A hem érfal komponensekre kifejtett közvetlen és közvetett patofiziológiai hatásai = Pathologic effects of heme on components of vessel wall via direct and indirect mechanisms

Kimutattuk, hogy az atheroma lipid magja prooxidáns környezetet teremt, ahol a vörösvértestek szétesnek, a hemoglobin ferri- és ferrylhemoglobinná oxidálódik, és a felszabaduló hem és vas lipidoxidációt indít el. Leírtuk, hogy a hemoglobin oxidáció (ferrylhemoglobin keletkezése) a vascularis endothelium aktiválása révén kifejezett proinflammatorikus hatással rendelkezik. Demonstráltuk, hogy a hemoxigenáz-1 (Hmox1 gén) megelőzi a malária központi idegrendszeri szövődményeit kísérleti állatmodellben. A jótékony hatásokat a szénmonoxid hemoglobinhoz történő kötődése okozta, megakadályozva a hemoglobin oxidációt és a hem disszociációját, ami az idegrendszeri szövődmények kialakulásáért felelős. Kutatásaink felvetik annak a lehetőségét, hogy a nemespenésszel érlelt élelmiszerek, nevezetesen a sajttermékek, és a sziderofórokat tartalmazó funkcionális élelmiszerek beiktatása a diétában csökkentik a szív és érrendszeri megbetegedések előfordulását. Felfetük, hogy a hemoxigenáz-1/ferritin rendszer aktivitása hatékonyan gátolja a kalcifikációt és a simaizomsejtek csontsejt irányú transzformációját, és a hatást elsősorban a ferritin nehéz láncának ferroxidáz aktivitása közvetíti, másodsorban a biliverdinnek köszönhető. Továbbá, eredményeik bizonyítékot szolgáltat arra vonatkozóan, hogy a hem-stressz gátolja a csont mineralizációt, és ez a hemoxigenáz-1/ferritin aktivációnak köszönhető, közelebbről a forroxidáz aktivitásnak. | We demonstrated that interior of advanced atheromatous lesions is a pro-oxidant environment in which erythrocytes are lysed, hemoglobin is readily oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. We revealed that oxidized hemoglobin, i.e. ferrylhemoglobin, acts as a proinflammatory agonist that targets vascular endothelial cells. We reported that heme oxygenase-1 (encoded by Hmox1) prevents the development of experimental cerebral malaria. These effects were mediated by the binding of carbon monoxide to hemoglobin, preventing hemoglobin oxidation and the generation of free heme, a molecule that triggers cerebral malaria pathogenesis. The consumption of mold-ripened food products such as aged cheeses and the introduction of functional foods and food additives rich in fungal iron chelators in diets may lower the risk of cardiovascular diseases. We conclude that induction of the heme oxygenase-1/ferritin system in response to heme prevents phosphate -mediated calcification and osteoblastic differentiation of human smooth muscle cells mainly via the ferroxidase activity of ferritin. Our studies provided evidence that heme decreases mineralization and demonstrates that this suppression is provided by heme-induced upregulation of ferritin. In addition, we conclude that inhibition of osteoblast activity, mineralization, and specific gene expression is attributed to the ferroxidase activity of ferritin

Hem-fehérjék okozta lipoprotein modifikációk: Oxidatív vascularis károsodások kialakulása és az endothelialis adaptáció indukciója = Oxidative modification of lipoproteins by heme proteins: Promotion of oxidation and induction of cytoprotectants in vascular endothelial cells

Számos vaszkuláris megbetegedésben a hem-vas eredetű endotheliális károsodás pathogenetikai szerepére egyre több adat utal. Munkánk során in vitro és in vivo körülmények között (humán hem oxigenáz-1 deficienciában) igazoltuk, hogy a hem-protein eredetű hem, amellett hogy önmagában is citotoxikus, az LDL oxidatív modifikációja révén is vezethet endotheliális funkciózavarhoz. Endotheliális sejtkárosodás végstádiumú veseelégtelenségben szenvedőkben is igazolást nyert. Munkánk során bizonyítottuk, hogy a hemodialízis során az antioxidáns tulajdonságú retenciós molekulák eltávolítása elősegítheti az LDL oxidatív modifikációját és a bekövetkező endothelsejt-károsodás veszélyeztetheti az érrendszert. Az endothelium gyorsan változó oxidatív környezete és a késlekedő adaptáció megnövelheti az atherosclerosis rizikóját a hemodializált krónikus veseelégtelenségben szenvedő betegekben. A hem okozta érkárosodások vizsgálata mellett klinikai tanulmányban igazoltuk, hogy az agyi erek korai érelmeszesedésének rizikója elsősorban az inflammációs markerek megemelkedett szintjével van összefüggésben. | Numerous pathologies may involve toxic side effects of free heme and heme derived iron. Deficinecy of the heme catabolizing enzyme, heme oxygenase-1 in both human and mice leads to abundance of circulating heme and damage to vascular endothelium. Although heme can be directly cytotoxic, we have shown that hemoglobin-derived heme might be indirectly cytotoxic through the generation of oxidized forms of low-density lipoprotein. Endothelial dysfunction has been observed in patients with chronic kidney disease on maintenance hemodialysis too. We have shown that oxidative modification of LDL and consequent endothelial cell damage is a result of depletion of retention solutes with antioxidant capacity, and might represent an immediate threat to the vasculature. The adaptation to such an insult may require many hours in order to gain defense mechanisms, leaving cells susceptible to oxidative damage. In a rapidly undulating oxidative environment of endothelium, the delayed adaptation may not be entirely sufficient to prevent lipid peroxidation and endothelial cell injury in uremic patients on hemodialysis, resulting in an enhanced risk for atherosclerosis

Red blood cell, hemoglobin and heme in the progression of atherosclerosis

For decades plaque neovascularization was considered as an innocent feature of advanced atherosclerotic lesions, but nowadays growing evidence suggest that this process triggers plaque progression and vulnerability. Neovascularization is induced mostly by hypoxia, but the involvement of oxidative stress is also established. Because of inappropriate angiogenesis, neovessels are leaky and prone to rupture, leading to the extravasation of red blood cells (RBCs) within the plaque. RBCs, in the highly oxidative environment of the atherosclerotic lesions, tend to lyse quickly. Both RBC membrane and the released hemoglobin (Hb) possess atherogenic activities. Cholesterol content of RBC membrane contributes to lipid deposition and lipid core expansion upon intraplaque hemorrhage. Cell-free Hb is prone to oxidation, and the oxidation products possess pro-oxidant and pro-inflammatory activities. Defense and adaptation mechanisms evolved to cope with the deleterious effects of cell free Hb and heme. These rely on plasma proteins haptoglobin (Hp) and hemopexin (Hx) with the ability to scavenge and eliminate free Hb and heme form the circulation. The protective strategy is completed with the cellular heme oxygenase-1/ferritin system that becomes activated when Hp and Hx fail to control free Hb and heme-mediated stress. These protective molecules have pharmacological potential in diverse pathologies including atherosclerosis

A közokirat-hamisítások módszerbeli változásai 1997 és 2017 között

The author provides an overview of how the technical and environment of forgery changed in the past two decades.A szerző áttekintést nyújt a hamisítások technikai és környezeti változásairól az elmúlt két évtizedben

Increasing Flame Ionization Detector Response by Silylation: The Effective Carbon Number of Carboxylic Acids

Detector response of carboxylic acids (C2–C12, straight and branched chain) were investigated using a flame ionization detector (FID) in a capillary gas chromatographic system. The response of the FID for hydrocarbons is almost directly proportional to the carbon quantity introduced into the flame. Heteroatoms in the molecule reduce signal magnitude, depending on their quality and on the bond they are involved in. We expressed this reduced response with the effective carbon number (ECN). We determined the ECN contribution (ΔECN) of the carboxyl group on the alkyl skeleton. We examined how the responses of carboxylic acids change if trimethylsilyl derivatives are evaluated and we compared the ECN of the neat and derivatized form

Investigation and Comparison of 5 % Diphenyl – 95 % Dimethyl Polysiloxane Capillary Columns

In gas chromatography, for the analysis, the most important thing is the well-chosen column. After having decided about which stationary phase is the best for our measurement and we know the length, the inner diameter and film thickness, we can buy the column from a lot of manufacturers. The products of these manufacturers’ look similar to each other, but they are different, because of the different manufacturing technologies. These differences could have significant influence on the separation. It is so important to compare the „same” columns, despite the manufacturers’ efforts to produce the best quality columns.5 % diphenyl – 95 % dimethyl polysiloxane stationary phase is widely used. Its slight polarity makes it able to determine very different compounds from the alkanes, through volatiles, drugs, fatty acid methyl esters, amines or phenols.In our work, we tested 5 % diphenyl – 95 % dimethyl polysiloxane stationary phase columns with an 8-component mixture. These columns were from different manufacturers. During isothermal conditions, we determined the height equivalent of theoretical plates on 8 linear velocity level. We represented these parameters as the function of linear velocity. With a constant linear velocity, we measured the excess sorption enthalpy and entropy. From the chromatograms we spotted differences in the retention and in resolution, which is important if we use the column for volatiles or for complex samples. With these parameters we can show many differences between the columns. These parameters have significant influence when we want to use our column for a given task