SkQ1 Improves Immune Status and Normalizes Activity of NADPH-Generating and Antioxidant Enzymes in Rats with Adjuvant-Induced Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a severe systemic autoimmune inflammatory disease. Oxidative stress and excessive formation of reactive oxygen species (ROS) by the mitochondria are considered as the central pathogenetic mechanisms of connective tissue destruction and factors responsible for a highly active inflammatory process and autoimmune response. The aim of this work was to evaluate the effect of mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on the immune status, intensity of free radical-induced oxidation, and functioning of the antioxidant system (AOS) and NADPH-generating enzymes in rats with the adjuvant-induced RA. Laboratory animals were divided into 4 groups: control group; animals with RA; animals injected intraperitoneally with SkQ1 at the doses of 1250 and 625 nmol/kg, respectively, every 24 h for 8 days starting from day 7 of RA development. Tissue samples for analysis were collected on day 15 of the experiment. Erythrocyte sedimentation rate, the content of circulating immune complexes, and the concentration of class A, M, and G immunoglobulins were determined by enzyme immunoassay. The intensity of free radical-induced oxidation was evaluated based on the assessment of the iron-induced biochemiluminescence, diene conjugate content, and activity of aconitate hydratase. Enzymatic activity and metabolite content in the tissue samples were analyzed spectrophotometrically. It was shown that the development of RA was associated with an increase in the manifestation of immune response markers and intensity of free radical-induced oxidation, as well as with disruption of the AOS functioning and activation of NADPH-generating enzymes. SkQ1 administration resulted in a dose-dependent changes in the oxidative status indicators towards the control values and normalization of the immune status parameters. SkQ1 decreased the level of mitochondrial ROS, resulting in the suppression of the inflammatory response, which might cause inhibition of free radical generation by immunocompetent cells and subsequent mitigation of the oxidative stress severity in the tissues.

Homocystamide Conjugates of Human Serum Albumin as a Platform to Prepare Bimodal Multidrug Delivery Systems for Boron Neutron Capture Therapy.

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)-a carrier protein with a long plasma half-life-is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-'click' chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro-closo-dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 µM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro-closo-dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

Effects of Melatonin-Aided Therapy on the Glutathione Antioxidant System Activity and Liver Protection.

Acute hepatitis results from oxidative stress triggered by hepatotoxic drugs causing liver injury and the activation of caspases cascade. The glutathione antioxidant system protects against reactive oxygen species and mitigates development of these processes. The effectiveness of silymarin, a polyphenolic flavonoid, essenthiale, composed of phosphatidyl choline, and melaxen, a melatonin-correcting drug, as hepatoprotectors has been investigated. The variation of 6-sulfatoxymelatonin (aMT6s), resulting from the biotransformation of melatonin, and GSH has been measured. The activities of caspase-1 and caspase-3, glutathione antioxidant system, and NADPH-generating enzymes were determined. The aMT6s decreases in patients with drug hepatitis and recovers with administration of mexalen. GSH increased in the presence of the studied hepatoprotectors. Pathologically activated caspase-1 and caspase-3 decreased their activities in the presence of hepatoprotectors with melaxen showing the highest effect. The positive effect of melatonin appears to be related to the suppression of decompensation of the glutathione antioxidant system functions, recovery of liver redox status, and the attenuation of inhibition of the NADPH supply.