Biomeditsinskaya khimiya最新文献

Vitaphospholip®, a water-soluble form of phosphatidylcholine, has been evaluated in a clinical trial aimed at reducing non-HDL-cholesterol (non-HDL-C) and triglyceride (TG) levels in patients with combined hyperlipidemia. The randomized, double-blind, placebo-controlled study included 100 patients. Vitaphospholip® or placebo was administered orally 500 mg twice a day for 12 weeks.Treatment with Vitaphospholip® resulted in a 13.2% decrease in non-HDL-C compared to 4.3% in the placebo group (p = 0.001). The absolute decrease of non-HDL-C was 0.6 mmol/l compared to -0.2 mmol/l in the placebo group (p = 0.001). The target non-HDL-C level of less than 3.4 mmol/L was achieved in 15 of 39 patients (38.5%) in the Vitaphospholip® group versus 2 of 41 patients (4.9%) in the placebo group (p = 0.000). The absolute decrease of TG in the group of patients treated with Vitaphospholip® was -0.7 mmol/l versus -0.1 mmol/L in the placebo group (p = 0.001). During therapy with Vitaphospholip®, a significant decrease in the levels of apolipoprotein B, total cholesterol, and very low-density lipoprotein cholesterol was observed. No changes in liver or kidney function, vital signs, or ECG were registered. No serious adverse events were identified. Thus, Vitaphospholip® significantly reduced the levels of non-HDL-C, TG, and atherogenic lipoprotein in patients with combined hyperlipidemia and moderate cardiovascular risk.

The use of pharmacological agents to trigger preconditioning mechanisms may improve the prevention and treatment of coronary heart disease. The aim of this study was to evaluate the ability of a structural analog of apelin-12 ((NαMe)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH, metilin) to reproduce the effect of ischemic preconditioning (IP) of rat hearts in vivo. Control rats were exposed to 40-min occlusion of the left descending coronary artery (LDCA) followed by 60-min restoration of coronary blood flow (reperfusion). IP was modeled by three cycles of 5-min occlusion/5-min reperfusion of the LDCA before prolonged regional myocardial ischemia and reperfusion. Metilin (5 mg/kg) was administered to rats intravenously by bolus injection 30 min before LDCA occlusion. IP or metilin had a significant impact on the studied parameters. The size of necrotic damage to the left ventricle, expressed as the percentage ratio of myocardial infarction/myocardial area at risk (MI/AAR, %), at the end of reperfusion was 26.9±2.0% and 29.3±2.6%, respectively, compared with 43.8±1.2% in the control (p < 0.01). The activity of creatine kinase-MB (CK-MB) in blood plasma decreased to 1026.1±93.9 IU/ml and 1195.2±142.0 IU/ml, respectively, compared with 1986.3±193.7 IU/ml in the control (p < 0.02). Administration of metilin, as well as IP, increased the reduced content of ATP, total adenine nucleotide pool (ΣAN) and phosphocreatine (PCr) in the AAR at the end of reperfusion compared to the control (p < 0.05-0.01). In the metilin group, the content of total creatine (ΣCr) in AAR was higher than in the control (p < 0.05). Intravenous administration of 5 mg/kg 5-hydroxydecanoate (5HD), an inhibitor of mitochondrial ATP-dependent K+ channels (mitoKATP), abolished the preconditioning effect of metilin, and increased the MI/AAR, %, and plasma CK-MB activity to values that insignificantly differed from the control (39.4±2.8% and 2258.2±179.1 IU/ml, respectively). Simultaneously, 5HD significantly reduced the ATP and ΣAN levels in AAR compared to those in the metilin group and the ATP, ΣAN, and PCr levels compared to the IP group. The results indicate that pharmacological preconditioning by metilin reduced cardiac ischemia/reperfusion injury via the involvement of mitoKATP in the mechanism of metilin action.

Mass spectrometric data obtained using a model of tandem carotid artery stenosis in mice with unstable and stable atherosclerosis were analyzed to identify differences in the level of post-translational modifications (PTMs) of proteins. The original proteomic data obtained by Chen et al. [DOI: 10.1038/s42003-023-04641-4] and deposited in the PRIDE repository (identifier PXD030857) were used. Based on results of the bioinformatic analysis, 12 proteins with PTMs (methylation, acetylation, and phosphorylation) were selected; comparison of healthy and atherosclerotic vascular sections showed that the selected proteins were characterized by significant changes in the level of individual modified peptides. According to the literature data, all 12 proteins are involved in the process of atherogenesis. Our study thus revealed putative points of regulation of the atherogenesis processes at the PTM level.

Immune thrombocytopenia (ITP) is one of the most common causes of decreased platelet count. Bleeding is the main clinical symptom of ITP; although its severity correlates with the depth of thrombocytopenia, it may also depend on changes in the functional activity of platelets. In this study we have compared platelet functional activity in healthy volunteers (HV) and in ITP patients, as well as in groups of ITP patients with different levels of bleeding. The study included 65 HV and 84 ITP patients. Platelet activity was assessed by flow cytometry. Platelets were activated with thrombin receptor activating peptide (TRAP) or ADP, and the exposure of activation markers, activated form of glycoprotein (GP) IIb-IIIa and alpha-granule membrane protein P-selectin, was determined on their surface by measuring the binding of PAC-1 and CD62P antibodies, respectively. Platelet-associated IgG (PA-IgG, an indicator of the level of antiplatelet autoantibodies), the percentage of "young" reticular platelets (RP, %) and platelet light scatter (an indicator of their size) were also assessed using flow cytofluorimetry. Platelet binding of PAC-1 (and, to a lesser extent, CD62P binding) was lower in ITP patients than in HV. In ITP patients, PAC-1 binding inversely correlated with the PA-IgG content. In contrast to HV, in ITP patients, PAC-1 and CD62P binding did not directly correlate with the platelet size and RP, %. In ITP patients with severe bleeding, the platelet count was lower, PAC-1 and CD62P binding was reduced and PA-IgG and RP, % levels were increased. Thus, a decrease in the content of activation markers on the platelet surface was registered in ITP patients; it was more pronounced in patients with severe bleeding. It is suggested that the cause of this decrease may be due to the effect of autoantibodies (PA-IgG) on platelets, and in particular on GP IIb-IIIa.

Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa; it develops when the immune system reacts to an allergen. Side effects of topical glucocorticosteroids (GCS) used for AR treatment, the development of steroid resistance in patients and the continuing increase in morbidity explain the clear need to search for new approaches for AR treatment. The tricyclic antidepressant nortriptyline has demonstrated anti-inflammatory properties in a number of experimental studies, as well as its ability to complement the action of corticosteroids. The aim of this study was to compare the effects of nortriptyline and the synthetic GCS mometasone on the culture of mononuclear cells (MNC) of AR patients. Blood MNCs from six AR patients were cultured in the presence of nortriptyline or mometasone, and then type 1, type 2, or type 17 immune response (IR) were stimulated by adding recombinant activator proteins (IL-2, IL-25, IL-33, TSLP, IL-12, IL-1β, IL-23). After 3 days, concentrations of proinflammatory cytokines TNF-α, IFN-γ, IL-6, IL-8, and IL-4 were determined in cell supernatants by enzyme immunoassay. Mometasone (10⁻⁸ M final concentration) effectively suppressed the secretion of proinflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-8 under conditions of stimulation of IR of all types. A similar decrease in secretion, although less pronounced, occurred when stimulated cells were cultured in the presence of nortriptyline. The concentration of TNF-α in the culture medium decreased under these conditions both with stimulation of type 1, type 2, and type 17 IR. The level of IFN-γ secretion decreased only in the case of type 1 and type 17 IR as compared to MNCs with the stimulated IR, which were cultured without this inhibitor. The level of IL-6 secretion decreased only in the culture medium of cells with stimulated type 1 and type 2 IR and IL-8 secretion decreased only under conditions of stimulated type 1 IR. This study has shown that mometasone and nortriptyline are able to suppress the secretion of proinflammatory cytokines by blood cells; their effect is selective and depends on the IR type.

The review highlights the role of reactive oxygen species (ROS) and the thiol system in the regulation of functional activity of neurons. Their controlling function has been analyzed in the context of processes of synaptic plasticity and functioning of neurotrophins, as well as participation in such cellular processes as proliferation, apoptosis, and cell aging. Special attention has been paid to the role of individual components of the thiol system, their interaction with H2О2 in the regulation of the redox signaling system of cells. Summarizing literature data reflecting the participation of H2О2 in the regulation of key metabolic cascades of nervous tissue and own results we have come to conclusion about the dual nature of the stress system components depending on the functional state of the organism. The manifestation of their toxic effect, first of all, depends on their concentration and chemical structure.

To date, a large body of data has been accumulated on the biological activity of a low-toxic natural glycoside, glycyrrhizic acid (GA), but the mechanism of its action at the molecular level has not been fully studied. Expanding knowledge about the spectrum of cellular protein targets of GA contributes to understanding new features of pharmacodynamics. The aim of the work was the experimental identification of a tissue-specific spectrum of protein molecules interacting with GA in a model system. Samples of an intact rat liver tissue lysate were incubated with GA covalently immobilized on EAH-Sepharose 4B, followed by elution of affinity-isolated protein molecules and their trypsinolysis. Using mass spectrometric analysis, 88 potential protein targets of GA were identified. According to the results of gel chromatographic separation of the rat liver lysate and semi-quantitative analysis of proteins, GA influenced Aldh6a1, Decr1, and Sod1 in fractions. Molecular docking in the Flare™ program used to model protein complexes with GA, resulted in selection of 5 proteins (Acox2, Acr1c9, Maoa, Mat1a, Nalcn), which formed complexes with GA with the most favorable ΔG and Rank score parameters. More than half (57%) of the affinity-isolated proteins are involved in the processes of basic cellular metabolism and biotransformation of endogenous and exogenous compounds. Data on the associations of potential protein targets of GA with diseases and different types of biological activity of GA have been systematized and compared.

The interaction of antirenalase antibodies with full-length recombinant human renalases RNLS1 and RNLS2, as well as fragments of these proteins encoded by alternative exons 9 and 10 and expressed as fusion proteins with dihydrofolate reductase (DHFR) in Escherichia coli cells has been investigated. In this study we used custom made polyclonal antibodies to the full-length recombinant RNLS1 (amino acid residues (aa) 1-342), created at our request, as well as commercially available monoclonal antibodies to the renalase fragment (aa - 18-342), specific for the RNLS1 isoform and its C-terminal sequence encoded by exon 9. According to Western blot analysis, the antibodies interacted not only with recombinant RNLS1 and RNLS2 preparations, but also with fusion proteins containing C-terminal sequences specific for these isoforms (DHFR-RNLS-9ex and DHFR-RNLS-10ex). The results obtained indicate that the studied antibodies, in addition to their direct targets, also "recognized" other protein constructs of RNLS1 and RNLS2, which were absent in the immunogen preparations used for antibody generation.

Chronic obstructive pulmonary disease (COPD) is one of the most common pathologies of the respiratory system; it is characterized by increasing airflow limitation. The course of COPD is unstable and is often accompanied by periods of exacerbation, when respiratory symptoms of the disease significantly increase. The frequency of COPD exacerbations is an important predictor of its course, allowing to predict the decline in lung tissue function and the outcome of the disease. Currently, the risk of future COPD exacerbations in a patient is assessed based on the history of previous exacerbations, and the improvement of his condition is evaluated on the basis of the weakening of COPD symptoms. However, the lack of objective criteria complicates unambiguous verdict on the probability of acute condition development and the effectiveness of treatment of COPD patients. Based on the analysis of literature data we propose determination of the levels of chemokines (CXCL5, CXCL8, CXCR1/2, CD44v6), HIF-1α, procalcitonin, albumin and C-reactive protein, leukocyte cells, as well as their possible combination in the peripheral blood as an informative tool for evaluation in COPD patients.

Carriers based on natural biominerals attract much attention in the context of the development of new drug delivery systems. In this study, the effects of native (CC) and hybrid vaterite microparticles with the inclusion of dextran sulfate (CCDS), chondroitin sulfate (CCCS), heparin (CCHE), fucoidan (CCFU), and pectin (CCPE) have been investigated on the viability and functional activity of neutrophils. Among the tested preparations, only CCFU exhibited a slight cytotoxic effect. Native CC stimulated actin cytoskeleton rearrangements and cell production of reactive oxygen species (ROS), which decreased in the presence of diphenyleneiodonium chloride (DPI), an inhibitor of NADPH oxidase assembly. The CC-induced NADPH oxidase activation was reduced in the presence of inhibitors of non-receptor tyrosine kinases of the Src family, phosphatidylinositol 3-kinase (PI3K), and phospholipase C (PLC). Similar to native CC, hybrid vaterite microparticles also initiated ROS production by neutrophils. After addition of CC and hybrid vaterite microparticles (except CCDS), an increase in the number of neutrophils characterized by higher values of the side scattering value was detected thus indicating a change in the morphological characteristics of the cells. Given the ability of hybrid vaterite microparticles with polysaccharides to activate neutrophil NADPH oxidase, they could be promising systems for the delivery of antibacterial and antiviral drugs.