Biochemistry (Moscow)最新文献

{"title":"Key Enzymes of the Serotonergic System – Tryptophan Hydroxylase 2 and Monoamine Oxidase A – In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153","authors":"Vitalii S. Moskaliuk,&nbsp;Rimma V. Kozhemyakina,&nbsp;Tatyana M. Khomenko,&nbsp;Konstantin P. Volcho,&nbsp;Nariman F. Salakhutdinov,&nbsp;Alexander V. Kulikov,&nbsp;Vladimir S. Naumenko,&nbsp;Elizabeth A. Kulikova","doi":"10.1134/S0006297924060105","DOIUrl":"10.1134/S0006297924060105","url":null,"abstract":"<p>At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes – tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) – in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of <i>Tph2</i> mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1109 - 1121"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic NMDA Receptors","authors":"Artem M. Kosenkov,&nbsp;Sergei A. Maiorov,&nbsp;Sergei G. Gaidin","doi":"10.1134/S0006297924060063","DOIUrl":"10.1134/S0006297924060063","url":null,"abstract":"<p>Astrocytic NMDA receptors (NMDARs) are heterotetramers, whose expression and properties are largely determined by their subunit composition. Astrocytic NMDARs are characterized by a low sensitivity to magnesium ions and low calcium conductivity. Their activation plays an important role in the regulation of various intracellular processes, such as gene expression and mitochondrial function. Astrocytic NMDARs are involved in calcium signaling in astrocytes and can act through the ionotropic and metabotropic pathways. Astrocytic NMDARs participate in the interactions of the neuroglia, thus affecting synaptic plasticity. They are also engaged in the astrocyte-vascular interactions and contribute to the regulation of vascular tone. Astrocytic NMDARs are involved in various pathologies, such as ischemia and hyperammonemia, and their blockade prevents negative changes in astrocytes during these diseases.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1045 - 1060"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to: Rational Design of Drugs Targeting G-Protein-Coupled Receptors: Ligand Search and Screening","authors":"Aleksandra P. Luginina,&nbsp;Andrey. N. Khnykin,&nbsp;Polina A. Khorn,&nbsp;Olga V. Moiseeva,&nbsp;Nadezhda A. Safronova,&nbsp;Vladimir A. Pospelov,&nbsp;Dmitrii E. Dashevskii,&nbsp;Anatolii S. Belousov,&nbsp;Valentin I. Borschevskiy,&nbsp;Alexey V. Mishin","doi":"10.1134/S0006297924060154","DOIUrl":"10.1134/S0006297924060154","url":null,"abstract":"","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1159 - 1159"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specificity of Photochemical Energy Conversion in Photosystem I from the Green Microalga Chlorella ohadii","authors":"Dmitry A. Cherepanov,&nbsp;Anastasiya A. Petrova,&nbsp;Mariya S. Fadeeva,&nbsp;Fedor E. Gostev,&nbsp;Ivan V. Shelaev,&nbsp;Victor A. Nadtochenko,&nbsp;Alexey Yu. Semenov","doi":"10.1134/S0006297924060129","DOIUrl":"10.1134/S0006297924060129","url":null,"abstract":"<p>Primary excitation energy transfer and charge separation in photosystem I (PSI) from the extremophile desert green alga <i>Chlorella ohadii</i> grown in low light were studied using broadband femtosecond pump-probe spectroscopy in the spectral range from 400 to 850 nm and in the time range from 50 fs to 500 ps. Photochemical reactions were induced by the excitation into the blue and red edges of the chlorophyll Qy absorption band and compared with similar processes in PSI from the cyanobacterium <i>Synechocystis</i> sp. PCC 6803. When PSI from <i>C. ohadii</i> was excited at 660 nm, the processes of energy redistribution in the light-harvesting antenna complex were observed within a time interval of up to 25 ps, while formation of the stable radical ion pair P₇₀₀⁺A₁⁻ was kinetically heterogeneous with characteristic times of 25 and 120 ps. When PSI was excited into the red edge of the Qy band at 715 nm, primary charge separation reactions occurred within the time range of 7 ps in half of the complexes. In the remaining complexes, formation of the radical ion pair P₇₀₀⁺A₁⁻ was limited by the energy transfer and occurred with a characteristic time of 70 ps. Similar photochemical reactions in PSI from <i>Synechocystis</i> 6803 were significantly faster: upon excitation at 680 nm, formation of the primary radical ion pairs occurred with a time of 3 ps in ~30% complexes. Excitation at 720 nm resulted in kinetically unresolvable ultrafast primary charge separation in 50% complexes, and subsequent formation of P₇₀₀⁺A₁⁻ was observed within 25 ps. The photodynamics of PSI from <i>C. ohadii</i> was noticeably similar to the excitation energy transfer and charge separation in PSI from the microalga <i>Chlamydomonas reinhardtii</i>; however, the dynamics of energy transfer in <i>C. ohadii</i> PSI also included slower components.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1133 - 1145"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase","authors":"Elena V. Koroleva,&nbsp;Anastasiya L. Ermolinskaya,&nbsp;Zhanna V. Ignatovich,&nbsp;Yury V. Kornoushenko,&nbsp;Alesia V. Panibrat,&nbsp;Vladimir I. Potkin,&nbsp;Alexander M. Andrianov","doi":"10.1134/S0006297924060099","DOIUrl":"10.1134/S0006297924060099","url":null,"abstract":"<p>Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed <i>in silico</i> their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC₅₀ values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1094 - 1108"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The C886T Mutation in the Th Gene Reduces the Activity of Tyrosine Hydroxylase in the Mouse Brain","authors":"Ismail Alsalloum,&nbsp;Vitalii S. Moskaliuk,&nbsp;Ilya A. Rakhov,&nbsp;Daria V. Bazovkina,&nbsp;Alexander V. Kulikov","doi":"10.1134/S000629792406004X","DOIUrl":"10.1134/S000629792406004X","url":null,"abstract":"<p>Tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine, the initial and rate-limiting step in the synthesis of dopamine, noradrenaline, and adrenaline. Mutations in the human <i>TH</i> gene are associated with hereditary motor disorders. The common C886T mutation identified in the mouse <i>Th</i> gene results in the R278H substitution in the enzyme molecule. We investigated the impact of this mutation on the TH activity in the mouse midbrain. The TH activity in the midbrain of <i>Mus musculus castaneus</i> (CAST) mice homozygous for the 886C allele was higher compared to C57BL/6 and DBA/2 mice homozygous for the 886T allele. Notably, this difference in the enzyme activity was not associated with changes in the <i>Th</i> gene mRNA levels and TH protein content. Analysis of the TH activity in the midbrain in mice from the F2 population obtained by crossbreeding of C57BL/6 and CAST mice revealed that the 886C allele is associated with a high TH activity. Moreover, this allele showed complete dominance over the 886T allele. However, the C886T mutation did not affect the levels of TH protein in the midbrain. These findings demonstrate that the C886T mutation is a major genetic factor determining the activity of TH in the midbrain of common laboratory mouse strains. Moreover, it represents the first common spontaneous mutation in the mouse <i>Th</i> gene whose influence on the enzyme activity has been demonstrated. These results will help to understand the role of TH in the development of adaptive and pathological behavior, elucidate molecular mechanisms regulating the activity of TH, and explore pharmacological agents for modulating its function.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1024 - 1030"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S000629792406004X.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-Integrational DNA Repair of HIV-1 Is Associated with Activation of the DNA-PK and ATM Cellular Protein Kinases and Phosphorylation of Their Targets","authors":"Andrey N. Anisenko,&nbsp;Anastasiia A. Nefedova,&nbsp;Igor I. Kireev,&nbsp;Marina B. Gottikh","doi":"10.1134/S0006297924060117","DOIUrl":"10.1134/S0006297924060117","url":null,"abstract":"<p>Integration of the DNA copy of HIV-1 genome into the cellular genome results in series of damages, repair of which is critical for successful replication of the virus. We have previously demonstrated that the ATM and DNA-PK kinases, normally responsible for repairing double-strand breaks in the cellular DNA, are required to initiate the HIV-1 DNA postintegrational repair, even though integration does not result in DNA double-strand breaks. In this study, we analyzed changes in phosphorylation status of ATM (pSer1981), DNA-PK (pSer2056), and their related kinase ATR (pSer428), as well as their targets: Chk1 (pSer345), Chk2 (pThr68), H2AX (pSer139), and p53 (pSer15) during the HIV-1 DNA postintegrational repair. We have shown that ATM and DNA-PK, but not ATR, undergo autophosphorylation during postintegrational DNA repair and phosphorylate their target proteins Chk2 and H2AX. These data indicate common signaling mechanisms between the double-strand DNA break repair and postintegrational repair of HIV-1 DNA.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1122 - 1132"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer’s Disease","authors":"Alla S. Dashkova,&nbsp;Vladimir I. Kovalev,&nbsp;Alina V. Chaplygina,&nbsp;Daria Yu. Zhdanova,&nbsp;Natalia V. Bobkova","doi":"10.1134/S0006297924060051","DOIUrl":"10.1134/S0006297924060051","url":null,"abstract":"<p>Alzheimer’s disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression. Cellular therapy and its further development in the form of cell vesicle and particularly mitochondrial transplantation represent promising approaches for treating neurodegeneration. The use of synaptosomes, due to uniqueness of their contents, could mark a new stage in the development of comprehensive therapies for neurodegenerative diseases, particularly AD. Synaptosomes contain unique memory mitochondria, which differ not only in size but also in functionality compared to the mitochondria in the neuronal soma. These synaptosomal mitochondria actively participate in cellular communication and signal transmission within synapses. Synaptosomes also contain other elements such as their own protein synthesis machinery, synaptic vesicles with neurotransmitters, synaptic adhesion molecules, and microRNAs – all crucial for synaptic transmission and, consequently, cognitive processes. Complex molecular ensemble ensures maintenance of the synaptic autonomy of mitochondria. Additionally, synaptosomes, with their affinity for neurons, can serve as an optimal platform for targeted drug delivery to nerve cells. This review discusses unique composition of synaptosomes, their capabilities and advantages, as well as limitations of their suggested use as therapeutic agents for treating neurodegenerative pathologies, particularly AD.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1031 - 1044"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formation of Amyloid-Like Conformational States of β-Structured Membrane Proteins on the Example of OMPF Porin from the Yersinia pseudotuberculosis Outer Membrane","authors":"Olga D. Novikova,&nbsp;Tatyana V. Rybinskaya,&nbsp;Elena A. Zelepuga,&nbsp;Vladimir N. Uversky,&nbsp;Nataliya Yu. Kim,&nbsp;Ekaterina A. Chingizova,&nbsp;Ekaterina S. Menchinskaya,&nbsp;Valentina A. Khomenko,&nbsp;Dmitriy K. Chistyulin,&nbsp;Olga Yu. Portnyagina","doi":"10.1134/S0006297924060087","DOIUrl":"10.1134/S0006297924060087","url":null,"abstract":"<p>The work presents results of the <i>in vitro</i> and <i>in silico</i> study of formation of amyloid-like structures under harsh denaturing conditions by non-specific OmpF porin of <i>Yersinia pseudotuberculosis</i> (YpOmpF), a membrane protein with β-barrel conformation. It has been shown that in order to obtain amyloid-like porin aggregates, preliminary destabilization of its structure in a buffer solution with acidic pH at elevated temperature followed by long-term incubation at room temperature is necessary. After heating at 95°C in a solution with pH 4.5, significant conformational rearrangements are observed in the porin molecule at the level of tertiary and secondary structure of the protein, which are accompanied by the increase in the content of total β-structure and sharp decrease in the value of characteristic viscosity of the protein solution. Subsequent long-term exposure of the resulting unstable intermediate YpOmpF at room temperature leads to formation of porin aggregates of various shapes and sizes that bind thioflavin T, a specific fluorescent dye for the detection of amyloid-like protein structures. Compared to the initial protein, early intermediates of the amyloidogenic porin pathway, oligomers, have been shown to have increased toxicity to the Neuro-2aCCL-131™ mouse neuroblastoma cells. The results of computer modeling and analysis of the changes in intrinsic fluorescence during protein aggregation suggest that during formation of amyloid-like aggregates, changes in the structure of YpOmpF affect not only the areas with an internally disordered structure corresponding to the external loops of the porin, but also main framework of the molecule, which has a rigid spatial structure inherent to β-barrel.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"1079 - 1093"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irreducible Complexity of Hox Gene: Path to the Canonical Function of the Hox Cluster","authors":"Milana A. Kulakova,&nbsp;Georgy P. Maslakov,&nbsp;Liudmila O. Poliushkevich","doi":"10.1134/S0006297924060014","DOIUrl":"10.1134/S0006297924060014","url":null,"abstract":"<p>The evolution of major taxa is often associated with the emergence of new gene families. In all multicellular animals except sponges and comb jellies, the genomes contain Hox genes, which are crucial regulators of development. The canonical function of Hox genes involves colinear patterning of body parts in bilateral animals. This general function is implemented through complex, precisely coordinated mechanisms, not all of which are evolutionarily conserved and fully understood. We suggest that the emergence of this regulatory complexity was preceded by a stage of cooperation between more ancient morphogenetic programs or their individual elements. Footprints of these programs may be present in modern animals to execute non-canonical Hox functions. Non-canonical functions of Hox genes are involved in maintaining terminal nerve cell specificity, autophagy, oogenesis, pre-gastrulation embryogenesis, vertical signaling, and a number of general biological processes. These functions are realized by the basic properties of homeodomain protein and could have triggered the evolution of ParaHoxozoa and Nephrozoa subsequently. Some of these non-canonical Hox functions are discussed in our review.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"89 6","pages":"987 - 1001"},"PeriodicalIF":2.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S0006297924060014.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}