Morpho-functional basis of endothelial dysfunction in diabetes mellitus

The diabetes mellitus (DM) inevitably progresses and leads to complications, among which the main place is occupied by micro- and macroangiopathies. The presence of endothelial damage in DM can be established even before macroscopically significant damage to the vessel. At the same time, there is no summary ED characteristic for diabetes. The aim of the study is to make a comprehensive evaluation of ED in DM -1 and DM-2 types.Materials and methods of research. 60 persons, including 53 DM type 1 and type 2, with a severe course (state of decompensation) participated in the present study. We used the method of estimating ED by the number of circulating desquamation endothelial cells (CECs) at the stages of decomposition with simultaneous determination of NO2- and NO3- metabolites of nitric oxide.Results and discussion. In patients with diabetes, the level of CECs increased in 3-5 times and ranged from 1800 to 11,200 cells / ml. The average amount of CECs in patients with diabetes was 3358.5 ± 366.3 cells / ml.Conclusions: Endothelium is involved in the pathological process at DM. This is evidenced by a significant increase in CECs in the blood plasma. The use of this method allows to detect ED before clinically considerable vascular impairment and reflects the severity of the course and duration of DM

The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1 alpha

The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1a via its tail region. Subsequently, CRY1 reduces HIF-1a half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis

Erythropoietin: a multimodal neuroprotective agent

The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent

Сьома міжнародна наукова-практична конференція «Комп’ютерне моделювання в хімії і технологіях та системах сталого розвитку»

Досліджена кінетика адсорбції барвників метиленового синього (катіонного типу) та оранжево-жовтого S (аніонного типу) з водних розчинів зразками композитів на основі активованого вугілля та оксиду титану (IV). На основі обробки інтегральних кінетичних кривих встановлено параметри процесу адсорбції барвників. Застосування моделей хімічної кінетики показало, що вклад в загальну швидкість процесу також вносить стадія хімічної взаємодії між молекулами барвників та функціональними групами адсорбенту.The kinetics of adsorption of dyes methylene blue (cationic type) and orange-yellow S (anionic type) from aqueous solutions with samples of composites based on activated carbon and titanium oxide (IV) was studied. Based on the processing of integral kinetic curves, the parameters of the dye adsorption process are established. The use of chemical kinetics models has demonstrated that the stage of chemical interaction of dye molecules with the functional groups of the adsorbent also contributes to the overall process rate.Изучена кинетика адсорбции красителей метиленового синего (катионного типа) и оранжево-желтого S (анионного типа) из водных растворов образцами композитов на основании активированного угля и оксида титана (IV). На основании обработки интегральных кинетических кривых установлены параметры процесса адсорбции красителей. Применение моделей химической кинетики показало, что вклад в общую скорость процесса также вносит стадия химического взаимодействия молекул красителей с функциональными группами адсорбента

Transmembrane prolyl 4-hydroxylase is a novel regulator of calcium signaling in astrocytes

Abstract Prolyl 4-hydroxylases (P4Hs) have vital roles in regulating collagen synthesis and hypoxia response. A transmembrane P4H (P4H-TM) is a recently identified member of the family. Biallelic loss of function P4H-TM mutations cause a severe autosomal recessive intellectual disability syndrome in humans, but functions of P4H-TM are essentially unknown at cellular level. Our microarray data on P4h-tm−/− mouse cortexes where P4H-TM is abundantly expressed indicated expression changes in genes involved in calcium signaling and expression of several calcium sequestering ATPases was upregulated in P4h-tm−/− primary mouse astrocytes. Cytosolic and intraorganellar calcium imaging of P4h-tm−/− cells revealed that receptor-operated calcium entry (ROCE) and store-operated calcium entry (SOCE) and calcium re-uptake by mitochondria were compromised. HIF1, but not HIF2, was found to be a key mediator of the P4H-TM effect on calcium signaling. Furthermore, total internal reflection fluorescence (TIRF) imaging showed that calcium agonist-induced gliotransmission was attenuated in P4h-tm−/− astrocytes. This phenotype was accompanied by redistribution of mitochondria from distal processes to central parts of the cell body and decreased intracellular ATP content. Our data show that P4H-TM is a novel regulator of calcium dynamics and gliotransmission

Loss of Cln5 leads to altered Gad1 expression and deficits in interneuron development in mice

The Finnish variant Late Infantile Neuronal Ceroid Lipofuscinosis (vLINCLFin), also known as CLN5 disease, is caused by mutations in the CLN5 gene. Cln5 is strongly expressed in the developing brain and expression continues into adulthood. CLN5, a protein of unknown function, is implicated in neurodevelopment but detailed investigation is lacking. Using Cln5-/- embryos of various ages and cells harvested from Cln5-/- brains we investigated the hitherto unknown role of Cln5 in the developing brain. Loss of Cln5 results in neuronal differentiation deficits and delays in interneuron development during in utero period. Spesifically, the radial thickness of dorsal telencephalon was significantly decreased in Cln5-/- mouse embryos at embryonic day 14.5 (E14.5), and expression of Tuj1, an important neuronal marker during development, was down-regulated. An interneuron marker calbindin and a mitosis marker p-H3 showed down-regulation in ganglionic eminences. Neurite outgrowth was compromised in primary cortical neuronal cultures derived from E16 Cln5−/− embryos compared to WT embryos. We show that the developmental deficits of interneurons may be linked to increased levels of the Repressor Element 1-Silencing Transcription factor (REST), which we report to bind to Gad1, which encodes glutamate decarboxylase (GAD) 67, a rate-limiting enzyme in the production of GABA. Indeed, adult Cln5-/- mice presented deficits in hippocampal parvalbumin-positive interneurons. Furthermore, adult Cln5-/- mice showed age-independent cortical hyper excitability as measured by electroencephalogram and auditory-evoked potentials. This study highlights the importance of Cln5 in neurodevelopment and suggests that in contrast to earlier reports, CLN5 disease is likely to develop during embryonic stages