Biochimica et biophysica acta. General subjects最新文献_第5页

Copper transporter 1 contributes to the progression of cholangiocarcinoma 铜转运蛋白1参与胆管癌的进展。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-02 DOI: 10.1016/j.bbagen.2025.130876

Yanpeng Ma , Longlong Liu , Jiayue Duan , Xiaojian Wang

Background

Cholangiocarcinoma (CCA) is characterized by poor prognosis and a lack of effective biomarkers and therapeutic targets. Although copper dysregulation has been implicated in CCA, the role of the copper transporter SLC31A1 (CTR1) in its progression remains poorly understood.

Methods

The mRNA and protein levels of SLC31A1 in tumor and adjacent non-tumor tissues was evaluated by RT-PCR and enzyme-linked immunosorbent assay, respectively. Tissue copper concentrations were determined using a colorimetric complexation assay. Correlations between SLC31A1 expression, copper accumulation, and clinicopathological parameters were evaluated using Pearson's analysis. Cell proliferation and colony formation were assessed by the cell counting kit 8 and colony formation assays, respectively. Mitochondrial function was assessed by measuring intracellular ATP levels, reactive oxygen species (ROS) production, and the glutathione redox ratio.

Results

Elevated SLC31A1 expression was significantly associated with microvascular invasion, larger tumor size (≥5 cm), and advanced AJCC stage (III–IV). Both SLC31A1 mRNA and protein levels were significantly upregulated in CCA tissues compared with adjacent non-tumor tissues and correlated with copper accumulation. In vitro, SLC31A1 was highly expressed across multiple CCA cell lines. Silencing SLC31A1 in RBE cells impaired cell proliferation and colony formation. Mechanistically, depletion of SLC31A1 increased intracellular ROS, reduced the GSH/GSSG ratio, and decreased ATP production, indicating disruption of mitochondrial function and redox homeostasis.

Conclusions

SLC31A1 promotes cholangiocarcinoma progression by maintaining copper homeostasis, mitochondrial integrity, and redox balance. These findings suggest that SLC31A1 may serve as a potential prognostic biomarker and a candidate therapeutic target.

背景：胆管癌（CCA）的特点是预后差，缺乏有效的生物标志物和治疗靶点。尽管铜的失调与CCA有关，但铜转运体SLC31A1 （CTR1）在其进展中的作用仍然知之甚少。方法：分别采用RT-PCR和酶联免疫吸附法检测肿瘤组织和癌旁非肿瘤组织中SLC31A1 mRNA和蛋白水平。用比色络合法测定组织铜浓度。使用Pearson分析评估SLC31A1表达、铜积累和临床病理参数之间的相关性。分别用细胞计数试剂盒8和菌落形成试验评估细胞增殖和菌落形成。通过测量细胞内ATP水平、活性氧（ROS）产生和谷胱甘肽氧化还原比来评估线粒体功能。结果：SLC31A1表达升高与微血管侵犯、较大肿瘤大小（≥5 cm）、晚期AJCC （III-IV）相关。与邻近非肿瘤组织相比，CCA组织中SLC31A1 mRNA和蛋白水平均显著上调，并与铜积累相关。在体外，SLC31A1在多个CCA细胞系中高表达。在RBE细胞中沉默SLC31A1会损害细胞增殖和集落形成。从机制上讲，SLC31A1的缺失增加了细胞内ROS，降低了GSH/GSSG比率，减少了ATP的产生，表明线粒体功能和氧化还原稳态受到破坏。结论：SLC31A1通过维持铜稳态、线粒体完整性和氧化还原平衡来促进胆管癌的进展。这些发现表明，SLC31A1可能作为潜在的预后生物标志物和候选治疗靶点。

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引用次数: 0

Structural characterization of a L-dehydroascorbic acid–L-homocysteine thiolactone reaction product: Intracellular formation in neuronal cells l -脱氢抗坏血酸- l -同型半胱氨酸硫内酯反应产物的结构表征：神经元细胞内形成

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-05 DOI: 10.1016/j.bbagen.2025.130882

Ghizlane Loubane , Gabriel Robert , Syed Benazir Firdaus , Raphaël Robidas , Christian Comeau , Pierre-Luc Boudreault , Jeampy E. Komba , Hugo Gagnon , J Richard Wagner , Stephen Naylor , Klaus Klarskov

Homocysteine thiolactone (HTL) has been implicated in cardiovascular and neurological pathologies. While homocysteine can S-homocysteinylate thiol groups in proteins, the chemical properties of HTL facilitates covalent binding to protein ε-amino groups on lysine residues, which can initiate protein aggregation. Ascorbate plays an important role in the prevention of oxidative stress. Ascorbate is easily oxidized by the loss of two electrons to dehydroascorbate (DHA), which can be reduced back to ascorbate by thiol-containing smaller and larger molecules. In the present study, reaction products between two aldehydes, formaldehyde and propionaldehyde as well as DHA with the physiological relevant isomer of homocysteine thiolactone i.e. L-HTL were purified, and their structure was determined by 1D and 2D-nuclear magnetic resonance. In all three cases the reaction products are likely formed by initial imine condensation, subsequent formation of a hemiaminal product followed by HTL ring opening and intramolecular nucleophilic attack of the resulting thiol anion to form a six-member thiazinane ring with a carboxylic acid group. The structure of the DHA, L-HTL reaction product was confirmed by high resolution accurate ESIMS/MS in negative mode. Formation of the reaction product between DHA and HTL prevented N-homocysteinylation of cytochrome c by HTL, confirming earlier observations. The reaction product is formed in human neuroblastoma cells (SH-SY5Y) when exposed to HTL and DHA or ascorbate, potentially preventing protein aggregation. The consequences associated with formation of a reaction product between DHA and HTL suggest that DHA could protect against protein N-homocysteinylation.

同型半胱氨酸硫内酯（HTL）与心血管和神经系统疾病有关。同型半胱氨酸可以使蛋白质中的巯基s -同型半胱氨酸化，而HTL的化学性质有助于与赖氨酸残基上的蛋白质ε-氨基共价结合，从而引发蛋白质聚集。抗坏血酸在预防氧化应激中起着重要作用。抗坏血酸很容易因失去两个电子而氧化为脱氢抗坏血酸（DHA），后者可以通过含有较小和较大硫醇的分子还原为抗坏血酸。本研究纯化了甲醛与丙醛两种醛以及DHA与同型半胱氨酸硫内酯生理相关异构体L-HTL的反应产物，并通过1D和2d核磁共振测定了它们的结构。在所有三种情况下，反应产物可能是由最初的亚胺缩合形成，随后形成半胺产物，然后是HTL环打开和产生的硫醇阴离子的分子内亲核攻击，形成具有羧基的六元噻嗪环。采用高精度ESIMS/MS负模式对反应产物DHA、L-HTL的结构进行了确证。DHA和HTL之间的反应产物的形成阻止了HTL对细胞色素c的n -同型半胱氨酸化，证实了早期的观察。当暴露于HTL和DHA或抗坏血酸时，反应产物在人神经母细胞瘤细胞（SH-SY5Y）中形成，可能阻止蛋白质聚集。DHA和HTL之间形成反应产物的结果表明，DHA可以防止蛋白质n -同型半胱氨酸化。

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引用次数: 0

Nanobody-based imaging: Advancing precision in molecular diagnostics 基于纳米体的成像：提高分子诊断的精度。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-08 DOI: 10.1016/j.bbagen.2025.130884

Zohre Eftekhari, Fatemeh Kazemi-Lomedasht

Molecular imaging is a cornerstone of modern medicine, enabling non-invasive visualization of biological processes at the molecular level. The emergence of nanobodies (Nbs), small single-domain antibody fragments derived from camelids, has transformed this field due to their superior tissue penetration, rapid clearance, and high target specificity compared to conventional antibodies. This review focuses on the integration of Nbs with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) two complementary molecular imaging modalities known for their high sensitivity, quantitative potential, and clinical relevance. Nb-based PET and SPECT imaging probes are emerging as powerful tools for detecting disease-associated molecular targets with exceptional precision. Their unique properties, including high affinity, specificity, and stability, make them ideal candidates for developing advanced radiotracers that enable early disease detection, monitoring of therapeutic responses, and evaluation of novel treatment strategies. Despite these advantages, several challenges remain, such as scalable Nb production, reduction of immunogenicity in clinical applications, and optimization of radiolabeling methods that preserve Nb integrity and function. This review highlights recent advances in Nb engineering, radiolabeling strategies, and preclinical and clinical applications of Nb-based PET and SPECT imaging, while outlining critical directions for future research. By addressing current limitations, Nb-based molecular imaging holds great promise for improving diagnostic accuracy, advancing personalized medicine, and expanding its clinical impact across diverse disease areas.

分子成像是现代医学的基石，能够在分子水平上对生物过程进行无创可视化。纳米体（Nbs）的出现，源自骆驼的小单域抗体片段，由于其与传统抗体相比具有优越的组织穿透性，快速清除和高靶向特异性，已经改变了这一领域。这篇综述的重点是Nbs与正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）的整合，这两种互补的分子成像方式以其高灵敏度、定量潜力和临床相关性而闻名。基于nb的PET和SPECT成像探针正在成为检测疾病相关分子靶标的强大工具，具有极高的精度。它们独特的特性，包括高亲和力、特异性和稳定性，使它们成为开发先进放射性示踪剂的理想候选者，可以用于早期疾病检测、监测治疗反应和评估新的治疗策略。尽管有这些优势，但仍存在一些挑战，例如可扩展的铌生产，临床应用中免疫原性的降低，以及保持铌完整性和功能的放射性标记方法的优化。本文综述了铌工程、放射性标记策略以及基于铌的PET和SPECT成像的临床前和临床应用方面的最新进展，同时概述了未来研究的关键方向。通过解决当前的局限性，基于nb的分子成像在提高诊断准确性、推进个性化医疗和扩大其在不同疾病领域的临床影响方面具有很大的前景。

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引用次数: 0

Selection and evaluation of new sites for splitting beta-lactamase to modulate auto-complementation enzyme activity β -内酰胺酶分裂调节自互补酶活性新位点的选择与评价

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-10-24 DOI: 10.1016/j.bbagen.2025.130867

Morgan C. Marsh , Shawn C. Owen

Split protein systems, including split fluorescent proteins and split enzymes, have predominantly been applied to monitor protein-protein interactions but have recently gained popularity as components in induced complementation diagnostic platforms. Many of these systems are limited by self-affinity which limits the dynamics or causes a false-positive high background signal. To overcome these challenges, it is necessary to either modify the interacting residues of established split fragments or by exploring new split-sites. Using the computational modeling tool SPELL to identify stable candidates, we developed five unique split sites for TEM-1 β-lactamase to compare structure and activity versus the original split site. We monitored structural changes through MMS IR spectroscopy as well as functional activity of each split enzyme. Expected structural changes of each fragment and changes in self-affinity driven complementation were observed. By utilizing specific binding proteins attached to the split enzyme, we monitored enzyme activity with forced complementation when bound to the target compared to auto-complementation when the enzymes were auto-complexed in solution. Of the five new split sites, one maintained high binding-mediated complementation activity with significant reduction in background auto-complementation. Changing the split site is a relatively simple approach to reduce background activity while maintaining on-target activity. The ability to tune split-systems has the potential to enable more sensitive and complex studies that previously were limited by the high background from self-affinity.

分裂蛋白系统，包括分裂荧光蛋白和分裂酶，主要用于监测蛋白质-蛋白质相互作用，但最近作为诱导互补诊断平台的组成部分越来越受欢迎。这些系统中的许多都受到自亲和性的限制，这限制了动态或导致假阳性高背景信号。为了克服这些挑战，有必要修改已建立的分裂片段的相互作用残基或通过探索新的分裂位点。使用计算建模工具SPELL来确定稳定的候选者，我们为TEM-1 β-内酰胺酶开发了五个独特的分裂位点，以比较其结构和活性与原始分裂位点的差异。我们通过MMS - IR光谱检测了各分裂酶的结构变化和功能活性。观察了每个片段的预期结构变化和自亲和互补的变化。通过利用附着在分裂酶上的特异性结合蛋白，我们监测了酶与靶标结合时的强制互补与酶在溶液中自动络合时的自动互补的活性。在五个新的分裂位点中，一个位点保持高结合介导的互补活性，背景自动互补显著降低。更改拆分站点是一种相对简单的方法，可以在保持目标活动的同时减少后台活动。调整分裂系统的能力有可能使更敏感和复杂的研究成为可能，而这些研究以前受到自亲和性高背景的限制。

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引用次数: 0

Rationally designed peptide induces apoptosis and cell cycle modulation in resistant melanoma 合理设计多肽诱导耐药黑色素瘤细胞凋亡和细胞周期调节。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-02 DOI: 10.1016/j.bbagen.2025.130877

Layza Sá Rocha , Ana Cristina Jacobowski , Eduarda Thiburcio , Rafael Araujo Pereira , Claudiane Vilharroel Almeida , Camila De Oliveira Gutierrez , Thaís de Andrade Farias Rodrigues , Rodrigo Juliano Oliveira , Gabriel B. Taveira , Priscila Aiko Hiane , Ana Paula de Araújo Boleti , Octávio Luiz Franco , Marlon Henrique Cardoso , Maria Ligia Rodrigues Macedo

The ineffectiveness of conventional therapies against melanoma necessitates the development of novel approaches characterized by high selectivity and low systemic toxicity. Using computational optimization, KW18, a synthetic α-helical peptide, was rationally engineered. It incorporates conserved bioactive motifs from patented peptides. The Joker algorithm was used to refine the peptide. This process enhanced its positive charge, hydrophobicity, and α-helical stability. In vitro, KW18 displayed potent cytotoxicity against melanoma cells (IC₅₀ = 11.41–21.75 μM) with 84–91 % inhibition at 128 μM, minimal toxicity to FN1 fibroblasts, hemolysis below 5 %, and stability exceeding 80 %. Functional assays revealed mitochondrial damage and caspase-dependent apoptosis (86.5 % late apoptosis at 24 h). Cell cycle analysis in B16F10-Nex2 cells revealed a moderate accumulation in G0/G1 phase (62.9 %) alongside a substantial S-phase population (25.8 %), with minimal Sub-G0 (5.2 %) and reduced G2/M (6.1 %). This profile suggests a cytostatic-like effect through partial cell cycle slowdown. Structural characterization via helical wheel projections and circular dichroism confirmed its α-helical conformation, consistent with membrane-targeting activity. In vivo, Galleria mellonella larvae exposed to KW18 exhibited 100 % survival, supporting a favorable safety profile. Collectively, KW18 combines apoptosis induction with cell cycle modulation, offering a dual mechanism against melanoma while sparing healthy cells. These findings designate KW18 as a stable, selective, and safe therapeutic option for drug-resistant melanoma and a beneficial element for combined treatments.

传统治疗方法对黑色素瘤无效，需要开发具有高选择性和低全身毒性的新方法。通过计算优化，对合成α-螺旋肽KW18进行了合理的工程化设计。它结合了来自专利肽的保守的生物活性基序。使用Joker算法对肽进行细化。该工艺增强了其正电荷性、疏水性和α-螺旋稳定性。在体外，KW18对黑色素瘤细胞（IC₅₀ = 11.41-21.75 μM）显示出强大的细胞毒性，在128 μM处抑制84-91 %，对FN1成纤维细胞的毒性最小，溶血率低于5 %，稳定性超过80 %。功能分析显示线粒体损伤和caspase依赖性凋亡（24 h时86.5 %晚期凋亡）。B16F10-Nex2细胞的细胞周期分析显示，在G0/G1期（62.9 %）和大量s期群体（25.8 %）中有适度的积累，亚G0期（5.2 %）最小，G2/M降低（6.1 %）。这表明细胞静态样效应通过部分细胞周期减慢。通过螺旋轮投影和圆二色性的结构表征证实了其α-螺旋构象，与膜靶向活性一致。在体内，暴露于KW18的mellongalleria幼虫的存活率为100% %，支持良好的安全性。总的来说，KW18结合了细胞凋亡诱导和细胞周期调节，在保护健康细胞的同时提供了抗黑色素瘤的双重机制。这些发现表明KW18是一种稳定、选择性和安全的耐药黑色素瘤治疗选择，也是联合治疗的有益元素。

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引用次数: 0

The CEBPA/FDX1 axis elevates sensitivity to cuproptosis in lung adenocarcinoma cells CEBPA/FDX1轴提高肺腺癌细胞对铜增生的敏感性。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-10-22 DOI: 10.1016/j.bbagen.2025.130872

Yongsheng Zhao , Renyan Zheng , Kexin Luo , Haiyang Zhao , Wanping Xiang

Background

The recent introduction of “cuproptosis” into the oncological lexicon has opened up new horizons for cancer therapy, yet our understanding of how this process operates in lung adenocarcinoma (LUAD) is still limited. In this work we have investigated the core genetic factors and provided theoretical support for the application of cuproptosis in the treatment of LUAD. Through bioinformatics analysis, we found that FDX1 was significantly downregulated in LUAD and highly correlated with cuproptosis markers. Therefore, we chose FDX1 as the research object.

Methods

Biochemical and bioinformatic analyses were assessed FDX1 and CEBPA expression in LUAD. The binding relationship between CEBPA and FDX1 was validated via CHIP and dual-luciferase assays. FDX1 expression in LUAD cells was evaluated by qRT-PCR and Western blot. The impact of FDX1 overexpression on LUAD progression was examined using CCK-8 and Transwell assays. Experiments involving CCK-8, copper ion measurement, cuproptosis-related protein detection, and DLAT immunofluorescence confirmed the successful LUAD cuproptosis model.

Results

FDX1 was downregulated in LUAD tissues and cells, and its overexpression inhibited LUAD cell migration, invasion, and proliferation. Cuproptosis significantly reduced LUAD cell viability and the protein levels of Lipoy-DLAT, DLAT, and FDX1, while increasing HSP70 expression, DLAT aggregation, and intracellular copper ion levels. CEBPA, a transcriptional activator of FDX1, positively correlated with and bound to it. Overexpressed FDX1 enhanced cuproptosis in LUAD cells, an effect partially reversible by CEBPA suppression.

Conclusion

These analyses were performed to construct a proposed cellular model of cuproptosis in LUAD.

背景：近年来，“铜增生”一词被引入肿瘤学词典，为癌症治疗开辟了新的视野，但我们对肺腺癌（LUAD）中这一过程如何运作的理解仍然有限。本研究探讨了其核心遗传因素，为其在LUAD治疗中的应用提供了理论支持。通过生物信息学分析，我们发现FDX1在LUAD中显著下调，并与cuprotosis标志物高度相关。因此，我们选择FDX1作为研究对象。方法：采用生化和生物信息学方法检测LUAD中FDX1和CEBPA的表达。通过CHIP和双荧光素酶实验验证了CEBPA与FDX1的结合关系。采用qRT-PCR和Western blot检测FDX1在LUAD细胞中的表达。使用CCK-8和Transwell检测FDX1过表达对LUAD进展的影响。通过CCK-8、铜离子测定、铜裂相关蛋白检测和DLAT免疫荧光等实验证实了LUAD铜裂模型的成功建立。结果：FDX1在LUAD组织和细胞中表达下调，其过表达抑制LUAD细胞迁移、侵袭和增殖。cuprotosis显著降低LUAD细胞活力和Lipoy-DLAT、DLAT和FDX1蛋白水平，同时增加HSP70表达、DLAT聚集和细胞内铜离子水平。CEBPA是FDX1的转录激活因子，与FDX1正相关并结合。过表达的FDX1增强LUAD细胞中的铜突起，这一作用通过抑制CEBPA部分可逆。结论：通过这些分析，我们建立了LUAD铜体畸形的细胞模型。

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引用次数: 0

Screening of biomarkers in autoimmune thyroid diseases (AITDs): preliminary study based on Raman spectroscopy and MALDI-ToF mass spectrometry 自身免疫性甲状腺疾病（AITDs）生物标志物的筛选：基于拉曼光谱和MALDI-ToF质谱的初步研究

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-05 DOI: 10.1016/j.bbagen.2025.130883

Sara Trzos , Sylwia Orzechowska , Paweł Link-Lenczowski , Grzegorz Sokołowski , Malgorzata Baranska , Ewa Pocheć

Hashimoto's thyroiditis (HT) and Graves' disease (GD), autoimmune thyroid diseases (AITDs), are among the most commonly reported autoimmune disorders. Early and unambiguous diagnosis and monitoring of the disease development are crucial to obtain the most effective treatment results. Matrix-assisted laser desorption/ionization with a time-of-flight analyzer mass spectrometry (MALDI-ToF MS) and Raman spectroscopy are promising analytical methods in this regard. These non-invasive and sensitive techniques provide information on specific features of proteins, including their post-translational modifications and the level of a wide range of biomolecules in the bloodstream, which are useful for assessing the health status of patients. This study screened for potential biomarkers in AITDs using both methods. Sera from HT patients at two stages of disease progression and GD patients before and after normalization of thyrotropic hormone following immunosuppressive treatment were used in the study. Serum biomolecule changes were analyzed using Raman spectroscopy. N-glycans released from serum glycoproteins were detected by MALDI-ToF mass spectrometry. We observed that the levels of phenylalanine, carotenoids, and phospholipids in HT sera correlate with increased inflammation accompanying this disease. The GD group showed a lower amount of serum collagen compared to the HT patients. Quantitative comparison of N-glycans revealed several differences between the study groups and healthy donors. The higher galactosylation and α2,6-sialylation of serum proteins in HT2 relative to GD patients are the main differences in N-glycan profiles of AITDs. The obtained preliminary results demonstrate that these analytical techniques have potential in diagnosing and monitoring AITDs, and can be a good alternative to the currently used methods. Analysis of a larger number of samples, as well as a more detailed MS methodology for precise decoding of glycan structures, is necessary for further research.

桥本甲状腺炎（HT）和格雷夫斯病（GD），自身免疫性甲状腺疾病（AITDs），是最常报道的自身免疫性疾病。早期和明确的诊断和监测疾病发展是至关重要的，以获得最有效的治疗结果。基质辅助激光解吸/电离与飞行时间分析仪质谱（MALDI-ToF MS）和拉曼光谱是这方面有前途的分析方法。这些非侵入性和敏感的技术提供了蛋白质的特定特征信息，包括它们的翻译后修饰和血液中各种生物分子的水平，这对评估患者的健康状况很有用。本研究使用这两种方法筛选AITDs的潜在生物标志物。本研究采用HT患者两期病程和GD患者经免疫抑制治疗后促甲状腺激素恢复正常前后的血清。用拉曼光谱分析血清生物分子变化。采用MALDI-ToF质谱法检测血清糖蛋白释放的n -聚糖。我们观察到HT血清中苯丙氨酸、类胡萝卜素和磷脂的水平与此病伴随的炎症增加相关。GD组血清胶原蛋白含量低于HT组。n -聚糖的定量比较揭示了研究组与健康供者之间的一些差异。与GD患者相比，HT2患者血清蛋白的半乳糖基化和α2,6-唾液基化水平较高是AITDs n -聚糖谱的主要差异。初步结果表明，这些分析技术在诊断和监测AITDs方面具有一定的潜力，可以作为现有方法的一个很好的替代方案。进一步的研究需要分析大量的样品，以及更详细的质谱方法来精确解码多糖结构。

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引用次数: 0

Hyperglycemia accelerated the metastasis of triple-negative breast cancer via promoting TNFα/Gli-1 axis in endothelial cells 高血糖通过促进内皮细胞中TNFα/ gli1轴的表达加速三阴性乳腺癌的转移。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.bbagen.2025.130875

Xiyu Mei , Chuang Ke , Ziyun Gao , Fan Yang , Zhenlin Huang , Bin Lu , Lili Ji

Diabetes mellitus (DM) is associated with a poor prognosis of aggressive breast cancer. Vascular dysfunction is commonly found during the development of both cancer and diabetes. We previously reported that the disruption of vascular endothelial phenotype induced by tumor necrosis factor-α (TNFα) accelerated the trans-endothelial metastasis of triple-negative breast cancer (TNBC). Herein, we explored the role of vascular endothelial cells in diabetes-induced TNBC metastasis. Both type 2 DM (T2DM) and type 1 DM (T1DM) enhanced the metastasis of TNBC in vivo. T2DM increased the expression of endothelial phenotype vascular endothelial cadherin (VE-cadherin), platelet-endothelial cell adhesion molecule (PECAM-1/CD31), and mesenchymal markers including vimentin and fibroblast specific protein-1 (FSP-1/S100A4) in tumor vessels. T1DM increased the expression of vimentin and FSP-1, but suppressed the expression of VE-cadherin in tumor vessels. Hyperglycemia elevated the production of TNFα in vivo and in vitro. TNFα reduced the trans-endothelial electrical resistance (TEER) value of both human mammary microvascular endothelial cells (HMMECs) and human umbilical vein endothelial cells (HUVECs). Expressions of vimentin and α-smooth muscle actin (α-SMA) were also increased in TNFα-treated both HMMECs and HUVECs. The number of trans-endothelial migrated MDA-MB-231 cells through TNFα-treated HMMECs or HUVECs monolayer was elevated. Moreover, glioma-associated oncogene 1 (Gli-1) was remarkably accumulated in the nucleus of TNFα-stimulated HMMECs and DM-induced tumor vessels. Both Gli-1 siRNA and GANT61 (an inhibitor of Gli-1) could abrogate the increased TNBC trans-endothelial migration through TNFα-treated ECs. We demonstrated that DM might promote TNBC metastasis via activating the TNFα/Gli-1 axis initiated vascular endothelial mesenchymal-like phenotype.

糖尿病（DM）与侵袭性乳腺癌预后不良相关。血管功能障碍在癌症和糖尿病的发展过程中都很常见。我们之前报道过肿瘤坏死因子-α (tnf -α)诱导的血管内皮表型破坏加速了三阴性乳腺癌（TNBC）的跨内皮转移。在此，我们探讨了血管内皮细胞在糖尿病诱导的TNBC转移中的作用。2型糖尿病（T2DM）和1型糖尿病（T1DM）均可促进TNBC在体内的转移。T2DM增加了内皮型血管内皮钙粘蛋白（VE-cadherin）、血小板-内皮细胞粘附分子（PECAM-1/CD31）以及血管entin和成纤维细胞特异性蛋白-1 （FSP-1/S100A4）等间充质标志物在肿瘤血管中的表达。T1DM增加了vimentin和FSP-1的表达，抑制了VE-cadherin在肿瘤血管中的表达。在体内和体外，高血糖升高了TNFα的产生。TNFα降低了人乳腺微血管内皮细胞（hmmes）和人脐静脉内皮细胞（HUVECs）的跨内皮电阻（TEER）值。在tnf α处理的hmmes和huvec中，波形蛋白和α-平滑肌肌动蛋白（α-SMA）的表达也增加。通过tnf α处理的hmmec或huvec单层，跨内皮迁移的MDA-MB-231细胞数量增加。此外，胶质瘤相关癌基因1 （gli1）在tnf α刺激的hmmec和dm诱导的肿瘤血管的细胞核中显著积累。gli1 siRNA和GANT61（一种gli1抑制剂）都可以通过tnf α处理的内皮细胞消除TNBC跨内皮迁移的增加。我们证明了糖尿病可能通过激活TNFα/ gli1轴启动的血管内皮间充质样表型来促进TNBC转移。

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引用次数: 0

m1A methylation-mediated upregulation of RILsPL1 promotes colorectal cancer progression via the CaMKII/CREB signaling pathway m1A甲基化介导的RILsPL1上调通过CaMKII/CREB信号通路促进结直肠癌的进展。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-12-01 Epub Date: 2025-09-05 DOI: 10.1016/j.bbagen.2025.130856

Songbo Yang , Xianghuai Long , Wuliang Diao , Jiaxing Yang , Anyuan Jiang , Hongfei Wu

Colorectal cancer (CRC) remains one of the most lethal malignancies globally, driven by complex molecular mechanisms that contribute to its progression and metastasis. This study focuses on the role of N1-methyladenosine (m¹A) RNA methylation in CRC, particularly its effect on Rab Interacting Lysosomal Protein-Like 1 (RILPL1) expression and the downstream activation of the CaMKII/CREB signaling pathway. Bioinformatics analysis identified RILPL1 as a key gene associated with poor CRC prognosis, exhibiting increased expression levels in cancerous tissues, with further elevation in metastatic samples. Functional assays demonstrated that m¹A methylation enhances the stability of RILPL1 mRNA, a process dynamically regulated by the opposing actions of the demethylase ALKBH1 and the methyltransferase TRMT6. Loss-of-function and gain-of-function studies showed that RILPL1 promotes CRC cell viability, invasion, and migration, highlighting its oncogenic role. In vivo, RILPL1 knockdown markedly suppressed tumor growth in a nude mouse xenograft model. Furthermore, the CaMKII/CREB signaling pathway was identified as a critical mediator, with RILPL1 expression levels directly correlating with the phosphorylation of CaMKII and CREB both in vitro and in vivo xenograft models. Pharmacological rescue experiments confirmed this dependency, as a CaMKII activator reversed the effects of RILPL1 knockdown, while a specific inhibitor blocked this rescue. These findings suggest that dynamic m¹A methylation-driven upregulation of RILPL1 contributes to CRC progression through the activation of the CaMKII/CREB signaling pathway, offering potential therapeutic targets for CRC treatment.

结直肠癌（CRC）仍然是全球最致命的恶性肿瘤之一，由复杂的分子机制驱动，有助于其进展和转移。本研究的重点是n1 -甲基腺苷（m1A） RNA甲基化在结直肠癌中的作用，特别是其对Rab相互作用溶酶体蛋白样1 （RILPL1）表达和CaMKII/CREB信号通路下游激活的影响。生物信息学分析发现RILPL1是与CRC预后不良相关的关键基因，在癌组织中表达水平升高，在转移样本中进一步升高。功能分析表明，m1A甲基化增强了RILPL1 mRNA的稳定性，这一过程由去甲基化酶ALKBH1和甲基转移酶TRMT6的相反作用动态调节。功能丧失和功能获得的研究表明，RILPL1促进CRC细胞活力、侵袭和迁移，突出了其致癌作用。在体内，RILPL1敲低可显著抑制裸鼠异种移植瘤模型中的肿瘤生长。此外，CaMKII/CREB信号通路被确定为一个关键的介质，在体外和体内异种移植模型中，RILPL1的表达水平与CaMKII和CREB的磷酸化直接相关。药理学拯救实验证实了这种依赖性，因为CaMKII激活剂逆转了RILPL1敲低的作用，而一种特定的抑制剂阻断了这种拯救。这些发现表明，m1A甲基化驱动的RILPL1的动态上调通过激活CaMKII/CREB信号通路有助于CRC的进展，为CRC治疗提供了潜在的治疗靶点。

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引用次数: 0

Seasonal and COVID-19 lockdown variations in PM2.5 composition to apoptosis pathways and chemical toxicity in lung cells PM2.5成分对肺细胞凋亡途径和化学毒性的季节性和COVID-19封锁变化。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-12-01 Epub Date: 2025-10-04 DOI: 10.1016/j.bbagen.2025.130864

Ting-Hsuan Wu , Yu-Cheng Chen , Hong-Lin Chan , Hsiu-Chuan Chou

Objective

To investigate seasonal and COVID-19-lockdown variations in PM2.5 chemical composition in Taipei and the effects of those compositional differences on lung cell toxicity.

Methods

PM2.5 was collected in warm (2021/07–2021/08) and cold (2021/11–2022/02) seasons and during LV2/LV3 COVID-19 alert periods. Composition (metals, PAHs) was analyzed and A549 and PC9 lung cells were exposed to equal mass concentrations (0–100 μg/mL) of extracted PM2.5. Cell viability, ROS, apoptosis, mitochondrial membrane potential and GSH/GPX4 were measured.

Results

At equivalent mass concentrations (50 μg/mL), warm-season PM2.5 induced higher ROS and greater reduction in viability than cold-season PM2.5. LV2-period PM2.5 contained higher metal content and caused more severe cellular damage than LV3. Spearman correlation plus single-compound assays identified cadmium and Dibenzo[a,e]pyrene as components strongly associated with cytotoxicity.

Conclusions

Seasonal and human-activity driven compositional changes—rather than mass concentration alone—affect PM2.5 toxicity in vitro; these results underscore the importance of controlling specific chemical emissions.

目的：探讨台北市PM2.5化学成分的季节性变化及其对肺细胞毒性的影响。方法：在温暖季节（2021/07-2021/08）和寒冷季节（2021/11-2022/02）以及LV2/LV3 COVID-19预警期采集PM2.5。分析其组成（金属、多环芳烃），并将A549和PC9肺细胞暴露于等质量浓度（0-100 μg/mL）的提取PM2.5中。测定细胞活力、ROS、凋亡、线粒体膜电位和GSH/GPX4。结果：在同等质量浓度（50 μg/mL）下，暖季PM2.5比冷季PM2.5诱导更高的ROS和更大的活力降低。与LV3相比，lv2期PM2.5的金属含量更高，造成的细胞损伤更严重。Spearman相关性加单化合物测定鉴定出镉和二苯并[a，e]芘是与细胞毒性密切相关的成分。结论：季节性和人类活动驱动的成分变化，而不是质量浓度单独影响PM2.5的体外毒性；这些结果强调了控制特定化学物质排放的重要性。

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引用次数: 0