Targeting of the alpha beta integrin complex by CAR-T cells leads to rapid regression of diffuse intrinsic pontine glioma and glioblastoma.

Background: Diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM) are two highly aggressive and generally incurable gliomas with little therapeutic advancements made in the past several decades. Despite immense initial success of chimeric antigen receptor (CAR) T cells for the treatment of leukemia and lymphoma, significant headway into the application of CAR-T cells against solid tumors, including gliomas, is still forthcoming. The integrin complex alpha beta (αβ) is present on multiple and diverse solid tumor types and tumor vasculature with limited expression throughout most normal tissues, qualifying it as an appealing target for CAR-T cell-mediated immunotherapy.

mTORC1 Enhances Early Phase Ribosome Processivity.

During translation elongation, the ribosome serially adds amino acids to a growing polypeptide over many rounds of catalysis. The ribosome remains bound to mRNAs over these multiple catalytic cycles, requiring high processivity. Despite its importance to translation, relatively little is known about how mRNA sequences or signaling pathways might enhance or reduce ribosome processivity.

[Effect of gangliosides on intensity of the lipid peroxidation process and structural changes in neuronal membranes, caused by toxic doses of glutamate].

We studied effects of gangliosides on the level of lipid peroxides and microviscosity of membrane lipid bilayer in primary dissociated cultures of cerebellar granule cells prepared from 8 day-old rats under conditions of neurotoxic effect of glutamate. It was found that glutamate (100 mkM) treatment of primary cultures activated the processes of lipid peroxidation and decreased microviscosity of neuronal membranes determined as a degree of pyrene excimerization. It was also shown that preincubation of granule cells with gangliosides did not prevent the accumulation of TBA-reactive products induced by glutamate.

Hypoxic and posthypoxic neuronal injury in hippocampal cell culture: attenuation by lipophylic antioxidant U-18 and superoxide dismutase.

The neuroprotective effects of synthesized lipophylic antioxidant from hindered phenol class (U-18) and hydrophylic antioxidative enzyme superoxide dismutase (SOD) were tested on long-term mouse hippocampal cell cultures exposed to hypoxia/reoxygenation. The application of U-18 to the cultures during 6-8 hr hypoxia followed by 16-18 hr reoxygenation in the absence of antioxidant significantly reduced neuronal death. Thus, lipophylic free radical scavenger may exert a delayed neuroprotective effect, probably owing to persistent incorporation into phospholipid membranes and prevention of their lipid peroxidation by means of prolonged intramembranous free radical quenching.

[Ganglioside participation in the regulation of free-radical reactions in brain membranes].

The effect of monosialoganglioside GM1 on induced free radical reactions in the synaptosomal and myelin membranes induced by Fe(2+)-H2O2 system was studied. The formation of free radicals was determined by measuring luminol-dependent chemoluminescence. It was found that preincubation of the membranes with GM1 (10(-11)-10(-6) M) and 12 or 12-palmitate, 13-acetate phorbol ester (10(-7)-10(-6) M) or alpha-tocopherol (10(-6) M) results in the decrease of chemiluminescent response.

[Protection of cultured hippocampal neurons in hypoxia and subsequent reoxygenation by antioxidant from the spatially hindered phenols class].

The influence of antioxidant from hindered phenols (U-18) on a hypoxic neurodestructive effect in mouse hippocampal cell cultures was studied. Morphological and biochemical quantitative analysis of neuronal damage showed that U-18 attenuates nerve cell death resultant from 6-7-hour hypoxia and subsequent 12-hour posthypoxic reoxygenation. This antidestructive action of U-18 was observed upon its introduction in nutrient medium both before and immediately after hypoxic period.

[Effects of nitroxyl radicals on pathogenic properties of herpesvirus (the spin-label technique in the study of virus-macrophage interactions)].

The effect of various concentrations of both methyl ether of 5-doxyl-stearic acid (M5DS) and 4-maleimido-TEMPO (4MT) on the pathogenicity of herpes simplex virus (HSV-1) was studied. It is known that the reagents modify the lipid matrix and the proteins of virion envelope. The decrease of the HSV-1 pathogenicity was shown when using the concentration of reagents more 5 x 10(-5) M.

[Role of isoprenoid chain of lateral mobility of alpha-tocopherol in lipid bilayer].

Using the quenching effect of the fluorescence by nitroxyl radicals the lateral mobility of chromanols in the lipid bilayer was studied. The lateral mobility of the chromanols was shown to increase when the length of phytol chain was diminished. The result is consistent with the idea that antioxidant affect of the chromanols depends on their lateral mobility.

[Alpha-tocopherol protects beta-adrenoreceptors of the rat brain from damaging effects of phospholipase A2].

The effect of synaptosomal membrane phospholipid hydrolysis by phospholipase A2 and alpha-tocopherol upon the state of beta-adrenergic receptors has been studied. The damaging action of phospholipase A2 on beta-adrenergic receptors, consisting in the decrease of specific binding of 3H-dihydroalprenolol at the expense of diminishing receptor affinity and Bmax was demonstrated. It was shown, that alpha-tocopherol protects beta-adrenergic receptors from damaging effect of phospholipase A2.

[Protection of beta-adrenoreceptors of the rat brain during emotional-pain stress by oxidants of the steric hindrance class of phenols].

Adaptogenic properties of a new antioxidant-isoquinoline derivative of hindered phenol class under pain-emotional stress have been investigated. This new antioxidant was shown to have stress-protective effects, i.e.

[Luminol and lucigenin-dependent chemiluminescence in 6-hydroxydopamine auto-oxidation].

It was shown by the methods of luminol- and lucigenin-dependent chemiluminescence that 6-hydroxydopamine 6-ONDA autooxidation is accompanied by generation of superoxide anion-radical which can further react with next 6-ONDA molecule. This fact is based on the observations that intensities of luminol- and lucigenin-dependent chemiluminescence during 6-ONDA autooxidation was increased in aprotonic aqueous solutions (with the decreasing of pH) and was extremely depended on 6-ONDA concentration. The obtained data allows to suggest that one of the possible mechanisms of 6-ONDA neurotoxic action includes the generation of superoxide, whose dismutation to hydrogen peroxide in the presence of transient valency ions gives rise to HO.

[Participation of gangliosides in protection of beta adrenergic receptors from damaging effect induced by lipid peroxidation in synaptosome membranes].

The induction of lipid peroxidation (LPO) in rat brain synaptosomes was shown to result in considerable decrease of the level of specific [3H]-dihydroalprenolol binding, decrease of Bmax and increase of KD. It was revealed that the preincubation of rat brain synaptosomes with monosialoganglioside GM1 (10(-8) M) or alpha-tocopherol (10(-6) M) led to a decrease in MDA accumulation after LPO induction by Fe(2+)-ascorbate system. AT the same time GM1 prevents damage of beta-adrenoreceptors, caused by LPO induction, having no effect on the functional state of beta-adrenoreceptors in control preparations.

[Mechanism of antioxidant action of carnosine].

The comparative study of the antiradical activity of carnosine and vitamin C was carried out by the means of the evaluation of quenching of ESR signals of 2,2-diphenyl-1-picrylhydrazyl (DFPH) and semiquinone radical of alpha-tocopherol. It was shown that carnosine is not able to quench the ESR signals of the stable radical of DFPH and semiquinone radical of alpha-tocopherol. It permits to conclude that: a) carnosine does not interact directly with highly active free radicals; b) carnosine is unable to regenerate the radical of alpha-tocopherol to form the antiradical synergistic couple.

[Vitamin E decreases the neurocytotoxic action of kainic acid in a cerebellar neuron culture].

Using primary cultures of cerebellar granule cells from 4-6-day old Wistar rats we showed the protective effect of vitamin E against kainate-induced neurotoxicity. The preincubation of 7-8-day old cultures with 5 x 10(-4) M alpha-tocopherol solution significantly (on 10-20%) reduces the number of damaged granule cells. As vitamin E takes part in stabilization of membrane lipids the data presented allows us to suggest that one of the possible mechanisms of neuronal injury includes lipid oxidation of the neuronal membranes which leads to additional influx of Ca2+ and results in neuronal death.

Mechanisms of stabilization of biomembranes by alpha-tocopherol. The role of the hydrocarbon chain in the inhibition of lipid peroxidation.

The effects of alpha-tocopherol and its homologues with different chain lengths (6-hydroxy-chromanes: C1, C6, C11) on lipid peroxidation in natural membranes (liver microsomes and mitochondria, brain synaptosomes) and liposomes were studied. It was shown that the antioxidant activity of alpha-tocopherol homologues decreased in the order: C1 greater than C6 greater than C11 greater than alpha-tocopherol (C16). Using fluorescent measurements, the possible reasons underlying these differences were investigated: (i) the distribution between the aqueous media and nonpolar phase of the membrane, which predetermines the binding of alpha-tocopherol homologues to membranes; (ii) the incorporation of alpha-tocopherol homologues into lipid bilayer; (iii) non-uniform distribution (formation of the clusters) of tocopherol homologues in the lipid bilayer; and (iv) transbilayer mobility of alpha-tocopherol homologues and accessibility of the inhibitors for radical-generating centres under enzymically and non-enzymically induced lipid peroxidation.

[The mechanisms of the antioxidant action of shielded phenols in biological membranes. The effects of 4-methyl-2,6-di-tert-butylphenol (ionol) and its derivatives].

According to Bulgarian-Soviet program "Biostab" we studied characteristics of different phenol compounds (ionol derivatives). The aim of the present study is to determine antiradical and antioxidant activity of a number of ionol derivatives in pure chemical systems and in different membrane fractions of a natural origin.

Lipid peroxidation-induced changes in physical properties of annular lipids in rat brain synaptosomal membranes.

The effects of lipid peroxidation (LPO) on the physical state (fluidity) of the rat brain synaptosomal lipid bilayer matrix and the annular lipid domains were investigated using the fluorescent probe pyrene. The parameters of pyrene fluorescence intensity alpha = IE/IM were measured at excitation wavelengths 280 nm and 340 nm (alpha 280 and alpha 340), reflecting fluidity of lipid bilayer matrix and annular lipids, respectively. LPO induction was shown to result in changes of fluidity of both the bilayer and annular lipids.

[Effects of alpha tocopherol and free fatty acids on physical properties of lipid matrix and adenylate cyclase activity in rat brain synaptosomes].

Using modification of physical state of synaptosome lipid matrix by free fatty acids and alpha-tocopherol it was shown that fluidity of lipid matrix isn't limiting regulating factor for the activity of alpha-adrenergic aden late cyclase. From the point of view that state of annular lipids is different from the state of lipid bilayer in synaptosomes we suggest that composition of annular lipids regulates alpha-adrenergic adenylate cyclase system in rat neuronal membranes.

[The relationship of the electrical reactions of the brain to lipid peroxidation processes in pathological aging].

The content of breathing air pentane as in vivo index of lipid peroxidation and electrophysiological parameters (visual evoked potentials and direct current (DC) potential level) of healthy volunteers and patients with senile dementia and Alzheimer's disease following weak stress sound influence were investigated. Unlike healthy subjects correlation between stress-induced changes of pentane level and electrophysiological parameters for patients with psychopathology was shown.