of treating PED-GBM.
- | Journal: Upregulation of tRNA-Ser-AGA-2-1 Promotes Malignant Behavior in Normal Bronchial Cells. (Pubmed Central) - May 20, 2022
Futhermore, tRNA(AGA) enhanced transformation potential in vitro, and promoted the establishment of slow growing tumors with aggressive features in nude mice. Our work highlights the importance of studying tRNA deregulation on early stage tumorigenesis, as they may be potential malignancy and aggressiveness biomarkers.
- | salubrinal / Soochow University
Journal: Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-β1-induced podocyte migration. (Pubmed Central) - Mar 9, 2022
This study demonstrated that TGF-β1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2α/CHOP pathway. This intracellular ROS then mediates integrin-β3 expression, which regulates podocyte migration.
- | Journal: An Overview of Methods for Detecting eIF2α Phosphorylation and the Integrated Stress Response. (Pubmed Central) - Feb 23, 2022
However, despite more than two decades of research and growing pharmacological interest, phosphorylation of eIF2α remains difficult to detect and quantify, because of its transient nature and because substoichiometric amounts of this modification are sufficient to profoundly reshape cellular physiology. This review aims to provide a roadmap for facilitating a robust evaluation of eIF2α phosphorylation and its downstream consequences in cells and organisms.
- | salubrinal / Soochow University
Journal: GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis. (Pubmed Central) - Jan 29, 2022
An increase in the eIF2α phosphorylation level by salubrinal treatment or transfection of constructs expressing wild-type eIF2α or an eIF2α phosphomimetic [eIF2α(S51D)] attenuated global protein synthesis and suppressed PRV replication...Knockdown of GADD34 and inhibition of PP1 activity by okadaic acid treatment led to increased eIF2α phosphorylation but significantly suppressed global protein synthesis and inhibited PRV replication. Collectively, these results demonstrated that PRV induces GADD34 expression to promote eIF2α dephosphorylation, thereby maintaining de novo protein synthesis and facilitating viral replication.
- promethazine / Generic mfg.
Pharmacological Hypothermia (PH) Promotes Plasticity Through RNA Binding Motif 3 (RBM3)-Mediated Cold Shock Pathway Following Ischemic Stroke (Hall B2, Poster Hall; Board No. P24) - Dec 21, 2021 - Abstract #ISC2022ISC_89;
Our study has provided evidence, for the first time, for a novel mechanism underlying hypothermia in which the neuroplasticity and rehabilitation were achieved after ischemic stroke. Our findings suggest that the RBM3-induce cold shock pathway is a potential target of hypothermia for neuroprotection and neurorehabilitation.
- | Journal: Endosomal trafficking and DNA damage checkpoint kinases dictate survival to replication stress by regulating amino acid uptake and protein synthesis. (Pubmed Central) - Dec 2, 2021
AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.
- | Journal: Higher-order phosphatase-substrate contacts terminate the integrated stress response. (Pubmed Central) - Nov 24, 2021
Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.
- | salubrinal / Soochow University
Journal: Modulation of Salubrinal-mediated Endoplasmic Reticulum Stress in Experimental Subarachnoid Hemorrhage Model. (Pubmed Central) - Nov 6, 2021
SLB, selective inhibitor of eIF2α dephosphorylation, and NMN, a calcium channel blocker, can ameliorate SAH-induced damage. Inhibition of eIF2α dephosphorylation and enhanced VEGF-A production with SLB may protect brain tissue from apoptosis.
- [VIRTUAL] Activation of the Integrated Stress Response Regulates the Production of IL-17 in Tissue Resident Memory T Cells () - Oct 17, 2021 - Abstract #KIDNEYWEEK2021KIDNEY_WEEK_2563;
Our study identifies a novel mechanism of how “poised Trm17 cells” use the integrated stress response - stress granules pathway to regulate IL-17A cytokine mRNA translation. Dysregulation of this pathway might have a pathogenic role in chronic relapsing and remitting inflammatory diseases.
- | chloroquine phosphate / Generic mfg., hydroxychloroquine / Generic mfg., azithromycin / Generic mfg.
Journal: Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response. (Pubmed Central) - Oct 3, 2021
Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.
- | salubrinal / Soochow University
Journal: eIF2α-ATF4 Pathway Activated by a Change in the Calcium Environment Participates in BCP-Mediated Bone Regeneration. (Pubmed Central) - Aug 4, 2021
An inhibitor of eIF2α dephosphorylation (salubrinal) was also used to explore the effect of the eIF2α-ATF4 pathway on BCP-mediated bone regeneration...In conclusion, the eIF2α-ATF4 pathway activated by a change in the calcium environment participates in BCP-mediated bone regeneration. eIF2α-ATF4 and ERs could provide new directions for further studies on new materials in bone tissue engineering.
- | Journal: Inhibition of eIF2α Phosphorylation by Peste des Petits Ruminant Virus Phosphoprotein Facilitates Viral Replication. (Pubmed Central) - Jul 28, 2021
We speculate that PPRV exploits eIF2α dephosphorylation to facilitate viral replication and that PPRV P protein is involved in this molecular mechanism. This work provides new insights into further understanding PPRV pathobiology and its viral/host interactions.
- | salubrinal / Soochow University
Journal: Pseudorabies virus infection inhibits stress granules formation via dephosphorylating eIF2α. (Pubmed Central) - May 15, 2021
Moreover, inhibition of PP1 activity by salubrinal could counteract PRV-mediated eIF2α dephosphorylation partially and inhibit virus replication. Our results revealed that, on the one hand, PRV infection activated eIF2α kinases PKR (latter inhibited) and PERK, and on the other hand, PRV encoded-functions dephosphorylated eIF2α and inhibited SGs formation to facilitate virus replication.