Formate dehydrogenase
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Po vystavení potkanů hypobarické hypoxii jsme zaznamenaly zvýšenou akumulaci laktátu v mozkové tkáni i v krevním oběhu. Po aplikaci L-karnitinu zvířatům před hypoxií došlo k významnému snížení tvorby laktátu. Cílem současné studie bylo zjistit, zda podání L-karnitinu ovlivní aktivitu klíčového enzymu anaerobní přeměny glykolýzy, laktátdehydrogenázy (LDH) v mozkové kůře a v séru u 14-, 21denních a dospělých (90denních) potkanů kmene Wistar. Aktivita LDH se zvyšovala v mozkové kůře s věkem, ale neměnila se v krevním séru. Výrazné rozdíly v aktivitě LDH vyvolané hypoxií nebo podáním L-karnitinu jsme nezaznamenaly. Účinek L-karnitinu tedy pravděpodobně postihuje kinetiku oxidativní dekarboxylace pyruvátu vzhledem ke zvýšené dostupnosti acetyl-CoA z lipidového metabolizmu, který L-karnitin ovlivňuje.
We observed the increased level of lactate in rat brain and blood after the exposure to hypobaric hypoxia. Rats pretreated with L-carnitine showed the significant decrease of the lactate formation. The aim of our study was to determine if the L-carnitine pretreatment could affect the key enzyme of anaerobic glucose metabolism, lactate dehydrogenase (LDH) in the brain cortex and serum in 14-, 21-day-old and adult (90-day-old) Wistar rats. Activity of LDH increased in the brain with the age of rats, but it did not change in blood serum. We did not found any significant differences in LDH activity after the exposure to hypobaric hypoxia or L-carnitine pretreatment. It seems that L-carnitine probably changes the kinetic of oxidative decarboxylation of pyruvate due to the increased accessibility of acetyl-CoA from lipid metabolism, which is influenced by L-carnitine.
Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.
- MeSH
- acetylace MeSH
- glutaráty metabolismus MeSH
- isocitrátdehydrogenasa genetika metabolismus MeSH
- isocitráty chemie MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- nádorové buněčné linie MeSH
- NADP metabolismus MeSH
- oxidace-redukce MeSH
- proteiny nervové tkáně metabolismus MeSH
- sirtuin 3 metabolismus MeSH
- umlčování genů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Abstract Hydrocephalus is the result of an imbalance between the formation and drainage of cerebrospinal fluid (CSF), characterized by an elevation of the CSF pressure within the brain. A primary method of its treatment is the surgical insertion of a shunt. The patient's condition is usually improved and he or she attends the hospital for periodic controls, at which CSF can be easily and repeatedly collected. Unfortunately, the effect of the operation is not durable and the number of patients in which the improvement of the clinical stage is recorded sinks considerably, and many of them develop dementia. Various biochemical markers in CSF have been searched to assess the response to surgical treatment and the further prognosis. They include classic clinical biochemistry parameters, some proteins occurring in excess in patients with Alzheimer's disease, other biomarkers generally reflecting the overall neuronal injury, and hormones, including steroids. The existing as well as the potential biomarkers enabling to predict the patient's fate after shunt operation are critically reviewed here. Special attention is paid to corticosteroids with respect to their role in influencing electrolyte balance in choroidal cells and consequently CSF and water flow among the ventricles. The importance of the local activity of steroid 11β-hydroxysteroid dehydrogenase (11β-HSD) of both types for regulation of the actual corticosteroid concentration is emphasized, and an original method for determination of cortisol/cortisone concentration in CSF is described. Preliminary results showing the changes of 11β-HSD activity in ten patients with hydrocephalus immediately after shunt introduction and after 1 month are provided.
Although the effects of glucocorticoids on proliferation, differentiation and apoptosis are well known, and steroid hormones have been identified to play a role in pathogenesis and the development of various cancers, limited data are available regarding the relationship between the local metabolism of glucocorticoids and colorectal adenocarcinoma (CRC) formation. Glucocorticoid metabolism is determined by 11β-hydroxysteroid dehydrogenases type 1 and 2 (11HSD1, 11HSD2), which increase the local concentration of cortisol due to the reduction of cortisone, or decrease this concentration due to the oxidation of cortisol. The objective of this study was to evaluate the extent of 11HSD1 and 11HSD2 mRNA in pre-malignant colorectal polyps and in CRC. The specimens were retrieved from patients by endoscopic or surgical resection and the expression of 11HSD1 and 11HSD2 was measured by real-time PCR. The polyps were of the following histological types: hyperplastic polyps and adenomas with low- or high-grade dysplasia. The neoplastic tissue of CRC obtained during tumor surgery was also studied. It was found that 11HSD2 was not only downregulated in CRC but already in the early stages of neoplastic transformation (adenoma with low-grade dysplasia). In contrast, the level of 11HSD1 was significantly increased in CRC but not in pre-malignant polyps. The results demonstrate that the downregulation of 11HSD2 gene expression is a typical feature of the development of colorectal polypous lesions and their transformation into CRC.
- MeSH
- 11-beta-hydroxysteroiddehydrogenasa typ 1 analýza biosyntéza MeSH
- 11-beta-hydroxysteroiddehydrogenasa typ 2 analýza biosyntéza MeSH
- adenokarcinom enzymologie MeSH
- adenomové polypy enzymologie MeSH
- dítě MeSH
- dospělí MeSH
- down regulace MeSH
- kolorektální nádory enzymologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- laserová záchytná mikrodisekce MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové biomarkery analýza MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- prekancerózy enzymologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transkriptom MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Multiple lines of evidence suggest the participation of the hippocampus in the feedback inhibition of the hypothalamus-pituitary-adrenal axis during stress response. This inhibition is mediated by glucocorticoid feedback due to the sensitivity of the hippocampus to these hormones. The sensitivity is determined by the expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors and 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that regulates the conversion of glucocorticoids from inactive to active form. The goal of our study was to assess the effect of stress on the expression of 11HSD1, GR and MR in the ventral and dorsal region of the CA1 hippocampus in three different rat strains with diverse responses to stress: Fisher 344, Lewis and Wistar. Stress stimulated 11HSD1 in the ventral but not dorsal CA1 hippocampus of Fisher 344 but not Lewis or Wistar rats. In contrast, GR expression following stress was decreased in the dorsal but not ventral CA1 hippocampus of all three strains. MR expression was not changed in either the dorsal or ventral CA1 region. These results indicate that (1) depending on the strain, stress stimulates 11HSD1 in the ventral hippocampus, which is known to be involved in stress and emotion reactions whereas (2) independent of strain, stress inhibits GR in the dorsal hippocampus, which is predominantly involved in cognitive functions.
- MeSH
- 11-beta-hydroxysteroiddehydrogenasa typ 1 biosyntéza genetika MeSH
- druhová specificita MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- potkani inbrední F344 MeSH
- potkani inbrední LEW MeSH
- potkani Wistar MeSH
- psychický stres genetika metabolismus psychologie MeSH
- steroidní receptory biosyntéza genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: The multifunctional mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 could play a role in the development of Alzheimer disease via its high-affinity binding to amyloid-beta peptides and its overexpression. METHODS: We evaluated the specificity of alterations in mRNA/enzyme expression levels in human right and left hippocampi. RESULTS: We observed a trend towards right/left laterality in nondemented nonpsychotic controls; however, the degree of asymmetry was higher for mRNA when compared to enzyme expression levels. In Alzheimer disease and schizophrenia, significant shifts to left/right asymmetry were found and the changes were associated with more marked increases in mRNA/enzyme expression in the left hemisphere. On the other hand, no alterations were observed in people with multi-infarct dementia. CONCLUSION: Our results support studies reporting an impairment of mitochondria in Alzheimer disease or schizophrenia and a higher vulnerability of the dominant hemisphere to pathological processes. Overexpression of the enzyme could be used to distinguish Alzheimer disease from multi-infarct dementia.
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy genetika metabolismus MeSH
- Alzheimerova nemoc patofyziologie patologie MeSH
- amyloidní beta-protein metabolismus MeSH
- cerebrální infarkt patofyziologie patologie MeSH
- funkční lateralita fyziologie MeSH
- hipokampus enzymologie patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- mitochondrie enzymologie MeSH
- psychotické poruchy patofyziologie patologie MeSH
- regulace genové exprese enzymů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Methanol is the simplest alcohol. Compared to ethanol that is fully detoxified by metabolism. Methanol gets activated in toxic products by the enzymes, alcohol dehydrogenase and aldehyde dehydrogenase. Paradoxically, the same enzymes convert ethanol to harmless acetic acid. This review is focused on a discussion and overview of the literature devoted to methanol toxicology and antidotal therapy. Regarding the antidotal therapy, three main approaches are presented in the text: 1) ethanol as a competitive inhibitor in alcohol dehydrogenase; 2) use of drugs like fomepizole inhibiting alcohol dehydrogenase; 3) tetrahydrofolic acid and its analogues reacting with the formate as a final product of methanol metabolism. All the types of antidotal therapies are described and how they protect from toxic sequelae of methanol is explained.
- MeSH
- alkoholdehydrogenasa antagonisté a inhibitory metabolismus MeSH
- antidota chemie farmakologie MeSH
- inhibitory enzymů chemie farmakologie MeSH
- lidé MeSH
- methanol antagonisté a inhibitory otrava MeSH
- molekulární struktura MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- acidóza etiologie MeSH
- aldehyddehydrogenasa MeSH
- alkoholdehydrogenasa MeSH
- biologické toxiny fyziologie metabolismus MeSH
- ethanol chemická syntéza metabolismus terapeutické užití MeSH
- formiáty metabolismus MeSH
- lidé MeSH
- methanol * chemická syntéza metabolismus otrava MeSH
- otrava farmakoterapie MeSH
- Check Tag
- lidé MeSH
