Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer.

Background: Colorectal cancer constitutes one of the most common cancer with a high mortality rate. The newest data has reported that activation of the pro-apoptotic PERK-dependent unfolded protein response signaling pathway by small-molecule inhibitors may constitute an innovative anti-cancer treatment strategy.

Objective: In the presented study, we evaluated the effectiveness of the PERK-dependent unfolded protein response signaling pathway small-molecule inhibitor 42215 both on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cell lines.

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis.

Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression.

Inhibition of the PERK-Dependent Unfolded Protein Response Signaling Pathway Involved in the Pathogenesis of Alzheimer's Disease.

Objectives: There is a body of evidence that neurodegenerative disease entities are directly correlated with the perturbations on the molecular level. Hence, the ER stress-mediated Unfolded Protein Response (UPR) is activated resulting in PERK-dependent phosphorylation of the Eukaryotic initiation factor 2 (eIF2α). Thus, the levels of ATF4 and CHOP proteins are significantly increased, which subsequently switches the pro-adaptive branch of the UPR into the pro-apoptotic directly leading to neuronal loss and initiation of the neurodegenerative process.

[Niskocząsteczkowe inhibitory szlaku adaptacyjnej odpowiedzi na stres zależnego od kinazy PERK jako nowatorska strategia terapeutyczna w leczeniu choroby Alzheimera].

Unlabelled: The characteristic hallmark of Alzheimer's disease (AD) are progressive changes in the brain structure and function, caused by aggregation of senile plagues, composed of improperly folded amyloid β(Aβ) protein, in the brain tissue. Recent research has suggested that causes of AD are closely associated with perturbation on the molecular level caused by the activation of the pro-apoptotic, PERKdependent Unfolded Protein Response (UPR) signaling pathway activated under Endoplasmic Reticulum (ER) stress conditions.

Aim: The aims of the study were evaluation of the activity of the smallmolecule inhibitors of PERK kinase, GSK2606414 and LDN-0060609, via the analysis of the level of the phosphorylation of eIF2α as one of the main markers of the UPR signaling pathway activation as well as evaluation of the cytotoxicity of the inhibitor LDN-0060609.

The relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with progression of primary open-angle glaucoma.

Background: Primary open-angle glaucoma (POAG) belongs to neurodegenerative diseases. Its etiology is not fully understood. However, a lot of reports have indicated that many biochemical molecules are involved in the retinal ganglion cell damage.

Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment.

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death.

Inhibition of PERK-dependent pro-adaptive signaling pathway as a promising approach for cancer treatment.

Unlabelled: Endoplasmic Reticulum (ER) is an organelle that is vital for cell growth and maintenance of homeostasis. Recent studies have reported that numerous human diseases, including cancer, are strictly connected to disruption of ER homeostasis. In order to counteract adverse intracellular conditions, cancer cells induce protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-dependent, pro-adaptive unfolded protein response (UPR) signaling branches.

[Small molecule inhibitors of PERK-dependent signaling pathway as a novel, therapeutic molecular strategy in Alzheimer's disease treatment].

Nowadays more than 24 million people suffer from Alzheimer's disease (AD) that is the most common progressive cause of dementia. Molecular mechanisms of neurodegeneration in Alzheimer's disease is closely link with accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). Deposition of senile plaques is one of the main feature of Alzheimer's disease as well as is strictly correlated with impairment of cognitive abilities.

[The role of the adaptive stress response in the pathogenesis of neurodegenerative diseases, cancer and diabetes mellitus type 2].

The ER (Endoplasmatic Reticulum) an intricate intracellular membrane system is responsible for many functions within cells; including folding and post-translational modifications of secretory proteins biosynthesis of ceramides, phospholipids and coordination of cell homeostasis. Perturbation of these ER processes leads to high levels unfolded and misfolded proteins within the lumen of the ER. These disturbances lead to activation of three primary receptors: PERK (Protein kinase RNA-like endoplasmic reticulum kinase), IRE1 (Inositol-Requiring-Enzyme 1) and ATF6 (Activating Transcription Factor 6).

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer's Disease.

Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α.