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Recent studies aimed at understanding the molecular mechanisms of human disease indicate that in the pathogenesis of many metabolic disorders, including inflammatory processes, aging of the organism, as well as cancer and neurodegenerative disorders, endoplasmic reticulum stress plays a significant role that is associated with the accumulation of misfolded proteins in the lumen of endoplasmic reticulum. In response to endoplasmic reticulum stress, the unfolded protein response pathway, that has a dualistic role, is induced. The unfolded protein response can restore endoplasmic reticulum homeostasis by degradation of unfolded proteins, inhibition of translation, and mobilization of chaperons, but it can also promote apoptosis when endoplasmic reticulum stress is prolonged. The unfolded protein response signaling pathways may be activated via three transmembrane receptors such as: PERK, IRE1 and ATF6. The most promising for development of new therapies of many human diseases, in particular cancer and neurodegeneration is PERK pathway, that inhibition shows positive therapeutic effects both in in vitro and in vivo studies.

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., Materials and Methods: The study was conducted on commercially available cell lines of wild type mouse embryotic fibroblasts 3T3 MEFs WT and with deletion of PERK gene 3T3 MEFs KO, mouse neurons CATH.a and human neuroblastoma SH-SY5Y with overexpression of amyloid precursor protein (APP). Cells were treated with commercially available inhibitor GSK2606414 or LDN-0060609, selected from the small-molecule compounds library Laboratory for Drug Discovery in Neurodegeneration, on appropriate cell culture medium with thapsigargin as an activator of Endoplasmic Reticulum (ER) stress conditions. To evaluate the level of eIF2α phosphorylation we used the Western blot technique. Detection of immune complexes was performed using the chemiluminescence. Evaluation of the LDN-0060609 compound cytotoxicity was carried out on SH-SY5Y cells using the XTT assay., Results: The results of the study showed that the commercially available GSK2606414 inhibitor at a concentration of 1 μM causes >85% inhibition of the phosphorylation of eIF2α in all tested cell lines. The newly tested LDN-0060609 inhibitor showed the highest inhibitory activity at 25 μM resulting in 52% inhibition of eIF2α phosphorylation. In addition, the LDN-0060609 inhibitor did not induce a cytotoxic effect at any used concentrations and incubation times. Conclusions. It is believed that the LDN-0060609., Conclusions: It is believed that the LDN-0060609 inhibitor, that in comparison with commercially available GSK2606414 inhibitor does not evoke a cytotoxic effect, may constitute a potential factor inhibiting activation of the PERK-dependent UPR signaling pathway responsible for neurodegenerative processes in AD. Small-molecule PERK inhibitors may constitute an innovative therapeutic strategy for AD treatment., (© 2019 MEDPRESS.)

Diabetes mellitus is a chronic metabolic disease with the manifestation possible in any period of life. The incidence of diabetes is rising around the world, and studies show that children are at an increasing risk of developing the disease. Type 1 diabetes accounts for over 90% of childhood and adolescent diabetes, although less than 10% of children suffer from type 2 diabetes. Over the last few decades, inherited monogenic forms of DM were discovered and studied. An extremely rare form of diabetes (less than 1-2% of all diabetes in young people), with neonatal diabetes as a subset, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. We present the first case reported in Ukraine of a child diagnosed with permanent neonatal diabetes resulting from a EIF2AK3 gene missense mutation of exon 15 (WolcottRallison Syndrome). Despite low incidence of the permanent neonatal diabetes, this diagnosis should be considered in infants with persistent hyperglycaemia requiring insulin therapy., (© Polish Society for Pediatric Endocrinology and Diabetology.)