Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry最新文献

We studied the interaction of the antitumor agent abiraterone and its pharmacologically active metabolite D4A, which is promising for use as an agent for the treatment of prostate cancer, with cytochrome P450 2C9 (CYP2C9). Using the absorption spectroscopy, it has been shown that both compounds under study cause spectral changes of CYP2C9, indicating the interaction of the nitrogen atom of the pyridine ring of the ligand with the heme iron ion of the active site of the enzyme. However, the ligand–enzyme interaction, which is mediated by water bound to the heme iron ion, is possible. Based on the spectral changes, the values of dissociation constants (K_S) of the complexes of abiraterone and D4A with CYP2C9 were determined, which amounted to 1.73 ± 0.14 µM and 3.95 ± 0.16 µM, respectively. Both compounds inhibited the O-demethylase activity of CYP2C9 toward the substrate of this enzyme, naproxen. At a naproxen concentration of 100 µM, the concentrations of abiraterone, D4A, and sulfaphenazole, which inhibit CYP2C9 activity by 50% (IC₅₀), were determined as 13.9 µM, 40 µM, and 41 µM, respectively. The data obtained can be used to predict drug-drug interactions at the CYP2C9 level when using abiraterone or D4A as an antitumor agent for the treatment of prostate cancer in complex pharmacotherapy.

The analysis of cytochrome P450 transcripts was carried out by the nanopore sequencing in liver tissue samples of three donors and HepG2 line cells. It was demonstrated that direct mRNA sequencing with a MinION nanopore sequencer (Oxford Nanopore Technologies) makes it possible to obtain quantitative profiles for transcripts (and their splice variants) of cytochrome P450 superfamily genes encoding isoforms involved in metabolism of the majority (~80%) of drugs. The splice variant profiles substantially differ for donors. The cytochrome P450 gene expression at the transcript level is significantly weaker in cells of the HepG2 line compared with that in the normal liver tissue. This limits the capability of the direct mRNA nanopore sequencing for studying alternative splicing of cytochrome P450 transcripts in HepG2 cells. Both quantitative and qualitative profiles of the cytochrome P450 gene expression at the transcript level notably differ in human liver tissue and HepG2 cells.

In recent years, there has been interest in the study of platelets, the functions of which, as it turned out, are not limited to their involvement in the mechanism of blood coagulation. Many works are devoted to the study of the functional state of platelets under conditions of acute and chronic alcohol exposure. The results of such studies can be useful in the development of new markers of the degree of alcohol intoxication of the body for the subsequent choice of a method for drug correction of disorders caused by acute or chronic alcohol effects. The review summarizes the results of studies on the effect of ethanol on the platelet biogenesis, abundance, morphology, and biochemistry. An analysis of studies performed both in vitro and in experimental animals in vivo, as well as the results of clinical observations, is presented.

Antioxidant and anti-ischemic properties of the pharmacological agonist of galanin receptor GalR2 WTLNSAGYLLGPβAH (Gal) and its C-terminal fragment, dipeptide carnosine (βAH), have been studied in the model of regional ischemia and reperfusion of a rat heart in vivo in the dose range of 0.5–5.0 mg/kg and Сu²⁺-induced free radical oxidation of low-density lipoproteins (LDLs) 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 at reducing 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 decreased 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 the model of Cu²⁺-initiated oxidation of human plasma LDLs 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 viewed as a promising agent that reduces myocardial injury during reperfusion and oxidative stress.

Some brain-derived neurotrophic factor (BDNF)-targeted miRNAs such as miR-30a-5p may be associated with alcohol addiction; however, their relationship with alcohol withdrawal syndrome (AWS) is not described. We aimed to measure serum BDNF concentration and relative content of miR-30a-5p over the course of alcohol abstinence and compare results with the clinics of AWS. Apart from that, we studied the serum relative content of miR-122, a miRNA that does not target BDNF but is associated with alcohol use disorder. Serum BDNF concentration increases over the course of alcohol abstinence. In contrast, the relative content of miR-122, but not miR-30a-5p, decreased. Moreover, miR-122 (but not miR-30a-5p) negatively correlated with serum BDNF concentrations in the course of AWS. The relative content of miR-122 negatively correlated with depression and anxiety levels on day 8 of abstinence. According to multiple regression analysis, the severity of craving for alcohol and cognitive disturbances may be predictors of serum BDNF concentration on day 21 of abstinence, and vice versa. Thus, serum BDNF concentration and relative content of miR-122 are associated with some aspects of AWS clinical manifestations and may dynamically reflect AWS severity.

Asparaginase is one of the most important chemotherapeutic agents against acute lymphoblastic leukemia, the most common form of blood cancer. To date, both asparaginases from E. coli and Dickeya dadantii (formerly known as Erwinia chrysanthemi), used in hematology, induce chemoresistance in cancer cells and side effects in the form of hypersensitivity of immune reactions. Leukemic cells may be resistant to asparaginase due to the increased activity of asparagine synthetase and other mechanisms associated with resistance to asparaginase. Therefore, the search for new sources of L-asparaginases with improved pharmacological properties remains a promising and prospective study. This article discusses the mechanisms of development of resistance and drug resistance to L-asparaginase, as well as possible ways to overcome them.

Sialic acids (SA) are neuraminic acid derivatives, located at the terminal position in the chains of monosaccharide residues of various glycoconjugates. SA play a dual role: they either mask recognition sites, or, on the contrary, represent biological targets that can be recognized by receptor proteins and serve as ligands. The desialylation/sialylation processes can be considered as a dynamic modification regulated by sialyltransferases and sialidases in response to external or internal stimuli. This review describes the structural and functional diversity and the potential use of SA fractions as biomarkers for various pathological conditions. Almost any extreme impact on the body and inflammatory processes are accompanied by an increase in the level of both total and free SA in the blood and tissues. Possible reasons for the increase of sialoglycoconjugate metabolism indicators in biological material include: (i) activation of the hepatocyte synthesis and secretion of various acute-phase proteins, many of which are sialoglycoproteins, (ii) impaired membrane integrity and destruction of body cells, (iii) high activity of sialidases (neurominidases) and sialyltransferases. Most acute and chronic liver diseases are characterized by the decrease in the total level of SA in the blood serum (because many plasma proteins are synthesized and glycosylated in hepatocytes). Aberrant sialylation results in changes of sialoglycoconjugate structure, its ability to perform biological functions and sialoglycoconjugate half-life. Glycosylation is the most common post-translational modification of proteins in the virus, which not only promotes the formation of specific conformation of viral proteins, but also modulates their interaction with receptors and affects host cell recognition, viral replication and infectivity. Serum total SA concentration increases in some benign and inflammatory conditions, which indicates a lack of specificity and limits their use for early detection and screening of neoplastic diseases. Clinical and diagnostic value of determining the sialoglycoconjugate metabolic indicators, including changes in the content of both SA fractions and specific proteins in various biological fluids and tissues, consists in establishing the causes and mechanisms of biochemical changes in the body in certain diseases. In combination with the measurement of existing markers, they can be used to improve diagnosis, staging and monitoring of therapeutic response in some pathological conditions where the need for specificity is less than for specific diagnostics.