The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders

BACE1 activity impairs neuronal glucose oxidation:rescue by beta-hydroxybutyrate and lipoic acid

Glucose hypometabolism and impaired mitochondrial function in neurons have been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis. Activity of the aspartic acid protease, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), responsible for beta amyloid peptide generation, has recently been demonstrated to modify glucose metabolism. We therefore examined, using a human neuroblastoma (SH-SY5Y) cell line, whether increased BACE1 activity is responsible for a reduction in cellular glucose metabolism. Overexpression of active BACE1, but not a protease-dead mutant BACE1, protein in SH-SY5Y cells reduced glucose oxidation and the basal oxygen consumption rate, which was associated with a compensatory increase in glycolysis. Increased BACE1 activity had no effect on the mitochondrial electron transfer process but was found to diminish substrate delivery to the mitochondria by inhibition of key mitochondrial decarboxylation reaction enzymes. This BACE1 activity-dependent deficit in glucose oxidation was alleviated by the presence of beta hydroxybutyrate or α-lipoic acid. Consequently our data indicate that raised cellular BACE1 activity drives reduced glucose oxidation in a human neuronal cell line through impairments in the activity of specific tricarboxylic acid cycle enzymes. Because this bioenergetic deficit is recoverable by neutraceutical compounds we suggest that such agents, perhaps in conjunction with BACE1 inhibitors, may be an effective therapeutic strategy in the early-stage management or treatment of AD

The termination of an employment contract on the basis of given notice for the reasons concerning the employee

This thesis deals with the issues of the termination of an employment contract on the basis of given notice for the reasons concerning the employee. Termination of a contract is a complex problem because on the one hand it is associated with providing appropriate selection of employees and the efficiency of the work process, and on the other hand it refers to the existence of the employees along with their families as well as the realization of the constitutional labour law. The termination of an employment contract differs in the manner depending on whether notice is given by the employer or the employee. Nevertheless, the notice period has to be equal for both sides and the notice has to be given in writing. The remaining elements of the so called course of action during the termination of an employment contract are diversified depending on which side gives notice. The labour law provides also detailed and specified principles concerning individual ways of terminating contracts of employment which are additionally differentiated depending on the type of the agreement linking both sides. There are also numerous protective norms excluding or reducing the employer’s course of action. These norms underpin basic function of the labour law which fundamentally protects the weaker side that is the employee. In the Polish law it is possible to find quite a lot of regulations protecting employees against dismissal. There are also numerous institutions designed to protect employees from the loss of work known as the universal protection of the permanence of the employment. In the case of the violation of the regulations concerning the form of the termination of an employment contract an employer can suffer adverse effects. Due to this, the industrial tribunal can adjudge the compensation for the employee or the reinstatement along with the remuneration for the jobless period. To sum up, correct and lawful termination of an employment contract is of paramount importance and it requires the familiarity with the rules preceding the termination of a contract.W niniejszym opracowaniu zostanie przedstawiona problematyka rozwiązania umowy o pracę za wypowiedzeniem z przyczyn dotyczących pracownika. Rozwiązanie stosunku pracy to problem złożony dotyczący najbardziej żywotnych interesów, ponieważ z jednej strony wiąże się z zapewnieniem właściwego doboru pracowników jak i sprawności procesu pracy, z drugiej jednak strony wiąże się z bytem pracownika wraz z jego rodziną oraz nie mniej ważną realizacją konstytucyjnego prawa pracy. Wypowiedzenie umowy o pracę różni się sposobem postępowania w zależności od tego która ze stron dokonuje wypowiedzenia tj. pracodawca lub pracownik. Wspólne natomiast dla wypowiedzenia umowy o pracę jest m.in. to, że okresy wypowiedzenia muszą być dla obydwu stron stosunku pracy jednakowe, że wypowiedzenie powinno nastąpić na piśmie. Pozostałe elementy tzw. trybu postępowania w czasie wypowiedzenia umowy o pracę są zróżnicowane w zależności od tego która ze stron stosunku pracy dokonuje wypowiedzenia. Prawo pracy przewiduje przy tym szczegółowe i skonkretyzowane zasady dotyczące poszczególnych sposobów rozwiązywania umów o pracę, które ponadto zróżnicowane są w zależności od rodzaju umowy łączącej strony. Istnieje także znaczna ilość norm ochronnych wyłączających lub istotnie ograniczających swobodę działania pracodawcy. Normy te są wyrazem podstawowej funkcji prawa pracy, które zasadniczo chroni słabszą stronę stosunku pracy – pracownika. W polskim prawie można znaleźć sporo przepisów chroniących pracowników przed zwolnieniem. Zatem istnieje szereg instytucji mających za zadanie chronić pracownika przed utratą pracy, które zawierają się pod pojęciami powszechnej ochrony trwałości stosunku pracy oraz ochrony szczególnej, jak również prawo to przewiduje inne przypadki gdy stosunek pracy podlega ochronie. W przypadku naruszenia przepisów dotyczących formy rozwiązania umowy o pracę, przyczyn bądź przepisów ochronnych, pracodawca może ponieść bardzo niekorzystne skutki. Z tego tytułu sąd pracy może zasądzić o odszkodowaniu na rzecz pracownika lub przywrócić go do pracy przy jednoczesnym przyznaniu mu wynagrodzenia za czas pozostawania bez pracy. Zważywszy na to, bardzo ważne znaczenie ma prawidłowe i zgodne z prawem rozwiązywanie umów o pracę, wymagające jednocześnie znajomości zasad postępowania poprzedzających ustanie stosunku pracy

Metabolizm acetylo-CoA w komórkach cholinergicznych a ich wrażliwość na czynniki neurotoksyczne

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Suppression of ID1 expression in colon cancer cells increases sensitivity to 5-fluorouracil

Adjuvant chemotherapy with 5-fluorouracil remains the basic treatment for patients with advanced colorectal carcinoma. The major obstacle in successful treatment is the ability of CRC cells to acquire chemoresistance. Here we examined the impact of ID1 silencing on the sensitivity of CRC cells to 5-FU. To suppress ID1 expression in HT-29 and HCT-116 cells the cells were transduced with a lentiviral vector carrying the ID1 silencing sequence. Cells with silenced ID1 showed altered expression of epithelial and mesenchymal markers and exhibited increased proliferation rate compared to the parental cells. HCT-116 cells with suppressed ID1 became sensitized to 5-FU and this was not observed in HT-29 cells. Silencing ID1 resulted in altered expression of genes encoding enzymes metabolizing 5-FU. HT-29 cells with suppressed ID1 had significantly reduced mRNA level for thymidine phosphorylase, uridine-cytydine kinase 2 and dihydropyrimidine dehydrogenase. ID1 suppression in HCT-116 cells resulted in an increase of mRNA level for thymidine phosphorylase, thymidine kinase and uridine-cytydine kinase 2 with concurrent drop of dihydropyrimidine dehydrogenase and thymidylate synthetase mRNA levels. In conclusion, ID1 expression impacts the sensitivity of colon cancer cells to 5-FU and may be considered as a potential predictive marker in CRC treatment