Sejt-autonóm és nem sejt-autonóm tényezők tanulmányozása a motoros idegsejtek degenerációja során = Study of the role of cell-autonomous and non cell-autonomous processes in the degeneration of motor neurons

Kísérleteink során a mozgató idegsejtek kalcium-kötő fehérje tartalmával jellemzett "sejt-autonóm" tulajdonsága és a környéki mikrogliális reakció mértékével jelzett "nem sejt-autonóm" sajátságok akut és krónikus stressz helyzetben kimutatható összefüggéseit vizsgáltuk. Akut sérülést előidéző modellen igazoltuk, hogy a természetesen különböző kalcium-kötő fehérje tartalmú mozgató idegsejtek kalcium-kötő fehérje tartalma és ellenálló képessége között korreláció áll fenn. Továbblépve, az idegsejtek egyfajta kalcium-kötő fehérje tartalmát (parvalbumin) génsebészeti módszerrel megemelve kimutattuk, hogy ezzel a beavatkozással a sejtek korlátozottan megnövelt ellenálló képességgel ruházhatók fel. Génsebészeti úton előidézett krónikus stressz alkalmazásával igazoltuk, hogy az ilyen jellegű ellenálló képesség növelés hatékonysága, kapacitása véges. Ezen kísérletek során derült fény arra, hogy az idegsejtek károsodásához, és pusztulásához a mozgató idegsejtek környéki mikroglia sejtjei aktívan hozzájárulnak, s igazoltuk, hogy a (mozgató) idegsejtek sérüléssel szembeni hatékony védelmének kidolgozásához a mikroglia sejteket is "kezelni" kell. Ezt, az állatkísérletekkel megfelelően alátámasztott stratégiát klinikai gyakorlatban is (csontvelő átültetéssel) kipróbáltuk. Bár az eljárásnak szignifikáns terápiás hatása nem volt, megmutattuk, hogy ezzel a beavatkozással a donor eredetű sejtek a sérülés helyére vándorolnak, melyek így felhasználhatók trofikus faktorok célzott bejuttatásához. | In our study, the interaction between the cell-autonomous properties (characterized by intracellular calcium buffering capacity) and non cell-autonomous properties (characterized by local microglial activation) of motor neurons has been examined experimentally in acute and chronic stress conditions. During acute lesion, evoked by nerve transection, the correlation between the naturally occurring elevated calcium binding protein capacity and increased resistance of motor neurons against injury has been demonstrated. Next, using transgenic technology, it has been proved that by this way though limited, but increased resistance could be transferred to motor neurons, by increasing their parvalbumin content. During these experiments it became also evident that, in certain stress conditions, the neighboring microglial cells could actively contribute to the destruction of motor neurons, thus, to develop an efficient protection against their injury, microglial cells has to be "treated", as well. This strategy, supported by firm experimental data from animal studies, has been tested clinically through bone marrow transplantation in (voluntary) patients with motor neuron disease. Although this intervention did not yield significant therapeutic benefit, it could be demonstrated that a certain population of cells of donor origin migrate to the site of injury, thus might be used as vehicles for targeted delivery of trophic factors to the lesion

A Triple Combination of Targeting Ligands Increases the Penetration of Nanoparticles across a Blood-Brain Barrier Culture Model

Nanosized drug delivery systems targeting transporters of the blood-brain barrier (BBB) are promising carriers to enhance the penetration of therapeutics into the brain. The expression of solute carriers (SLC) is high and shows a specific pattern at the BBB. Here we show that targeting ligands ascorbic acid, leucine and glutathione on nanoparticles elevated the uptake of albumin cargo in cultured primary rat brain endothelial cells. Moreover, we demonstrated the ability of the triple-targeted nanovesicles to deliver their cargo into midbrain organoids after crossing the BBB model. The cellular uptake was temperature- and energy-dependent based on metabolic inhibition. The process was decreased by filipin and cytochalasin D, indicating that the cellular uptake of nanoparticles was partially mediated by endocytosis. The uptake of the cargo encapsulated in triple-targeted nanoparticles increased after modification of the negative zeta potential of endothelial cells by treatment with a cationic lipid or after cleaving the glycocalyx with an enzyme. We revealed that targeted nanoparticles elevated plasma membrane fluidity, indicating the fusion of nanovesicles with endothelial cell membranes. Our data indicate that labeling nanoparticles with three different ligands of multiple transporters of brain endothelial cells can promote the transfer and delivery of molecules across the BBB

The effect of serum triglyceride concentration on the outcome of acute pancreatitis

Elevated serum triglyceride concentration (seTG, >1.7 mM or >150 mg/dL) or in other words hypertriglyceridemia (HTG) is common in the populations of developed countries. This condition is accompanied by an increased risk for various diseases, such as acute pancreatitis (AP). It has been proposed that HTG could also worsen the course of AP. Therefore, in this meta-analysis, we aimed to compare the effects of various seTGs on the severity, mortality, local and systemic complications of AP, and on intensive care unit admission. 16 eligible studies, including 11,965 patients were retrieved from PubMed and Embase. The results showed that HTG significantly elevated the odds ratio (OR = 1.72) for severe AP when compared to patients with normal seTG (5.6 mM or >11.3 mM versus <5.6 mM or <11.3 mM, respectively. We conclude that the presence of HTG worsens the course and outcome of AP, but we found no significant difference in AP severity based on the extent of HTG