Archives of biochemistry and biophysics最新文献

{"title":"Insights into CdTe quantum dots induced hepatotoxicity: Regulation of cytochromes P450 isoenzymes function in liver microsomes from in vivo and in vitro studies","authors":"Jiayi Li ,&nbsp;Ao Li ,&nbsp;Kui Luo ,&nbsp;Hong Yang ,&nbsp;Shuqin Jiang ,&nbsp;Peili Huang","doi":"10.1016/j.abb.2025.110369","DOIUrl":"10.1016/j.abb.2025.110369","url":null,"abstract":"<div><div>The widespread use of QDs raises health and environmental concerns, and the ROS induced oxidative stress is reported as the main mechanism of QDs toxicity. Cytochrome P450 (CYP450) superfamily, the primary enzyme system for metabolizing external compounds in the liver, also generates reactive oxygen species (ROS), making it crucial for detoxification and ROS production. Therefore, we investigated whether QDs could cause liver tissue damage by affecting the activity of CYP450 isoenzymes (CYP1A2, CYP2E1, CYP2D2, and CYP3A1) in liver microsomes, thereby altering ROS generation. This mechanism has not been previously reported. Our experiments indicate that CdTe QDs exhibit a dose/time-dependent relationship with the enzymatic activities of CYP1A2 and CYP2E1, which are closely related to ROS generation. However, an inconsistency was observed between the data for CYP2E1 activity in vivo and in vitro due to the complexity of in vivo regulatory factors. More importantly, in vitro experiments have shown that CdTe QDs can significantly promote the enzymatic activity of CYP1A2. Therefore, we speculate that CdTe QDs may induce ROS generation by enhancing CYP450 enzyme activities. In addition, molecular docking experiments were conducted to illustrate the impact of CdTe QDs on the structure of CYP1A2, leading to functional change (i.e., enzyme activity). These findings suggest a novel mechanism by which CdTe QDs regulate CYP450 activities in liver microsomes, particularly CYP1A2. This may represent a crucial pathway through which CdTe QDs induce excessive ROS generation, leading to oxidative stress and liver damage.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110369"},"PeriodicalIF":3.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells.","authors":"Yuqi Wang, Hao Wu, Xun Hu","doi":"10.1016/j.abb.2025.110367","DOIUrl":"https://doi.org/10.1016/j.abb.2025.110367","url":null,"abstract":"<p><strong>Background: </strong>The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.</p><p><strong>Results: </strong>In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2%, 24.0%, and 5.7%, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6%), conversion from serine (45.1%), and other sources (9.4%). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7%) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3%) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100%), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation substantially mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.</p><p><strong>Conclusions: </strong>By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.</p>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":" ","pages":"110367"},"PeriodicalIF":3.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Protein Disulfide Isomerase in Mediating Sulfasalazine-Induced Ferroptosis in HT22 Cells: The PDI-NOS-NO-ROS/Lipid-ROS Cascade.","authors":"Yufei Wu, Bao Ting Zhu","doi":"10.1016/j.abb.2025.110366","DOIUrl":"https://doi.org/10.1016/j.abb.2025.110366","url":null,"abstract":"<p><p>Ferroptosis is a form of regulated cell death resulting from excessive lipid peroxidation. Sulfasalazine (SAS), an anti-inflammatory drug, can induce ferroptosis through inhibiting the system Xc^- and triggering glutathione depletion. SAS has attracted considerable interest in recent years because of its potential for repurposing as an anticancer agent. Our recent studies have shown that protein disulfide isomerase (PDI) is an upstream mediator of chemically-induced ferroptosis through catalyzing the dimerization of nitric oxide synthase (NOS) and NO accumulation in cultured HT22 hippocampal neuronal cells. The present study aims to investigate SAS-induced ferroptotic cell death in HT22 cells with a focus on determining the role of PDI in mediating SAS-induced ferroptosis. We find that SAS induces ferroptotic cell death in HT22 cells, which is accompanied by a time-dependent sequential increase in the accumulation of cellular NO, ROS and lipid-ROS. We find that treatment of HT22 cells with SAS activates PDI-mediated iNOS activation (dimerization) and NO accumulation. In addition, SAS also strongly upregulates iNOS protein levels in HT22 cells. PDI knockdown or pharmacological inhibition of PDI's activity each suppresses SAS-induced iNOS dimerization, which is associated with abrogation of SAS-induced accumulation of NO, ROS and lipid-ROS, and a strong protection against ferroptotic cell death. On the other hand, PDI activation through the use of a TrxR1 inhibitor can strongly sensitize cells to SAS-induced ferroptosis. Together, these experimental observations demonstrate a crucial role of PDI in SAS-induced ferroptosis in a cell culture model through the activation of the PDI → NOS → NO → ROS/lipid-ROS pathway. Insights gained from this study also provide effective strategies to selectively sensitizing human cancer cells to SAS-induced ferroptosis, such as through the use of NO-releasing agents or TrxR1 inhibitors.</p>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":" ","pages":"110366"},"PeriodicalIF":3.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential activity of chicken amniotic fluid in epidermal development by promoting keratinocyte differentiation","authors":"Tokuji Tsuji ,&nbsp;Ryo Onogawa ,&nbsp;Hideki Tatsukawa ,&nbsp;Atsushi Murai ,&nbsp;Kiyotaka Hitomi","doi":"10.1016/j.abb.2025.110365","DOIUrl":"10.1016/j.abb.2025.110365","url":null,"abstract":"<div><div>Epidermal barrier formation during fetal development, a fundamental biological process in mammals and birds, occurs in the amniotic cavity filled with amniotic fluid (AF). In keratinocytes, indispensable proteins for barrier formation are produced during differentiation, including transglutaminase 1 (TG1) and structural proteins encoded by a gene cluster, epidermal differentiation complex. In general, the chicken fetus rapidly forms a robust epidermal barrier during a relatively short embryonic day (ED); however, little is known about how chicken AF (cAF) contributes to the controls of gene expression of the factors involved in epidermal development. Here, we first demonstrated that the cross-linking activity of TG1 gradually increased, followed by the development of barrier function until ED18 in the chicken fetal epidermis. Then, we revealed that cAF harvested at specific fetal stages had the ability to enhance the expression and activity of TG1, and to facilitate the expression of genes for the other epidermal transglutaminases, structural proteins, and differentiation-related transcription factors in human cultured keratinocytes. Furthermore, the thermal denaturation of cAF components reduced cAF efficacy in promoting the expression of those factors. The fractionated proteinaceous solution of cAF possessed the activity to induce the protein expression of barrier formation-related factors, such as the transcription factor zinc finger protein 750. These results indicated that proteinaceous molecules in cAF have the potential to activate the gene expression networks involved in epidermal barrier formation. This finding will provide novel insights into the physiological role of AF in fetal epidermal development.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110365"},"PeriodicalIF":3.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin and eugenol restore autophagic flux and alleviate oxidative, inflammatory, and fibrotic perturbations in an arginine-induced chronic pancreatitis rat model.","authors":"Amal Ahmed Abd El-Fattah, Nermin Abdel Hamid Sadik, Ahmad Mustafa Shahin, Nancy Nabil Shahin","doi":"10.1016/j.abb.2025.110357","DOIUrl":"https://doi.org/10.1016/j.abb.2025.110357","url":null,"abstract":"<p><p>Chronic pancreatitis (CP), a progressive inflammatory disease characterized by pancreatic tissue destruction and fibrosis, is considered a challenging health burden due to insufficiencies of current management procedures. Autophagy impairment has emerged as a major triggering event in pancreatitis, raising interest in exploring the potential of targeting autophagy as a possible interventional strategy. This study aimed to evaluate the possible ameliorative effect of two autophagy modulators, simvastatin and eugenol, on CP-related perturbations in an arginine-induced rat model. Repeated L-arginine administration (5 g/kg divided into 2 doses with a 1 hr interval, given intraperitoneally every 3^rd day for a total of 10 times) provoked CP features, demonstrated by acinar damage, oxidative stress, inflammation, and fibrosis. Arginine-triggered pancreatitis was accompanied by hampered pancreatic autophagic flux, evidenced by overexpression of pancreatic p62 and LC3-Ⅱ and downregulation of pancreatic AMPK and LAMP-1 mRNA expression. Treatment with simvastatin (20 mg/kg, intraperitoneally 24 hr, before each arginine dose) and eugenol (50 mg/kg/day orally for 30 days) achieved significant anti-oxidative, anti-inflammatory, and anti-fibrotic effects, and reversed the arginine-instigated autophagic blockade, with superior ameliorative effects attained by eugenol. Altogether, simvastatin and eugenol provide a promising interventional approach for CP, at least partly, by restoring the impaired autophagic flux associated with CP.</p>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":" ","pages":"110357"},"PeriodicalIF":3.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the therapeutic potential of Diosgenin as a Semaphorin-4D antagonist against neurodegenerative disorders","authors":"Ayushi Gupta ,&nbsp;Princy Choudhary ,&nbsp;Sneha Ranjan ,&nbsp;Sangeeta Singh","doi":"10.1016/j.abb.2025.110356","DOIUrl":"10.1016/j.abb.2025.110356","url":null,"abstract":"<div><div>Neurodegenerative disorders represent a significant health challenge for the population, with their mechanisms of action being poorly understood. The development of inhibitory pharmaceuticals has encountered several obstacles, resulting in therapies that lacks the necessary efficacy. Neurodegenerative disorders are marked by a gradual deterioration of neurons, leading to a decline in various functions directed by central nervous system (CNS) including motor and non-motor symptoms. Recent focus has turned towards targeting Sema4D as a potential target for mitigating neuroinflammation and inhibiting demyelination, prevalent in various neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, etc. But despite the efforts the treatment options developed poses a major hindrance in terms of side effects. An effective answer to this is Ayurvedic phytochemicals. Phytochemicals of the Piperaceae family have been known to reverse the adversities caused by neurodegeneration. In pursuit of effective interventions, this study has conducted <em>In-silico</em> and <em>In-vitro</em> studies to evaluate the efficacy of <em>Piper nigrum</em> and <em>Piper betle</em> bioactive phytochemicals as antagonists against Sema4D. Among these, Diosgenin has emerged with notable promise, demonstrating a remarkable binding affinity of −8.84 kcal/mol with Sema4D. Molecular dynamics simulations (RMSF, RMSD, PCA, SASA, FEL, etc.) have further underscored its stability, exhibiting a consistent complex structure over 100 ns. In addition to its favourable binding properties, Diosgenin has exhibited compelling effects <em>In-vitro</em>. It's not only enhanced cellular viability and proliferation but also exerts protective effects against oxidative stress-induced injury in PC12 cells. These findings suggest Diosgenin's potential as a therapeutic agent against Sema4D, offering a promising avenue in the battle against neurodegenerative diseases. However, further studies are required to elucidate its precise molecular mechanisms, assess its bioavailability and toxicity in vivo, and validate its therapeutic efficacy in animal models and clinical settings.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110356"},"PeriodicalIF":3.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidation of α-hydroxy acids by D-2-hydroxyglutarate dehydrogenase enzymes","authors":"Joanna Afokai Quaye ,&nbsp;Bilkis Mehrin Moni ,&nbsp;Jessica Eyram Kugblenu ,&nbsp;Giovanni Gadda","doi":"10.1016/j.abb.2025.110355","DOIUrl":"10.1016/j.abb.2025.110355","url":null,"abstract":"<div><div>α-Hydroxy acids are naturally occurring organic molecules with various medical and industrial applications. However, some α-hydroxy acids, like D-2-hydroxyglutarate (D2HG), have been implicated in cancers and neurometabolic disorders such as D2HG aciduria. Several studies on the D2HG oxidizing enzyme D-2-hydroxyglutarate dehydrogenase (D2HGDH) from various eukaryotic and prokaryotic sources focus on the use and application of the enzyme as biosensors for detecting D2HG. A recent gene knockout study on the bacterial D2HGDH homologs from <em>Pseudomonas stutzeri</em> and <em>Pseudomonas aeruginosa</em> identified the D2HGDH to be essential for bacterial survival by driving <span>l</span>-serine biosynthesis. Thus, D2HGDH is a good candidate for a therapeutic target against the multidrug-resistant <em>P</em>. <em>aeruginosa</em>. However, there is no consensus on the D2HGDH catalytic mechanism, and several D2HGDH homologs have not been characterized in their structural properties, which are two crucial features for therapeutic design. <em>P. aeruginosa</em> D2HGDH, the most extensively studied D2HGDH homolog, is emerging as a paradigm for D2HGDH and flavoproteins with metal ions in their active site. In this review, we have explored the structures of all published D2HGDH homologs from 12 species using AlphaFold 3 and highlighted the fully conserved structure and active site topologies of all D2HGDH homologs. Additionally, evolutionary and functional studies coupled with analyses of enzymatic activities reveal that prokaryotic and eukaryotic D2HGDH homologs, diverging from two distinct ancestors, may have differentially evolved to specialize in their α-hydroxy acid catalysis. Additionally, this review identifies all D2HGDH homologs as metal and FAD-dependent enzymes that employ a metal-triggered FAD reduction in their catalysis. Elucidation of the D2HGDH mechanism will allow designing antibiotics that target these enzymes as potential therapeutics against pathogenic bacteria like <em>P. aeruginosa</em> in addition to the application of D2HGDH homologs as biosensors.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110355"},"PeriodicalIF":3.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dynamic modulators attenuate iron overload-mediated cardiac toxicity via decreased mitochondrial fission, mitophagy/autophagy, and apoptosis in iron-overloaded rats","authors":"Sirinart Kumfu ,&nbsp;Jirapas Sripetchwandee ,&nbsp;Chanisa Thonusin ,&nbsp;Chayodom Maneechote ,&nbsp;Busarin Arunsak ,&nbsp;Titikorn Chunchai ,&nbsp;Aphisek Kongkaew ,&nbsp;Siriporn C. Chattipakorn ,&nbsp;Nipon Chattipakorn","doi":"10.1016/j.abb.2025.110354","DOIUrl":"10.1016/j.abb.2025.110354","url":null,"abstract":"<div><div>One of the leading causes of death for individuals with iron overload is iron overload cardiomyopathy (IOC). Iron overload causes cardiac mitochondrial dysfunction, which ultimately results in heart failure and death. The potential mechanism of iron overload-induced mitochondrial dysfunction involves the disequilibrium between cardiac mitochondrial fission and fusion. Nevertheless, the information regarding cardiac mitochondrial dynamics under iron overload conditions remains limited. The roles of mitochondrial dynamics were identified in IOC. To induce iron overload, male Wistar rats were injected with iron dextran for four weeks. Then, while continuing iron dextran injection, four groups of iron-overloaded rats were given injections of either vehicle, mitochondrial fusion promoter (M1), mitochondrial division inhibitor 1 (Mdivi-1), or iron chelator deferoxamine (DFO) for two weeks. In the non-iron loaded (control) group, rats received vehicles without iron dextran injection. Cardiac function, mitochondrial function, mitochondrial dynamics, mitophagy/autophagy, and apoptosis were assessed at the end of treatment. The increased expression of mitochondrial fission-, mitophagy/autophagy-, and apoptosis-related proteins were correlated with impaired mitochondrial and cardiac functions in iron-overloaded rats. Interestingly, both mitochondrial dynamics modulators reduced cardiac mitochondrial fission, mitophagy/autophagy, and apoptosis, as well as restored cardiac function to be comparable to those treated with iron chelator DFO. Our findings indicated that the imbalance of mitochondrial dynamics is a potential mechanism responsible for cardiomyocyte death induced by IOC, and this could be a novel target for interventions for IOC via either the promotion of mitochondrial fusion or the inhibition of mitochondrial fission.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"767 ","pages":"Article 110354"},"PeriodicalIF":3.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phylogenetic and structural analysis of Hydra ADAR","authors":"Xander E. Wilcox ,&nbsp;Howard Zhang ,&nbsp;Jasmine L. Mah ,&nbsp;Jack F. Cazet ,&nbsp;Sukanya Mozumder ,&nbsp;Srinidhi Venkatesh ,&nbsp;Celina E. Juliano ,&nbsp;Peter A. Beal ,&nbsp;Andrew J. Fisher","doi":"10.1016/j.abb.2025.110353","DOIUrl":"10.1016/j.abb.2025.110353","url":null,"abstract":"<div><div>Adenosine deaminases acting on RNAs (ADARs) perform adenosine-to-inosine (A-to-I) RNA editing for essential biological functions. While studies of editing sites in diverse animals have revealed unique biological roles of ADAR editing including temperature adaptation and reproductive maturation, rigorous biochemical and structural studies of these ADARs are lacking. Here, we present a phylogenetic sequence analysis and AlphaFold computational structure prediction to reveal that medusozoan ADAR2s contain five dsRNA binding domains (dsRBDs) with several RNA binding residues in the dsRBDs and deaminase domain conserved. Additionally, we identified evolutionary divergence between the medusozoan (e.g. <em>Hydra</em>) and anthozoan cnidarian subphyla. The anthozoan ADAR deaminase domains more closely resemble human ADARs with longer 5′ RNA binding loops, glutamate base-flipping residues, and a conserved TWDG dimerization motif. Conversely, medusozoan ADAR deaminase domains have short 5’ binding loops, glutamine flipping residues, and non-conserved helix dimerization motif. We also report the direct detection of A-to-I RNA editing by an ADAR ortholog from the freshwater cnidarian <em>Hydra vulgaris</em> (hyADAR). We solved the crystal structure of the monomeric deaminase domain of hyADAR (hyADARd) to 2.0 Å resolution, showing conserved active site architecture and the presence of a buried inositol hexakisphosphate known to be required for ADAR activity. In addition, these data demonstrate that medusozoans have evolved novel ADAR structural features, however the physiological consequence of this remains unknown. In addition, these results provide a framework for biochemically and structurally characterizing ADARs from evolutionarily distant organisms to understand the diverse roles of ADAR editing amongst metazoans.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"767 ","pages":"Article 110353"},"PeriodicalIF":3.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterodimeric vipoxin and its individual monomeric subunits display a dynamic structure-function relationship on RPE cells","authors":"Yulia Petsevа,&nbsp;Kirilka Mladenova,&nbsp;Maria Ganeva,&nbsp;Venelina Radeva,&nbsp;Pavel Videv,&nbsp;Jordan Doumanov,&nbsp;Svetla Petrova","doi":"10.1016/j.abb.2025.110351","DOIUrl":"10.1016/j.abb.2025.110351","url":null,"abstract":"<div><div>Known as some of the most toxic venom components, snake venom Phospholipases A₂ (<em>sv</em>PLA₂) impress with their great arsenal of activities, based on catalytic specificity and a variety of non-catalytic “pharmacological” effects using complex molecular mechanisms that can affect different tissues and organs.</div><div>Here, we aim to reveal the role of the intricate interactions between the monomeric subunits of the heterodimeric neurotoxic complex vipoxin in order to perform multiple differentiated and regulated biological activities in RPE cells. Vipoxin, isolated from the venom of <em>Vipera ammodytes</em> ssp. <em>meridionalis</em>, is composed of a basic and toxic secreted PLA₂ enzyme subunit (GIIA sPLA₂, <em>v</em>ipoxin <em>b</em>asic <em>c</em>omponent, VBC) and an acidic, enzymatically inactive and non-toxic subunit (<em>v</em>ipoxin <em>a</em>cidic <em>c</em>omponent, VAC).</div><div>We established that vipoxin and its separated monomeric subunits affect integrity and viability of the cells of two RPE lines using a combination of catalytic and non-catalyticmechanisms. Individual monomeric subunits VBC and VAC induce cytotoxicity, cytoskeletal rearrangements, affect transepithelial resistance and cell monolayer integrity, trigger apoptosis, p38 MAPK signaling pathway and genotoxicity, provoking very elaborate cellular response in both cell lines. VBC uses its catalytic and pharmacological activities more pronounced in RPE-1 than in ARPE-19 cell line, triggering DNA double-strand damage as well as a higher degree of cytotoxicity (up to 45 %) in a concentration-dependent manner. In contrast, the non-catalyticVAC exhibited insignificant effect on the membrane integrity of both RPE cell lines but induced very high degree of DNA damage in ARPE-19 cells. Heterodimeric vipoxin displaced its complex and dynamic biological efficiency in both cell lines. In general, all the investigated activities of vipoxin and its individual monomeric subunits proved our assumption for the existence of complex dynamic conformational and structural interactions between the subunits providing an immediate selection of the enzymatic or “pharmacological” mode of action, strongly dependent on RPE cell membrane composition and their microenvironment.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"768 ","pages":"Article 110351"},"PeriodicalIF":3.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}