Modulation of Salubrinal-Mediated Endoplasmic Reticulum Stress in an Experimental Subarachnoid Hemorrhage Model

Şenol, Nurgül; Oğuzoğlu, Ali Serdar; Erzurumlu, Yalçın; Aşçı, Halil; Savran, Mehtap; Gülle, Kanat; İlhan, İlter; Sadef, Mustafa; Hasseyid, Nursel; Göksel, H. Murat

doi:10.1016/j.wneu.2021.07.005

Cited by 2 publications

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“…Recently, a number of pathways that indicate stress in intracellular organelles after inflammation have been identified. ER stress develops secondary to inflammation, especially in cerebral and metabolic diseases, and causes permanent damage if prolonged [ 8 , 10 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…PERK activation after inflammation and ischemia, ER stress, and accumulation of misfolded and unfolded proteins is mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation [ 9 ]. Salubrinal, a selective eIF2α phosphorylation inhibitor, reduces the load of unfolded proteins by inhibiting eIF2α phosphorylation via PERK inhibition [ 10 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model

et al. 2023

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Background and Objectives: Ocular alkaline burn is a clinical emergency that can cause permanent vision loss due to limbal stem cell deficiency and corneal neovascularization (CNV). Although the basic pathogenetic mechanisms are considered to be acute oxidative stress and corneal neovascularization triggered by inflammation, the underlying intracellular mechanisms have not been clearly elucidated. The aim of this study was to investigate the role of endoplasmic reticulum (ER) stress on inflammation and neovascularization, and the effect of the ER stress inhibitor salubrinal (SLB), as a novel treatment in a corneal alkaline burn model in rats. Methods: Chemical burns were created by cautery for 4 s using a rod coated with 75% silver nitrate and 25% potassium nitrate in the corneal center for the corneal neovascularization (CNV) model. Twenty-eight Wistar albino rats were divided into four groups: SHAM, CNV, CNV + SLB, and CNV + bevacizumab (BVC). After the CNV model was applied to the right eye, a single subconjunctival dose (0.05 mL) of 1 mg/kg salubrinal was injected into both eyes in the CNV + SLB group. A total of 1.25 mg/mL of subconjunctival BVC was administered to the CNV + BVC group. Fourteen days after experimental modeling and drug administration, half of the globes were placed in liquid nitrogen and stored at −20 °C until biochemical analysis. The remaining tissues were collected and fixed in 10% buffered formalin for histopathological and immunohistochemical analysis. Three qualitative agents from three different pathways were chosen: TNFR for inflammation, endothelial nitric oxide synthase (e-NOS) for vascular endothelial growth factor (VEGF)-mediated vascular permeability, and caspase-3 for cellular apoptosis. Results: Significantly lower caspase-3 and eNOS levels were detected in the CNV + SLB and CNV + BVC groups than in the CNV group. Additionally, histopathological evaluation revealed a significant decrease in neovascularization, inflammatory cell infiltration, and fibroblast activity in the CNV + SLB and CNV + BVC groups. The endoplasmic reticulum stress inhibitor, salubrinal, administered to the treatment group, attenuated apoptosis (caspase-3) and inflammation (e-NOS). In the control group (left eyes of the SLB group), salubrinal did not have a toxic effect on the healthy corneas. Conclusion: The ER stress pathway plays an important role in angiogenesis after alkaline corneal burns, and treatment with SLB modulates this pathway, reducing caspase-3 and eNOS levels. Further studies are needed to understand the molecular mechanisms altered by SLB-mediated therapy. The fact that more than one mechanism plays a role in the pathogenesis of CNV may require the use of more than one molecule in treatment. SLB has the potential to affect multiple steps in CNV pathogenesis, both in terms of reducing ER stress and regulating cellular homeostasis by inhibiting the core event of integrated stress response (ISR). Therefore, it can be used as a new treatment option and as a strengthening agent for existing treatments. Although blockade of intracellular organelle stress pathways has shown promising results in experimental studies, more in-depth research is needed before it can be used in routine practice. To the best of our knowledge, this study is the first to report the role of ER stress in corneal injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model

et al. 2023

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In Silico ADME Profiling of Salubrinal and Its Analogues

Zadorozhnii

Kiselev

Харченко

2022

Future Pharmacology

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This work reports on a complex in silico assessment of the ADME properties of Salubrinal (S1) and 54 of its structural analogues containing a cinnamic acid residue (S2–S40) or a quinoline ring (S41–S55). In the work for (Q)SAR forecast, the online servers SwissADME, ADMETlab, admetSAR 2.0, Molinspiration, ALOGPS 2.1, pkCSM, SuperCYPsPred, and Vienna LiverTox were used. In addition, using AutoDock Vina, molecular docking studies were performed with transporter proteins and metabolic enzymes, which were intended to interact with the test compounds. In silico assessment of the ability of the S1–S55 compounds to be absorbed in the intestine was carried out using the SAR classification models implemented in these servers, as well as on the basis of two empirical rules—Lipinski’s and Veber’s. Most of the studied compounds had moderate lipophilicity (MLogP ˂ 4.15) and a polar surface area of less than 140 Å2. They complied with Lipinski’s and Veber’s rules, and are predicted to have good intestinal absorption. In silico analysis of the distribution of the S1–S55 compounds throughout the body, the volume of distribution at steady-state (Vdss), the ability to bind to blood plasma proteins and cross the blood-brain barrier (BBB) were taken into account. Most compounds are predicted to have low or medium Vdss and the ability to cross the BBB. Molecular docking studies were carried out with the structures most important for drug binding of blood plasma proteins, human serum albumin (HSA), and alpha-1-acid glycoprotein (AGP). The studies showed that these substances can effectively bind to blood plasma proteins. When assessing metabolism, the prediction of inhibitory and substrate activity to cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was carried out. For most of these enzymes, the analyzed compounds are likely to be potential inhibitors, as indicated by the molecular docking data. For all studied compounds, a low total clearance (CLtot. ˂ 5 mL/min/kg) and a half-life time (T1/2 ˂ 3 h) are predicted.

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Modulation of Salubrinal-Mediated Endoplasmic Reticulum Stress in an Experimental Subarachnoid Hemorrhage Model

Cited by 2 publications

References 32 publications

Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model

Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model

In Silico ADME Profiling of Salubrinal and Its Analogues

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