Archives of biochemistry and biophysics最新文献

{"title":"Exploring the structure and nucleic acid interactions of the Leishmania sp. telomerase reverse transcriptase N-terminal region","authors":"Stephany C. Paiva ,&nbsp;Guilherme Henrique Marchi Salvador ,&nbsp;Patrick S. Barbosa ,&nbsp;Hamine Cristina de Oliveira ,&nbsp;Carlos Alexandre H. Fernandes ,&nbsp;Carlos H.I. Ramos ,&nbsp;Marcos Roberto de M. Fontes ,&nbsp;Maria Isabel N. Cano","doi":"10.1016/j.abb.2025.110289","DOIUrl":"10.1016/j.abb.2025.110289","url":null,"abstract":"<div><div>Leishmaniasis is a neglected tropical disease caused by protozoans of the <em>Leishmania</em> genus, against which no effective treatment or control is available. Like other eukaryotes, parasite telomeres are maintained by telomerase, a ribonucleoprotein complex vital for genome stability. Its protein component, TERT (telomerase reverse transcriptase), presents four structural and functional domains, with the TEN (Telomerase N-terminal) and TRBD (Telomerase RNA-binding) located at its N-terminal. The enzyme also contains an RNA component that carries the template copied by the TERT during telomere elongation<strong>.</strong> Here, we show that the tertiary structure of <em>Leishmania major</em> TERT (LmTERT) is conserved compared to other eukaryotes. However, the LmTERT N-terminal (LmTERT-NT) portion shows structural changes not detected in the entire protein, mainly in the TEN domain. Besides the disordered elements, the TEN gains two long β-sheets but preserves the GQ motif and the residues in β-sheet 5 that interact with the TRAP motif. In both structures, a linker flanks the TEN and TRBD. The TRBD is partially conserved in both structures and contains the canonical QFP and T motifs, invariant residues, and the putative CP and two trypanosomatid-specific motifs (TSM) besides genus-specific amino acid substitutions. Despite the structural changes, the recombinant LmTERT-NT preserves a hydrophobic cavity that binds specifically and in the picomolar range to the telomeric G-rich DNA and the TER 5′ end region. Thus, LmTERT-NT shares the canonical structural domains and motifs and is biochemically active. We discuss the importance of the TERT N-terminal region in the parasite's telomerase catalysis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110289"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943263","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":"Structural and functional snapshots of a broad-specificity endoglucanase from Thermogutta terrifontis for biomass saccharification","authors":"Naveed Hussain ,&nbsp;Halina Mikolajek ,&nbsp;Peter J. Harrison ,&nbsp;Neil Paterson ,&nbsp;Muhammad W. Akhtar ,&nbsp;Saima Sadaf ,&nbsp;James H. Naismith","doi":"10.1016/j.abb.2024.110274","DOIUrl":"10.1016/j.abb.2024.110274","url":null,"abstract":"<div><div>Multifunctionality, processivity, and thermostability are critical for the cost-effective enzymatic saccharification of non-food plant biomass polymers such as β-glucans, celluloses, and xylans to generate biofuels and other valuable products. We present molecular insights into a processive multifunctional endo-1,3-1,4-β-<span>d</span>-glucanase (Tt_End5A) from the hyperthermophilic bacterium <em>Thermogutta terrifontis</em>. Tt_End5A demonstrated activities against a broad spectrum of β-polysaccharides, including barley glucan, lichenan, carboxymethyl cellulose, regenerated amorphous cellulose (RAC), Avicel, xylan, laminarin, mannan, curdlan, xanthan, and various chromogenic substrates at pH 7 and temperatures ranging from 70 to 80°C. The enzyme exhibited a high level of processivity on RAC and retained over 90% activity at 80°C for an extended period, indicating exceptional thermal stability. The 1.20 Å crystal structure of the Tt_End5A catalytic domain revealed an archetypal glycoside hydrolase family 5 (GH5) catalytic TIM-(β/α)₈-barrel, supplemented with additional β-strands, elongated α-helices, and a rare <em>cis</em>-non-Pro (His481-<em>cis</em>-Ala482) peptide. A large central cleft was observed in the 3D structure, which is likely related to the enzyme's multifunctionality and processivity. The catalytic domain is preceded by a novel N-terminal multivalent carbohydrate-binding module (CBM) that enhances the enzymatic degradation of insoluble polysaccharides. Mutagenesis studies, ligand interaction analyses, and the structurally conserved positions of E329 and E448 in Tt_End5A suggest that these residues function as the proton donor and nucleophile in the catalytic mechanism. Owing to its multifunctionality and processivity, Tt_End5A can reduce the need for multiple saccharification enzymes to generate fermentable sugars from plant biomass for bioethanol production. Additionally, it holds promise for applications in the pharmaceutical, feed, and food industries.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110274"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862911","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":"Light regulation of flavin reduction by NAD(P)H: Activation of 2-haloacrylate hydratase","authors":"Karina Kizjakina ,&nbsp;Yumin Dai ,&nbsp;Pablo Sobrado","doi":"10.1016/j.abb.2024.110285","DOIUrl":"10.1016/j.abb.2024.110285","url":null,"abstract":"<div><div>We report a novel light-dependent activation mechanism for 2-haloacrylate hydratase (2HAH), a flavin-dependent dehalogenase. Initial assays revealed inconsistent enzyme activity, stabilized only after chemical reduction or exposure to bright light. Spectroscopic analysis showed that light accelerates flavin reduction by NAD(P)H, completing in 30 s under bright light versus slow reduction in the dark. Blue light specifically triggered full activation, while red light had no effect. Sequence and structural analyses indicate that 2HAH does not share homology with known light-sensitive flavoproteins, suggesting an uncharacterized regulatory mechanism. These findings advance our understanding of flavin enzyme regulation and introduce light as a potential tool for modulating 2HAH activity.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110285"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920681","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":"Modulating vascular smooth muscle cell phenotype via Wnt-Independent FRZB pathways","authors":"Hyomin Kim ,&nbsp;Eun Kyoung Kim ,&nbsp;Yeuni Yu ,&nbsp;Hye Jin Heo ,&nbsp;Dokyoung Kim ,&nbsp;Su-Yeon Cho ,&nbsp;Yujin Kwon ,&nbsp;Won Kyu Kim ,&nbsp;Kihun Kim ,&nbsp;Dai Sik Ko ,&nbsp;Yun Hak Kim","doi":"10.1016/j.abb.2025.110290","DOIUrl":"10.1016/j.abb.2025.110290","url":null,"abstract":"<div><h3>Background and aims</h3><div>Vascular smooth muscle cells are pivotal in atherosclerosis, transitioning from a contractile to a synthetic phenotype, which is associated with increased proliferation and inflammation. FRZB, a Wnt signaling modulator, has been implicated in vascular pathology, but its specific role in vascular smooth muscle cell phenotype modulation is not well understood. This study investigates the role of FRZB in regulating vascular smooth muscle cell phenotypes.</div></div><div><h3>Methods</h3><div>Vascular smooth muscle cell regions were categorized based on FRZB expression levels, and various analyses, including differential gene expression, KEGG pathway analysis, and Disease Ontology analysis, were conducted. FRZB knockdown in human aortic vascular smooth muscle cell was performed using siRNA, followed by assessments of cell migration, proliferation, and phenotype marker expression.</div></div><div><h3>Results</h3><div>FRZB expression was significantly reduced in synthetic type compared to contractile type in both mouse models and human samples. FRZB knockdown in human vascular smooth muscle cells led to increased cell migration and proliferation, alongside decreased expression of contractile markers and increased synthetic markers. Unexpectedly, FRZB knockdown suppressed Wnt signaling. Pathway analysis revealed associations with the PI3K-Akt signaling pathway, focal adhesion, and ECM interactions.</div></div><div><h3>Conclusions</h3><div>Our study highlights FRZB's role in Vascular smooth muscle cell phenotype modulation, showing that reduced FRZB expression correlates with a synthetic phenotype and increased disease markers. FRZB does not enhance Wnt signaling but may regulate vascular smooth muscle cell behavior through alternative pathways. These findings suggest FRZB as a potential therapeutic target for stabilizing vascular smooth muscle cells and managing atherosclerosis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110290"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942658","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 CaMKIIα cysteines inhibits autonomous activation induced by phosphorylation","authors":"Nathália Rocco-Machado ,&nbsp;Max Deng ,&nbsp;Yi He ,&nbsp;Rodney L. Levine","doi":"10.1016/j.abb.2024.110268","DOIUrl":"10.1016/j.abb.2024.110268","url":null,"abstract":"<div><div>Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) “autonomous” activation induced by Thr286 phosphorylation has a crucial role in synaptic plasticity. Previous studies showed that in Alzheimer's disease brain, CaMKIIα autophosphorylation at Thr286 is reduced while the level of cysteine-oxidized CAMKIIα is elevated. We performed tryptic mapping of the oxidized CaMKIIα and discovered the formation of a disulfide between the N-terminal Cys6 and the regulatory domain Cys280. The apparent pK_a values of Cys6 and Cys280 are 7.1 and 7.7, respectively, lower than the 8.5 for free Cys. The low apparent pK_a of Cys6 facilitates the oxidation of its thiol to the sulfenic acid at physiological pH. The thiolate of Cys280 can then attack the sulfenic acid to form a disulfide. Using an antibody against phosphorylated Thr286, we showed that disulfide formation prevents Thr286 phosphorylation. CaMKIIα autonomous activation induced by disulfide formation is much lower than the autonomous activation induced by phosphorylation. The decreased autonomous activation may contribute to the synaptic impairment of Alzheimer's disease. We also generated a CaMKIIα mutant in which Cys6 was mutated to Ser6. This mutation prevented disulfide formation and restored autonomous activation induced by phosphorylation. Our findings provide insight into the mechanistic details of CaMKIIα autonomous activation induced by disulfide formation that may contribute to the impairment of long-term potentiation in Alzheimer's disease.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110268"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823945","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":"Tools to investigate oxygen-related challenges with flavin-dependent enzymes","authors":"Ariadna Pié Porta,&nbsp;Elif Erdem,&nbsp;John M. Woodley","doi":"10.1016/j.abb.2024.110246","DOIUrl":"10.1016/j.abb.2024.110246","url":null,"abstract":"<div><div>Enzymes have multiple applications in medicine but during the past decades interest in the application of enzymes as (bio)catalysts to produce a wide range of valuable molecules in various industries has increased. Many chemical compounds (from pharmaceuticals to bulk commodities) can be produced by a series of enzymatically-catalysed chemical steps, and in many cases one of these steps is an oxidation.</div><div>The use of molecular oxygen as an oxidising agent in biocatalytic processes is a double-edged approach. From one side, the oxygen is supplied to the reactor in the form of air bubbling, which is cheap, highly available and non-toxic. From the other side, bubbling air into the reaction media creates a gas-liquid interface which adsorbs enzymes and compromises their stability. Moreover, the oxygen is quite insoluble in water, which often results in oxygen-limited reactions.</div><div>These aspects are the main limiting factors for the stability and kinetics of enzymes that perform oxidative biocatalysis and prevent the reaction from happening at a rate that is high/competitive enough for industrial feasibility. Therefore, we need systems to mimic and understand better these factors to try and mitigate their effects upon scale-up.</div><div>In this review, we present two complementary systems to study these factors: one apparatus that ensures a constant gas-liquid interface and another one that maintains a constant oxygen partial pressure. Both can provide highly valuable information regarding the maximum rate of reaction and about the deactivation profiles of enzymes in the presence of bubbles.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110246"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765727","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":"MXene-encapsulated ZIF-8@Liposomes for NIR-enhanced photothermal therapy in hepatocellular carcinoma treatment: In vitro, in vivo, and in silico study","authors":"Shehab Elbeltagi ,&nbsp;Nawal Madkhali ,&nbsp;Hanan M. Alharbi ,&nbsp;Zienab E. Eldin","doi":"10.1016/j.abb.2024.110256","DOIUrl":"10.1016/j.abb.2024.110256","url":null,"abstract":"<div><div>Photothermal therapy (PTT) utilizes near-infrared (NIR) light to enhance localized, non-invasive cancer treatments and drug delivery systems (DDS). Combination chemotherapy with PTT (chemo-PTT) offers multiple therapeutic advantages, involving synergistic effects, reduced side effects, and decreased drug toxicity. In this study, 2D titanium carbide (Ti₃C₂T_x) MXene nanosheets were encapsulated in a zeolitic imidazolate framework-8 (ZIF-8) to form (MX-ZIF-8) nanoparticles (NPs) for PTT applications. Sorafenib (SB), an anticancer drug was loaded onto MX-ZIF-8 and further modified with a liposomes (LPs) lipid bilayer to create (SB-MX-ZIF-8@LPs) nanocomposites. TEM imaging revealed that SB-MX-ZIF-8@LPs had a lamellar structure and spherical shape, with an average diameter of 75.2 nm and a zeta potential (ZP) of −8.4 ± 4.5 mV. Additionally, the PT stability, drug encapsulation, and in-vitro release kinetics of SB-MX-ZIF-8@LPs were assessed. These nanocomposites exhibited an impressive PT conversion efficiency of 55 % at 50 μg/mL under NIR irradiation. The cumulative release of SB from SB-MX-ZIF-8@LPs reached 86.15 % at pH 7.4 and 89.3 % at pH 4.8 under NIR over a period of 72 h, with an encapsulation efficiency of 87.34 %. MTT assays revealed strong cytotoxicity against HepG2 cells, with SB-MX-ZIF-8@LPs showing an IC₅₀ value of 2.7 μg/mL and inducing approximately 96 % total apoptosis. The SB-MX-ZIF-8@lip nanocomposite demonstrated excellent biological stability in a serum environment, retaining over 98 % of sorafenib and maintaining consistent particle size (∼347 nm) over 30 days. An in vivo xenograft study in BALB/c mice further demonstrated the efficacy of SB-MX-ZIF-8@LPs, with this treatment group showing the smallest tumor volume compared to other groups and a significantly higher tumor volume reduction than SB alone. Molecular docking studies indicated that SB exhibited strong binding affinities particularly with ABL1 (−8.7 kcal/mol) and EGFR (−9.3 kcal/mol). Docking interactions between MXene and SB, conducted using the Hdock Server, resulted in a docking score of −10.53, with one bond forming at a distance of 4 Å. These findings were consistent with experimental results, highlighting the favorable interaction between MXene and SB. ADMET analysis confirmed that MX-ZIF-8@LPs possessed favorable drug carrier properties, including high intestinal absorption (96.6 %), and low toxicity supporting its potential as an effective DDS for cancer therapy.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110256"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783938","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":"Cuproptosis regulation by long noncoding RNAs: Mechanistic insights and clinical implications in cancer","authors":"Nahla E. El-Ashmawy ,&nbsp;Eman G. Khedr ,&nbsp;Mariam A. Abo-Saif ,&nbsp;Sara M. Hamouda","doi":"10.1016/j.abb.2025.110324","DOIUrl":"10.1016/j.abb.2025.110324","url":null,"abstract":"<div><div>Although survival rates have been improved in recent years, the prognosis of many cancer types remains inadequate, mostly owing to treatment resistance. Moreover, there is a continued need for exploring novel and reliable tumor markers to achieve accurate diagnosis. Understanding the molecular complexity of cancer allows for the development of more effective and personalized treatments and facilitates the discovery of biomarkers that surpass traditional ones and assist in cancer diagnosis and monitoring disease progression and response to treatment. Recent studies exploring the complexity of cancer biology have identified a new form of cell death, known as cuproptosis, which is driven by the accumulation of copper and subsequent stress induced by dysregulation of copper homeostasis. Increased copper level enables cancer cells to maintain their accelerated growth rates and metastatic potential, yet these cells can evade cuproptosis. Long noncoding RNAs (lncRNAs) have been recognized for their pivotal role in different hallmarks of cancer, including resistance to cell death. They have been found to be implicated in controlling copper balance and cuproptosis. Besides, lncRNAs associated with cuproptosis pathway have demonstrated their potential as diagnostic and prognostic cancer biomarkers as well as indicators of treatment response. Our review aims to summarize recent studies focusing on the intricate relationship between lncRNAs and cuproptosis and explore the mechanisms by which lncRNAs can modulate copper homeostasis and regulate cuproptosis pathway. We also highlight recent discoveries concerning the role of cuproptosis-related lncRNAs in diagnosis, prognosis, and therapy of different types of cancer. By elucidating the significance of cuproptosis-related lncRNAs, this review provides insights into how these lncRNAs can be used to develop new therapeutic strategies to improve treatment outcomes.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110324"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143104586","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":"PROTAC-attractive site as a new target for suppressing P-glycoprotein activity","authors":"Tatyana A. Grigoreva,&nbsp;Aleksandra Sagaidak,&nbsp;Daria S. Novikova,&nbsp;Vyacheslav G. Tribulovich","doi":"10.1016/j.abb.2024.110258","DOIUrl":"10.1016/j.abb.2024.110258","url":null,"abstract":"<div><div>P-glycoprotein (P-gp) plays an important role in the rapid release of various small molecule substances from the cell. In turn, inhibition of this efflux transporter is an attractive strategy for both overcoming chemoresistance and facilitating oral absorption of drugs or CNS drug delivery. In this work, we adopt an approach typical for PROteolysis Targeting Chimera (PROTAC), which is based on the artificial drawing together of the target protein to E3 ubiquitin ligase, to P-gp. Forced ubiquitinylation of a transmembrane protein will provoke its removal from the cell membrane and promote its subsequent degradation. Within this concept, we investigated the possibility of P-gp ubiquitinylation by a number of PROTAC-specific E3 ligases using several approaches. We also identified the most promising site for the development of P-gp ligands. By screening a diversified library of compounds, we not only identified a number of scaffolds suitable for the construction of specific ligands, but also proposed dorsomorphin as a convenient platform for creating the constituent of a bifunctional chimera. We show that dorsomorphin both has the structural characteristics necessary to develop a PROTAC-like molecule and exhibits P-gp inhibitory activity. In conclusion, the proposed approach is universal and can be applied to other transmembrane proteins associated with the pathogenesis of certain diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110258"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783939","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":"The primary studies of epigallocatechin-3-gallate in improving brain injury induced by chronic high-altitude natural environment in rats by 7.0T high-field MR imaging","authors":"Chen Chen ,&nbsp;Haotian Chen ,&nbsp;Duojie Dingda ,&nbsp;Lei Wang ,&nbsp;Fabao Gao","doi":"10.1016/j.abb.2024.110224","DOIUrl":"10.1016/j.abb.2024.110224","url":null,"abstract":"<div><h3>Background</h3><div>Epigallocatechin-3-gallate (EGCG) is one of the most abundant and important bioactive polyphenolic compounds in green tea. However, despite its potent antioxidant effects, its neuroprotective effects on chronic high altitude (HA)-induced nerve damage have not been reported. The purpose of this study is to use quantitative susceptibility mapping (QSM) with pathology to dynamically evaluate the status of brain damage and the effect of EGCG.</div></div><div><h3>Methods</h3><div>A model of HA environments-induced brain injury was established of Sprague-Dawley (SD) rats in a natural plateau environment for 4 weeks, 8 weeks, 12 weeks and 20 weeks. Behavioral alterations were then observed and assessed with the open field test (OFT) and Morris water maze (MWM) test. The microglial activation, nissl staining and neural degeneration by Fluoro Jade B in the hippocampus of the rats were observed by immunohistochemistry. In the rats, serum erythropoietin (EPO), hippocampal inflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), ferritin, oxidative stress (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT] and malondialdehyde [MDA]) were detected using ELISA kits and biochemical methods. Iron accumulation was observed by QSM and colorimetry. Iron metabolisms (ceruloplasmin [Cp], transferrin [Tf], divalent metal transport1 [DMT1] and hepcidin [Hep]) were detected using qPCR. Neural ultrastructural changes were evaluated with electron microscope. Salidroside treatment was chosen as the positive control group in ELISA, biochemical detection and electron microscopy.</div></div><div><h3>Results</h3><div>The susceptibility values in the left and right hippocampus, the hippocampal ferritin, serum and hippocampal iron content increased significantly after HA exposure. The expression of hippocampal Cp and Hep decreased and the expression of Tf increased. Nissl staining revealed that the neurons of hippocampal CA1 region of h-20w group were small and irregular, atrophied, and nuclear shrinkage. Tissue oxidative stress and inflammatory indicators (MDA, TNF-α, IL-1β, IL-6) increased while antioxidant enzymes (SOD, CAT, GSH-Px) decreased. EGCG attenuated HA environments-induced cognitive impairment, iron accumulation, microglial activation and neural degeneration. The effects of EGCG in reducing EPO and the metal chelating property with respect to iron were dose-dependent, with effects of EGCG (50 mg/kg) being similar to those of salidroside (50 mg/kg).</div></div><div><h3>Conclusions</h3><div>EGCG can act as a neuroprotective agent against chronic HA environments-mediated neural injuries. QSM provides a potential complementary imaging technique to detect the effect of treating HA diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110224"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715160","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}