Pub Date : 2024-07-04DOI: 10.1134/s0006297924060051
Alla S. Dashkova, Vladimir I. Kovalev, Alina V. Chaplygina, Daria Yu. Zhdanova, Natalia V. Bobkova
Abstract
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.
{"title":"Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer’s Disease","authors":"Alla S. Dashkova, Vladimir I. Kovalev, Alina V. Chaplygina, Daria Yu. Zhdanova, Natalia V. Bobkova","doi":"10.1134/s0006297924060051","DOIUrl":"https://doi.org/10.1134/s0006297924060051","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><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":null,"pages":null},"PeriodicalIF":2.8,"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}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060087
Olga D. Novikova, Tatyana V. Rybinskaya, Elena A. Zelepuga, Vladimir N. Uversky, Nataliya Yu. Kim, Ekaterina A. Chingizova, Ekaterina S. Menchinskaya, Valentina A. Khomenko, Dmitriy K. Chistyulin, Olga Yu. Portnyagina
Abstract
The work presents results of the in vitro and in silico study of formation of amyloid-like structures under harsh denaturing conditions by non-specific OmpF porin of Yersinia pseudotuberculosis (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.
{"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, Tatyana V. Rybinskaya, Elena A. Zelepuga, Vladimir N. Uversky, Nataliya Yu. Kim, Ekaterina A. Chingizova, Ekaterina S. Menchinskaya, Valentina A. Khomenko, Dmitriy K. Chistyulin, Olga Yu. Portnyagina","doi":"10.1134/s0006297924060087","DOIUrl":"https://doi.org/10.1134/s0006297924060087","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><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":null,"pages":null},"PeriodicalIF":2.8,"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}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060075
Natalia V. Belosludtseva, Mikhail V. Dubinin, Konstantin N. Belosludtsev
Abstract
Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming β-barrel proteins that carry out controlled “filtration” of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.
{"title":"Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role","authors":"Natalia V. Belosludtseva, Mikhail V. Dubinin, Konstantin N. Belosludtsev","doi":"10.1134/s0006297924060075","DOIUrl":"https://doi.org/10.1134/s0006297924060075","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming β-barrel proteins that carry out controlled “filtration” of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550535","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}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060026
Aksinya N. Uvarova, Elena A. Tkachenko, Ekaterina M. Stasevich, Elina A. Zheremyan, Kirill V. Korneev, Dmitry V. Kuprash
Abstract
Currently, numerous associations between genetic polymorphisms and various diseases have been characterized through the Genome-Wide Association Studies. Majority of the clinically significant polymorphisms are localized in non-coding regions of the genome. While modern bioinformatic resources make it possible to predict molecular mechanisms that explain influence of the non-coding polymorphisms on gene expression, such hypotheses require experimental verification. This review discusses the methods for elucidating molecular mechanisms underlying dependence of the disease pathogenesis on specific genetic variants within the non-coding sequences. A particular focus is on the methods for identification of transcription factors with binding efficiency dependent on polymorphic variations. Despite remarkable progress in bioinformatic resources enabling prediction of the impact of polymorphisms on the disease pathogenesis, there is still the need for experimental approaches to investigate this issue.
摘要 目前,通过全基因组关联研究(Genome-Wide Association Studies),已经确定了许多基因多态性与各种疾病之间的关联。大多数具有临床意义的多态性位于基因组的非编码区。虽然现代生物信息学资源使预测非编码多态性对基因表达影响的分子机制成为可能,但这些假设需要实验验证。本综述讨论了阐明疾病发病机制依赖于非编码序列中特定基因变异的分子机制的方法。其中特别关注鉴定转录因子与多态性变异的结合效率的方法。尽管生物信息学资源在预测多态性对疾病发病机制的影响方面取得了重大进展,但仍需要通过实验方法来研究这一问题。
{"title":"Methods for Functional Characterization of Genetic Polymorphisms of Non-Coding Regulatory Regions of the Human Genome","authors":"Aksinya N. Uvarova, Elena A. Tkachenko, Ekaterina M. Stasevich, Elina A. Zheremyan, Kirill V. Korneev, Dmitry V. Kuprash","doi":"10.1134/s0006297924060026","DOIUrl":"https://doi.org/10.1134/s0006297924060026","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Currently, numerous associations between genetic polymorphisms and various diseases have been characterized through the Genome-Wide Association Studies. Majority of the clinically significant polymorphisms are localized in non-coding regions of the genome. While modern bioinformatic resources make it possible to predict molecular mechanisms that explain influence of the non-coding polymorphisms on gene expression, such hypotheses require experimental verification. This review discusses the methods for elucidating molecular mechanisms underlying dependence of the disease pathogenesis on specific genetic variants within the non-coding sequences. A particular focus is on the methods for identification of transcription factors with binding efficiency dependent on polymorphic variations. Despite remarkable progress in bioinformatic resources enabling prediction of the impact of polymorphisms on the disease pathogenesis, there is still the need for experimental approaches to investigate this issue.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550531","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}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060014
Milana A. Kulakova, Georgy P. Maslakov, Liudmila O. Poliushkevich
Abstract
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.
{"title":"Irreducible Complexity of Hox Gene: Path to the Canonical Function of the Hox Cluster","authors":"Milana A. Kulakova, Georgy P. Maslakov, Liudmila O. Poliushkevich","doi":"10.1134/s0006297924060014","DOIUrl":"https://doi.org/10.1134/s0006297924060014","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><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":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060130
Naima N. Niyazova, Irada M. Huseynova
Abstract
Water shortage induces physiological, biochemical, and molecular alterations in plant leaves that play an essential role in plant adaptive response. The effects of drought and post-drought rewatering on the activity of antioxidant enzymes and levels of H2O2, phenolic compounds, ascorbic acid, and proline were studied in six local tomato (Solanum lycopersicum L.) varieties. The contents of H2O2 and ascorbic acid increased in all drought-exposed tomato plants and then decreased upon rewatering. The level of phenolic compounds also decreased in response to water shortage and then recovered upon rehydration, although the extent of this response was different in different varieties. The activities of ascorbate peroxidase (APX) and guaiacol peroxidase (POX) and the content of proline significantly increased in the drought-stressed plants and then decreased when the plants were rewatered. The activities of 8 constitutive APX isoforms and 2 constitutive POX isoforms varied upon exposure to drought and were observed after rewatering in all studied varieties. The information on the response of tomato plants to drought and subsequent rewatering is of great importance for screening and selection of drought-tolerant varieties, as well as for development of strategies for increasing plant productivity under adverse environmental conditions.
{"title":"The Antioxidant Defense System of Tomato (Solanum lycopersicum L.) Varieties under Drought Stress and upon Post-Drought Rewatering","authors":"Naima N. Niyazova, Irada M. Huseynova","doi":"10.1134/s0006297924060130","DOIUrl":"https://doi.org/10.1134/s0006297924060130","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Water shortage induces physiological, biochemical, and molecular alterations in plant leaves that play an essential role in plant adaptive response. The effects of drought and post-drought rewatering on the activity of antioxidant enzymes and levels of H<sub>2</sub>O<sub>2</sub>, phenolic compounds, ascorbic acid, and proline were studied in six local tomato (<i>Solanum lycopersicum</i> L.) varieties. The contents of H<sub>2</sub>O<sub>2</sub> and ascorbic acid increased in all drought-exposed tomato plants and then decreased upon rewatering. The level of phenolic compounds also decreased in response to water shortage and then recovered upon rehydration, although the extent of this response was different in different varieties. The activities of ascorbate peroxidase (APX) and guaiacol peroxidase (POX) and the content of proline significantly increased in the drought-stressed plants and then decreased when the plants were rewatered. The activities of 8 constitutive APX isoforms and 2 constitutive POX isoforms varied upon exposure to drought and were observed after rewatering in all studied varieties. The information on the response of tomato plants to drought and subsequent rewatering is of great importance for screening and selection of drought-tolerant varieties, as well as for development of strategies for increasing plant productivity under adverse environmental conditions.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550442","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}
Pub Date : 2024-07-04DOI: 10.1134/s0006297924060038
Aleksei A. Popov, Irina O. Petruseva, Olga I. Lavrik
Abstract
Damages of various origin accumulated in the genomic DNA can lead to the breach of genome stability, and are considered to be one of the main factors involved in cellular senescence. DNA repair systems in mammalian cells ensure effective damage removal and repair of the genome structure, therefore, activity of these systems is expected to be correlated with high maximum lifespan observed in the long-lived mammals. This review discusses current results of the studies focused on determination of the DNA repair system activity and investigation of the properties of its key regulatory proteins in the cells of long-lived rodents and bats. Based on the works discussed in the review, it could be concluded that the long-lived rodents and bats in general demonstrate high efficiency in functioning and regulation of DNA repair systems. Nevertheless, a number of questions around the study of DNA repair in the cells of long-lived rodents and bats remain poorly understood, answers to which could open up new avenues for further research.
摘要 基因组 DNA 中积累的各种来源的损伤会导致基因组稳定性受到破坏,被认为是细胞衰老的主要因素之一。哺乳动物细胞中的 DNA 修复系统可确保有效清除损伤和修复基因组结构,因此,这些系统的活性预计与长寿哺乳动物的最长寿命相关。这篇综述讨论了目前的研究成果,这些研究的重点是确定 DNA 修复系统的活性以及调查长寿啮齿动物和蝙蝠细胞中其关键调控蛋白的特性。根据综述中讨论的工作,可以得出结论:长寿啮齿类动物和蝙蝠在 DNA 修复系统的运作和调节方面普遍表现出很高的效率。尽管如此,围绕长寿啮齿类动物和蝙蝠细胞中 DNA 修复研究的一些问题仍然鲜为人知,这些问题的答案将为进一步的研究开辟新的途径。
{"title":"Activity of DNA Repair Systems in the Cells of Long-Lived Rodents and Bats","authors":"Aleksei A. Popov, Irina O. Petruseva, Olga I. Lavrik","doi":"10.1134/s0006297924060038","DOIUrl":"https://doi.org/10.1134/s0006297924060038","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Damages of various origin accumulated in the genomic DNA can lead to the breach of genome stability, and are considered to be one of the main factors involved in cellular senescence. DNA repair systems in mammalian cells ensure effective damage removal and repair of the genome structure, therefore, activity of these systems is expected to be correlated with high maximum lifespan observed in the long-lived mammals. This review discusses current results of the studies focused on determination of the DNA repair system activity and investigation of the properties of its key regulatory proteins in the cells of long-lived rodents and bats. Based on the works discussed in the review, it could be concluded that the long-lived rodents and bats in general demonstrate high efficiency in functioning and regulation of DNA repair systems. Nevertheless, a number of questions around the study of DNA repair in the cells of long-lived rodents and bats remain poorly understood, answers to which could open up new avenues for further research.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550532","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}
Pub Date : 2024-07-01DOI: 10.1134/S0006297924070095
Oksana P Gerzen, Iulia K Potoskueva, Alena E Tzybina, Tatiana A Myachina, Larisa V Nikitina
Lead and cadmium are heavy metals widely distributed in the environment and contribute significantly to cardiovascular morbidity and mortality. Using Leadmium Green dye, we have shown that lead and cadmium enter cardiomyocytes, distributing throughout the cell. Using an in vitro motility assay, we have shown that sliding velocity of actin and native thin filaments over myosin decreases with increasing concentrations of Pb2+ and Cd2+. Significantly lower concentrations of Pb2+ and Cd2+ (0.6 mM) were required to stop sliding of thin filaments over myosin compared to the stopping actin sliding over the same myosin (1.1-1.6 mM). Lower concentration of Cd2+ (1.1 mM) needed to stop actin sliding over myosin compared to the Pb2++Cd2+ combination (1.3 mM) and lead alone (1.6 mM). There were no differences found in the effects of lead and cadmium cations on relative force developed by myosin heads or number of actin filaments bound to myosin. Sliding velocity of actin over myosin in the left atrium, right and left ventricles changed equally when exposed to the same dose of the same metal. Thus, we have demonstrated for the first time that Pb2+ and Cd2+ can directly affect myosin and thin filament function, with Cd2+ exerting a more toxic influence on myosin function compared to Pb2+.
{"title":"Cardiac Myosin and Thin Filament as Targets for Lead and Cadmium Divalent Cations.","authors":"Oksana P Gerzen, Iulia K Potoskueva, Alena E Tzybina, Tatiana A Myachina, Larisa V Nikitina","doi":"10.1134/S0006297924070095","DOIUrl":"https://doi.org/10.1134/S0006297924070095","url":null,"abstract":"<p><p>Lead and cadmium are heavy metals widely distributed in the environment and contribute significantly to cardiovascular morbidity and mortality. Using Leadmium Green dye, we have shown that lead and cadmium enter cardiomyocytes, distributing throughout the cell. Using an <i>in vitro</i> motility assay, we have shown that sliding velocity of actin and native thin filaments over myosin decreases with increasing concentrations of Pb<sup>2+</sup> and Cd<sup>2+</sup>. Significantly lower concentrations of Pb<sup>2+</sup> and Cd<sup>2+</sup> (0.6 mM) were required to stop sliding of thin filaments over myosin compared to the stopping actin sliding over the same myosin (1.1-1.6 mM). Lower concentration of Cd<sup>2+</sup> (1.1 mM) needed to stop actin sliding over myosin compared to the Pb<sup>2+</sup>+Cd<sup>2+</sup> combination (1.3 mM) and lead alone (1.6 mM). There were no differences found in the effects of lead and cadmium cations on relative force developed by myosin heads or number of actin filaments bound to myosin. Sliding velocity of actin over myosin in the left atrium, right and left ventricles changed equally when exposed to the same dose of the same metal. Thus, we have demonstrated for the first time that Pb<sup>2+</sup> and Cd<sup>2+</sup> can directly affect myosin and thin filament function, with Cd<sup>2+</sup> exerting a more toxic influence on myosin function compared to Pb<sup>2+</sup>.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103089","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}
Pub Date : 2024-07-01DOI: 10.1134/S000629792407006X
Nina Kraskovskaya, Anna Koltsova, Polina Parfenova, Alla Shatrova, Natalya Yartseva, Vladimir Nazarov, Ekaterina Devyatkina, Mikhail Khotin, Natalia Mikhailova
Huntington's disease (HD) is an incurable hereditary disease caused by expansion of the CAG repeats in the HTT gene encoding the mutant huntingtin protein (mHTT). Despite numerous studies in cellular and animal models, the mechanisms underlying the biological role of mHTT and its toxicity to striatal neurons have not yet been established and no effective therapy for HD patients has been developed so far. We produced and characterized a new line of dermal fibroblasts (HDDF, Huntington's disease dermal fibroblasts) from a patient with a confirmed HD diagnosis. We also studied the growth characteristics of HDDF cells, stained them for canonical markers, karyotyped these cells, and investigated their phenotype. HDDF cells was successfully reprogrammed into induced striatal neurons via transdifferentiation. The new fibroblast line can be used as a cell model to study the biological role of mHTT and manifestations of HD pathogenesis in both fibroblasts and induced neuronal cells obtained from them by reprogramming techniques.
亨廷顿氏病(Huntington's disease,HD)是一种无法治愈的遗传性疾病,由编码突变亨廷蛋白(mHTT)的 HTT 基因中的 CAG 重复序列扩增引起。尽管在细胞和动物模型中进行了大量研究,但 mHTT 的生物学作用及其对纹状体神经元的毒性机制尚未确定,迄今为止尚未开发出针对 HD 患者的有效疗法。我们从一名确诊为 HD 的患者身上制备了一种新的真皮成纤维细胞(HDDF,亨廷顿氏病真皮成纤维细胞),并对其进行了表征。我们还研究了HDDF细胞的生长特性,对它们进行了典型标志物染色,对这些细胞进行了核型分析,并调查了它们的表型。通过转分化,我们成功地将 HDDF 细胞重编程为诱导纹状体神经元。这种新的成纤维细胞系可作为细胞模型,用于研究mHTT的生物学作用以及HD发病机制在成纤维细胞和通过重编程技术获得的诱导神经元细胞中的表现。
{"title":"Dermal Fibroblast Cell Line from a Patient with the Huntington's Disease as a Promising Model for Studying Disease Pathogenesis: Production and Characterization.","authors":"Nina Kraskovskaya, Anna Koltsova, Polina Parfenova, Alla Shatrova, Natalya Yartseva, Vladimir Nazarov, Ekaterina Devyatkina, Mikhail Khotin, Natalia Mikhailova","doi":"10.1134/S000629792407006X","DOIUrl":"https://doi.org/10.1134/S000629792407006X","url":null,"abstract":"<p><p>Huntington's disease (HD) is an incurable hereditary disease caused by expansion of the CAG repeats in the <i>HTT</i> gene encoding the mutant huntingtin protein (mHTT). Despite numerous studies in cellular and animal models, the mechanisms underlying the biological role of mHTT and its toxicity to striatal neurons have not yet been established and no effective therapy for HD patients has been developed so far. We produced and characterized a new line of dermal fibroblasts (HDDF, Huntington's disease dermal fibroblasts) from a patient with a confirmed HD diagnosis. We also studied the growth characteristics of HDDF cells, stained them for canonical markers, karyotyped these cells, and investigated their phenotype. HDDF cells was successfully reprogrammed into induced striatal neurons via transdifferentiation. The new fibroblast line can be used as a cell model to study the biological role of mHTT and manifestations of HD pathogenesis in both fibroblasts and induced neuronal cells obtained from them by reprogramming techniques.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103091","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}
Pub Date : 2024-07-01DOI: 10.1134/S0006297924070046
Sergey V Pushkarev, Evgeny M Kirilin, Vytas K Švedas, Dmitry K Nilov
Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the SN1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2'A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3'A-OH group.
{"title":"Mechanism of PARP1 Elongation Reaction Revealed by Molecular Modeling.","authors":"Sergey V Pushkarev, Evgeny M Kirilin, Vytas K Švedas, Dmitry K Nilov","doi":"10.1134/S0006297924070046","DOIUrl":"https://doi.org/10.1134/S0006297924070046","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the S<sub>N</sub>1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2'<sub>A</sub>-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3'<sub>A</sub>-OH group.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103097","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}