Biomeditsinskaya khimiya最新文献

Although the relationship between the amount of vitamin B12 and the quality of sperm exists, but results are controversial and require several additional research. The objective of our study was to analyse the amount of vitamin B12 in the sperm samples from patients with chronic prostatitis and varicocele with accompanying asthenozoospermia, and to identify the relationship between the amount of vitamin B12 and asthenozoospermia. The research was carried out of men with chronic prostatitis and varicocele with accompanying asthenozoospermia and infertility at the age of 27±2 years. The material of the investigation was spermoplasm. A chemical microscopic examination of the ejaculate was carried out with a sperm analyzer and with the light microscopy. The amount of vitamin B12 in the spermoplasm was determined by the method of competitive ELISA. It was found that the level of vitamin B12 was 3.6 times lower in patients with chronic prostatitis III B and asthenozoospermia then in the control group. Among patients with varicocele of II and III grade and asthenozoospermia, the level of vitamin B12 was 4.4 times lower than in control group. A positive correlation relationship of average strength was revealed (r=0,683; p=0,001). Additionally, it was revealed that among patients with Chronic prostatitis III B and varicocele of II and III grades with accompanying asthenozoospermia, there was the positive correlation relationship of average strength (r=0,690; p=0,001) between the amount of vitamin B12 and sperm mobility. A decrease in vitamin B12 levels may serve as a marker of reproductive dysfunction in men.

The SARS-CoV-2 pandemia had stimulated the numerous publications emergence on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), primarily when it was found that high mortality in some regions corresponded to the regions with deficient α1-PI alleles. By analogy with the last century's data, when the root cause of the α1-antitrypsin, genetic deficiency leading to the elastase activation in pulmonary emphysema, was proven. It is evident that proteolysis hyperactivation in COVID-19 may be associated with α1-PI impaired functions. The purpose of this review is to systematize scientific data, critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a target in therapy. This review describes the proteinase-dependent stages of a viral infection: the reception and virus penetration into the cell, the plasma aldosterone-angiotensin-renin, kinins, blood clotting systems imbalance. The ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases role in the virus tropism, proteolytic cascades activation in blood, and the COVID-19-dependent complications is presented. The analysis of scientific reports on the α1-PI implementation in the SARS-CoV-2-induced inflammation, the links with the infection severity, and comorbidities were carried out. Particular attention is paid to the acquired α1-PI deficiency in assessing the patients with the proteolysis overactivation and chronic non-inflammatory diseases that are accompanied by the risk factors for the comorbidities progression, and the long-term consequences of COVID-19 initiation. Analyzed data on the search and proteases inhibitory drugs usage in the bronchopulmonary cardiovascular pathologies therapy are essential. It becomes evident the antiviral, anti-inflammatory, anticoagulant, anti-apoptotic effect of α1-PI. The prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders are presented.

Antioxidant and anti-ischemic properties of the pharmacological agonist of galanin receptor GalR2 WTLNSAGYLLGPβAH (Gal) and its C-terminal fragment, dipeptide carnosine (βAH), were studied in the model of regional ischemia and reperfusion of the rat heart in vivo in the dose range of 0.5-5.0 mg/kg and Cu²⁺-induced free radical oxidation of low density lipoproteins (LDL) of human plasma in vitro for peptide concentrations of 0.01 mM and 0.1 mM. Gal was obtained by automatic solid phase synthesis using the Fmoc methodology; its structure was characterized by 1H-NMR spectroscopy and MALDI-TOF mass spectrometry. Intravenous administration of the optimal dose of Gal (1 mg/kg) to rats after ischemia was more effective than carnosine in reducing of the myocardial infarct size and the activity of creatine kinase-MB and lactate dehydrogenase in blood plasma at the end of reperfusion. It also improved the metabolic state of the reperfused myocardium and reduced the formation of peroxidation products during reperfusion. Gal reduced more effectively the formation of adducts of hydroxyl radicals in the interstitium of the area at risk (AAR) of the rat heart than carnosine. Carnosine at a dose of 1 mg/kg more effectively increased the activity of catalase and glutathione peroxidase in the AAR by the end of reperfusion compared to Gal. In a model of Cu²⁺-initiated oxidation of human plasma LDL 0.1 mM carnosine demonstrated a significantly more pronounced reduction in the formation of lipid radicals compared to Gal. The results show that Gal can be considered as a promising agent that reduces myocardial injury during reperfusion and oxidative stress.

The aim of this work is to study of ozone effect on blood oxygen-dependent processes under hypercapnia conditions. The studied blood samples are pretreated with a hypercapnic gas mixture followed by the addition of ozonized isotonic sodium chloride solution (with an ozone concentration of 6 mg/l), as well as gaseous transmitters donors, nitroglycerin and sodium hydrosulfide. It has been established that hypercapnia enhanced the ozone effect on the blood oxygen transport function and was characterized by the oxyhemoglobin dissociation curve shift to the right, also increased hydrogen sulfide synthesis and absence of changes in the nitrates/nitrites concentration. Under these conditions nitroglycerin and sodium hydrosulfide did not change the parameters of the blood gas transport function, but increased the level of nitrate/nitrite and hydrogen sulfide. Preliminary hypercapnia does not eliminate the activating effect of ozone on the free radical oxidation processes, and the addition of the applied gaseous transmitter donors does not contribute to the regulation of the studied parameters.

Cyclooxygenase and lipoxygenase derived lipid metabolites of polyunsaturated fatty acids (PUFAs), as well as their role in the inflammation, have been studied quite thoroughly. However, cytochrome P450 derived lipid mediators, as well as their participation in the regulation of the inflammation, need deeper understanding. In recent years, it has become known that PUFAs are oxidized by cytochrome P450 epoxygenases to epoxy fatty acids, which act as the extremely powerful lipid mediators involved in resolving inflammation. Recent studies have shown that the anti-inflammatory mechanisms of ω-3 PUFAs are also mediated by their conversion to the endocannabinoid epoxides. Thus, it is clear that a number of therapeutically relevant functions of PUFAs are due to their conversion to PUFA epoxides. However, with the participation of cytochrome P450 epoxygenases, not only PUFA epoxides, but also other metabolites are formed. They are further are converted by epoxide hydrolases into pro-inflammatory dihydroxy fatty acids and anti-inflammatory dihydroxyeicosatrienoic acids. The study of the role of PUFA epoxides in the regulation of the inflammation and pharmacological modeling of the activity of epoxide hydrolases are the promising strategies for the treatment of the inflammatory diseases. This review systematizes the current literature data of the fatty acid epoxides, in particular, the endocannabinoid epoxides. Their role in the regulation of inflammation is discussed.

Interactions of cytochrome P450 2C9 (CYP2C9) were studied with the antitumor drug abiraterone and its pharmacologically active metabolite D4A, promising as an agent for prostate cancer treatment. It was shown by absorption spectroscopy, that both investigated compounds induced spectral changes of CYP2C9, indicating interactions of the pyridine nitrogen atom with the heme iron ion of the active site of the enzyme, but interactions of the ligands with the enzyme could be mediated by a water molecule bound to the heme iron ion. Based on the spectral changes, the values of dissociation constants (KS) for complexes of abiraterone and D4A with CYP2C9 were calculated as 1.73±0.14 μM and 3.95±0.16 μM. Both compounds inhibited O-demethylase activity of CYP2C9 towards its substrate. At 100 μM concentration of naproxen the concentrations of abiraterone, D4A and sulfaphenazole inhibiting CYP2C9 activity by 50% (IC50) were determined as 13.9 μM, 40 μM and 41 μM, respectively. The obtained results can be used for prognosis of drug-drug interactions at CYP2C9 level during administration of abiraterone or D4A as an antitumor agent for prostate cancer treatment in complex pharmacotherapy.

Non-small cell carcinoma (NSCLC) prevails in the structure of the incidence of lung cancer. In patients with I stage NSCLC, only 60-70% overcome the 5-year survival barrier, and at II stage it decreases to 35-40%. The reason for such a high mortality rate is almost always a relapse of the disease. The main histological forms of NSCLC - adenocarcinoma (AC) and squamous cell carcinoma (SCLC) - differ in the course, protocols and effectiveness of the treatment. Comparative survival data for AK and PCLC are controversial, and reliable biomarkers for determining the risk of tumor progression are lacking. In thus study we have investigated the possibility of using laboratory parameters characterizing the level of some blood proteins involved in carcinogenesis in patients with early stages of AC and SCLC to determine the risk of disease progression. We retrospectively analyzed the duration of the relapse-free period after surgical treatment for one year in 1250 patients (816 with stages I and II of adenocarcinoma, G1-3 and 434 with early stages of SCLC, G1-3). In 81 patients with AC and 36 - with SCLC (stages I-II, G1-3) the level of CYFRA 21-1 and SCC by electrochemiluminescent method, chemokines CXCL5, CXCL8, TPA, pyruvate kinase M2, HIF-1α and hyaluronic acid by enzyme immunoassay, receptors CXCR1, CXCR2, CD44v6 by flow cytometry were determined. Using the Kaplan-Meier graphical analysis, groups of low (stage I G1-2 + stage II G1) and high (stage I G3 + stage II G2-3) risk of tumor progression were identified. In the case of the one-year survival rate of patients with AC was higher than with SCLC. In patients with AC and a high risk of tumor recurrence, compared with a low one, the level of CYFRA 21-1, the mean intensity of fluorescence (MFI) of the CXCR1 receptor in granulocytes, and the relative content of the CXCR2 receptor in lymphocytes were higher. In the case of rapid progression of SCLC in patients, the relative content of the CXCR2 receptor in lymphocytes, the proportion of monocytes equipped with the CD44v6 receptor, and the SCC level were higher than with slow progression. Regression equations, including combinations of the above parameters (threshold value for AC - 0,512, for SCLC - 0,409, sensitivity - 91,9% and 90,0%, specificity - 90,0% and 87,5%, respectively), allow to predict the probability of tumor recurrence.

Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases (EC 3.4.22). Cts are known as lysosomal proteases responsible for the intracellular proteins degradation. All Cts are synthesized as zymogens, activation of which occurs autocatalytically. Their activity is regulated by endogenous inhibitors. Cts can be secreted into the extracellular environment, which is of particular importance in tumor progression. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling, processing and/or release of cell adhesion molecules, growth factors, cytokines and chemokines. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space, which correlates with neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, therefore, their role in the tumor development differs depending on their cellular origin. The mechanism of Cts action in cancer is not limited only by their proteolytic action. The Cts influence on signal transduction pathways associated with cancer development, including the pathway involving growth factors, which is mediated through receptors tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), has been proven. In addition, Cts are able to promote the epithelial-mesenchymal transition (EMT) by activating signal transduction pathways such as Wnt, Notch, and the pathway involving TGF-β. So, Ctc perform specific both destructive and regulatory functions, carrying out proteolysis, both inside and outside the cell.

The experimental data obtained by Simats A. et al. (Molecular and Cellular Proteomics, 2020, 19(12), 1921-1936) was analysed using a bioinformatic approach. Original experimental results available in the ProteomeXchange database were obtained using a comprehensive multidomain approach to identify potential blood biomarkers in ischemic stroke in mice. The identification of peptides with post-translational modification (PTM) was performed by us using the raw data (accession code PXD016538). Only phosphorylation and deamination were considered as PTMs. Different combinations of data sets (ischemic tissue with intact tissue, ischemic tissue with control taken from mice after sham surgery, etc.) were compared both in terms of the ratio of abundance for the modified peptide to the unmodified variant and in terms of absolute values of abundance. The most likely change in precisely PTM levels was shown for 27 proteins, which include dynamin, glycogen phosphorylase and 70 kDa heat shock protein.

Extracellular vesicles (EVs) are spherical structures of cell membrane origin, ranging in the size from 40 nm to 5000 nm. They are involved in the horizontal transfer of many proteins and microRNAs. The mechanisms EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders in adults; the incidence and prevalence increase in parallel with the obesity epidemic. Since adipose tissue plays a crucial role in the development of insulin resistance, EVs secreted by adipose tissue can be a kind of information transmitter in this process. EVs of adipocytic origin are predominantly absorbed by tissue macrophages, adipocytes themselves, hepatocytes, and skeletal muscles. This contributes to the M1 polarization of macrophages, a decrease in glucose uptake by hepatocytes and myocytes due to the transfer of functionally active microRNAs by these EVs, which affect carbohydrate and lipid metabolism. Patients with T2DM and impaired glucose tolerance have significantly higher levels of CD235a-positive (erythrocyte) EVs, as well as a tendency to increase CD68-positive (leukocyte) and CD62p-positive (platelets/endothelial cells) EVs. The levels of CD31+/CD146-positive BB (endothelial cells) were comparable between diabetic and euglycemic patients. EVs from diabetic patients were preferably internalized by monocytes (mainly classical and intermediate monocyte fractions and to a lesser extent by non-classical monocyte fractions) and B cells compared to euglycemic patients. Internalization of EVs from patients with T2DM by monocytes leads to decreased apoptosis, changes in differentiation, and suppression of reactions controlling oxidative stress in monocytes. Thus, insulin resistance increases secretion of EVs, which are preferentially internalized by monocytes and influence their function. EVs are considered as sources of promising clinical markers of insulin resistance, complications of diabetes mellitus (endothelial dysfunction, retinopathy, nephropathy, neuropathy), and markers of EVs can also be used to monitor the effectiveness of therapy for these complications.