Biochimica et biophysica acta. General subjects最新文献

Anticancer activity of Pseudomonas fluorescens lectin (PFL) targeting high-mannose glycans on breast cancer cells 荧光假单胞菌凝集素（PFL）靶向高甘露糖聚糖对乳腺癌细胞的抗癌作用。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1016/j.bbagen.2026.130914

Yuichiro Sato , Kohei Kawabata , Chiho Murakami , Yuta Hatori , Takanori Kubo , Yuya Ohtsuki , Hiroyuki Nishi , Akira Tokumura , Kinjiro Morimoto

Aberrant glycosylation is one of the key characteristics of cancer cells. High-mannose-type N-glycans are highly expressed in various types of cancer, making them potentially important therapeutic targets. As a basis for developing new therapeutic drugs targeting high-mannose glycans, we employed Pseudomonas fluorescens lectin (PFL) that specifically binds to high-mannose glycans as a model compound, and analyzed the cellular responses of MDA-MB-231 and T47D breast cancer cell lines. In both cell types, PFL induced the internalization and degradation of cancer-associated molecules such as epidermal growth factor receptor (EGFR), integrins, and immune checkpoint ligands via autophagy, ultimately leading to apoptotic cell death. In T47D cells, changes were observed in the cellular distribution and expression levels of hormone receptors and human epidermal growth factor receptor 2 (HER2) upon treatment with PFL, suggesting a possible compensatory response. Comprehensive analysis of cellular lipids revealed that lysophospholipids were dramatically increased by PFL treatment, regardless of breast cancer cell type. These changes may reflect the dynamic reorganization of lipid membranes associated with membrane traffic and autophagy. Time-lapse experiments using a redox sensor designed to localize to the cell membrane showed that cells transitioned to an oxidized state following PFL treatment. Furthermore, inflammatory substances such as interleukin 8 (IL-8) were significantly increased in MDA-MB-231 cells but not in T47D cells. The results provide insight into the responses and resistance of breast cancer cells to glycan-targeted therapies.

异常糖基化是癌细胞的关键特征之一。高甘露糖型n -聚糖在各种类型的癌症中高度表达，使其成为潜在的重要治疗靶点。我们以特异性结合高甘露糖聚糖的荧光假单胞菌凝集素（PFL）为模型化合物，分析了MDA-MB-231和T47D乳腺癌细胞株的细胞反应，为开发靶向高甘露糖聚糖的新型治疗药物奠定了基础。在这两种细胞类型中，PFL通过自噬诱导癌症相关分子（如表皮生长因子受体（EGFR）、整合素和免疫检查点配体）的内化和降解，最终导致凋亡细胞死亡。在T47D细胞中，经PFL治疗后，观察到激素受体和人表皮生长因子受体2 （HER2）的细胞分布和表达水平发生变化，提示可能存在代偿反应。细胞脂质综合分析显示，无论乳腺癌细胞类型如何，PFL治疗后溶血磷脂均显著增加。这些变化可能反映了与膜运输和自噬相关的脂质膜的动态重组。使用定位于细胞膜的氧化还原传感器的延时实验表明，PFL处理后细胞转变为氧化状态。此外，炎症物质如白细胞介素8 （IL-8）在MDA-MB-231细胞中显著升高，而在T47D细胞中无显著升高。这些结果提供了深入了解乳腺癌细胞对聚糖靶向治疗的反应和耐药性。

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引用次数: 0

High-dose ascorbic acid prolongs the suppression of cell proliferation by enhancing intracellular oxidative stress–induced damage and inhibits invasion and adhesion in human fibrosarcoma HT-1080 cells 大剂量抗坏血酸通过增强细胞内氧化应激诱导的损伤和抑制人纤维肉瘤HT-1080细胞的侵袭和粘附，延长了对细胞增殖的抑制。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-24 DOI: 10.1016/j.bbagen.2026.130908

Yasukazu Saitoh , Yusuke Tanimura , Shun Ueda , Tomoya Furuhata , Manato Takeda , Kouichi Okawachi , Yusuke Fukukita

Pharmacological vitamin C (VC) infusion therapy has shown efficacy against various cancer types; however, there are few reports on its effects on fibrosarcoma. This study investigated the impact of high-dose ascorbic acid (AsA), the reduced form of VC, on human fibrosarcoma HT-1080 cells. High-dose AsA (2–5 mM) markedly decreased HT-1080 cell viability compared with normal fibroblasts, indicating cancer cell selectivity. In contrast, dehydroascorbic acid (DehAsA), the oxidized form of AsA, exhibited no cytotoxicity toward cancer cells. Studies using D-AsA and AsA transport inhibitors demonstrated that intracellular AsA transport was not required for cytotoxicity in HT-1080 cells. Our results showed that high-dose AsA induced extracellular H₂O₂ production and increased intracellular H₂O₂, reactive oxygen species (ROS), and Fe²⁺ levels in HT-1080 cells compared with normal fibroblasts, suggesting that strong oxidative stress triggers actin disruption, ATP depletion, DNA damage, and reduced DNA synthesis. Additionally, a 1-h AsA exposure produced a sustained inhibitory effect on cell proliferation lasting at least 72 h. Moreover, high-dose AsA inhibited HT-1080 cell invasion and adhesion, with increased intracellular ROS likely contributing to these effects. These results indicate that high-dose AsA generates extracellular H₂O₂ and subsequently induces cancer cell-specific oxidative damage due to differences in intracellular H₂O₂ and Fe²⁺ levels, which differ between normal fibroblasts and HT-1080 cells. These actions lead to cancer cell-selective toxicity and prolonged growth-suppressive effects induced by high-dose AsA.

药理维生素C （VC）输注治疗已显示出对多种类型癌症的疗效；然而，关于其对纤维肉瘤的作用的报道很少。本研究探讨了大剂量抗坏血酸（AsA）（VC的还原形式）对人纤维肉瘤HT-1080细胞的影响。与正常成纤维细胞相比，高剂量AsA（2-5 mM）显著降低HT-1080细胞活力，表明癌细胞选择性。相反，脱氢抗坏血酸（DehAsA）， AsA的氧化形式，对癌细胞没有细胞毒性。使用D-AsA和AsA转运抑制剂的研究表明，HT-1080细胞的细胞毒性不需要细胞内AsA转运。我们的研究结果表明，与正常成纤维细胞相比，高剂量AsA诱导HT-1080细胞外的H₂O₂产生，增加细胞内的H₂O₂、活性氧（ROS）和Fe2+水平，表明强氧化应激会引发肌动蛋白破坏、ATP消耗、DNA损伤和DNA合成减少。此外，1小时AsA暴露对细胞增殖产生持续抑制作用，持续至少72 小时。此外，高剂量AsA抑制HT-1080细胞的侵袭和粘附，细胞内ROS的增加可能有助于这些作用。这些结果表明，高剂量AsA产生细胞外h2o2，随后由于细胞内h2o2和Fe2+水平的差异而诱导癌细胞特异性氧化损伤，这在正常成纤维细胞和HT-1080细胞之间是不同的。这些作用导致高剂量AsA诱导的癌细胞选择性毒性和长时间的生长抑制作用。

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引用次数: 0

COX-2 downregulation via G-quadruplex structure induction in the PTGS2-promoter region by mononuclear octahedral cobalt(III) Schiff base complex [CoL3] in colorectal cancer cells 结直肠癌细胞中单核八面体钴（III）希夫碱配合物[CoL3]通过g -四重体结构诱导ptgs2启动子区COX-2下调

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-23 DOI: 10.1016/j.bbagen.2026.130909

Abdolvahab Moshtaghian , Abasalt Hosseinzadeh Colagar , Ali Khaleghian , Tahereh Zahedi

G-quadruplex structures within the promoter regions of some oncogenes diminish transcriptional activity. The suppression and downregulation of Cyclooxygenase-2 (COX-2), which is encoded by the prostaglandin-endoperoxide synthase 2 (PTGS2) gene, could control the size of colorectal cancer tumors. This study aimed to investigate the impact of a mononuclear octahedral cobalt(III) Schiff base complex [CoL₃] (L = 2-((allylimino)methyl)-6-methoxyphenol) on the G-quadruplex structures in the PTGS2 promoter region and to assess its downregulation effects in the human colorectal cancer cell line HT-29. At first, molecular docking was used to evaluate the binding of [CoL₃] to the PTGS2 promoter region. Then, the potential and stabilization of G-quadruplex formation in the PTGS2 promoter motifs were investigated using circular dichroism (CD) spectroscopy, polyacrylamide gel electrophoresis, and polymerase chain reaction (PCR) stop assays. COX-2 expression was also assessed by real-time PCR and western blot. Molecular docking analysis indicates that [CoL₃] has a potent interaction with the PTGS2 promoter region. Additionally, [CoL₃] has an intense inhibitory effect on the PTGS2-PCR stop assay. The CD measurements confirmed the conformational property of G-quadruplex DNA structures induced by [CoL₃]. Treatment of colorectal cancer cells with the [CoL₃] resulted in a modest increase in PTGS2 expression by a mean factor of 1.69 (p < 0.05). Conversely, the expression of COX-2 proteins was downregulated significantly, with a mean protein intensity of 0.47 (p < 0.001). Therefore, [CoL₃] induces G-quadruplex formation in the promoter region of PTGS2, which ultimately inhibits protein expression of COX-2. This means that [CoL₃] can be an effective agent for colorectal cancer treatment.

某些癌基因启动子区域内的g -四重结构会降低转录活性。前列腺素内过氧化物合成酶2 （PTGS2）基因所编码的环氧化酶-2 （COX-2）的抑制和下调可以控制结直肠癌肿瘤的大小。本研究旨在探讨单核八面体钴（III）希夫碱配合物[CoL3] （L = 2-((allylimino)methyl)-6-甲氧基苯酚）对PTGS2启动子区g -四重体结构的影响，并评估其在人结直肠癌细胞系HT-29中的下调作用。首先，通过分子对接来评估[CoL3]与PTGS2启动子区域的结合。然后，利用圆二色性（CD）光谱、聚丙烯酰胺凝胶电泳和聚合酶链反应（PCR）停止分析研究了PTGS2启动子基序中g -四重体形成的可能性和稳定性。real-time PCR和western blot检测COX-2的表达。分子对接分析表明，[CoL3]与PTGS2启动子区存在有效的相互作用。此外，[CoL3]对PTGS2-PCR停止试验具有强烈的抑制作用。CD测量证实了[CoL3]诱导的g -四重体DNA结构的构象性质。用[CoL3]处理结直肠癌细胞导致PTGS2表达适度增加，平均增加1.69倍（p 3），诱导PTGS2启动子区g -四重体形成，最终抑制COX-2的蛋白表达。这意味着[CoL3]可以成为治疗结直肠癌的有效药物。

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引用次数: 0

Dendrimer-based therapeutics in neurological disorders: Innovations and clinical prospects 神经系统疾病的树突基治疗：创新与临床前景。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-09 DOI: 10.1016/j.bbagen.2026.130903

Karthikeya Lalitha Siddhartha Pallem, Anjali Jain, Anurag Aswal, Smita Jain, Umesh Gupta

The incidence of brain tumors and other neurodegenerative diseases has been increasing, whereas the treatment opportunities are limited. Brain delivery of the therapeutics has been restricted because of the presence of blood-brain barrier (BBB). Only molecules of molecular weight <400 Da and lipid-soluble are able to cross the BBB making it hard for the treatment. This demands the development of effective nano-carriers that can penetrate the BBB and deliver the therapeutics more efficiently and site specifically. Dendrimers are highly branched polymers having unique structural and functional properties, emerging as the promising carriers for delivering chemotherapy and gene therapy to the central nervous system (CNS). This review comprehensively explores the development of dendrimers, mechanisms in delivering therapeutic agents to the brain across the blood-brain barrier (BBB) and the progress over past years in utilizing the dendrimers for brain delivery of therapeutics.

脑肿瘤和其他神经退行性疾病的发病率一直在增加，而治疗机会却有限。由于血脑屏障（BBB）的存在，治疗药物的脑输送受到限制。只有分子量相等的分子

引用次数: 0

Heterogeneous expression of the laminin-binding O-mannosyl glycan on α-dystroglycan in pancreatic cancer cell line MIA PaCa-2 and the correlation with cell properties 层粘连蛋白结合的o -甘露糖基聚糖在胰腺癌细胞系MIA - PaCa-2中α-失调糖的异质表达及其与细胞特性的相关性

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-16 DOI: 10.1016/j.bbagen.2026.130907

Rieko Imae , Yuuki Shichi , Satoshi Ninagawa , Toshiyuki Ishiwata , Hiroshi Manya

α-Dystroglycan (α-DG) is a central component of the dystrophin-glycoprotein complex, with the characteristic O-mannosyl glycan modification, which binds to several extracellular matrix proteins such as laminin. Disruption in the synthesis of laminin-binding glycan on α-DG is related to muscular dystrophies. In addition, loss of this glycan is frequently observed in many cancers, including pancreatic ductal adenocarcinoma (PDAC), correlating with poor prognosis. However, the significance of this glycan in the pathology of cancer remains unclear. This study aimed to clarify the biological significance of laminin-binding O-mannosyl glycan on α-DG in PDAC cells. Since a tumor-derived cancer cell line consists of cells with diverse characteristics, we first obtained several single-cell-derived clones using MIA PaCa-2, a commonly used undifferentiated PDAC cell line, and found that the laminin-binding glycan modification level on α-DG differs among the various clones. The glycan modification level correlated well with the mRNA expression level of LARGE1, the enzyme that synthesizes the laminin-binding structure on the glycan. We analyzed several PDAC cell properties, such as cellular morphology, proliferation and migration/invasion abilities, and examined their correlation with the glycan modification. We found that a high level of laminin-binding O-mannosyl glycan modification on α-DG correlated with the elongated cell morphology, high invasion ability, and low membrane blebbing activity, and vice versa. Furthermore, manipulation of the laminin-binding O-mannosyl glycan synthesis confirmed that this glycan partially contributed to these properties. Overall, this study provides valuable insights into the roles of the laminin-binding glycan on α-DG in PDAC.

α-肌营养不良聚糖（α-DG）是肌营养不良蛋白-糖蛋白复合物的核心成分，具有o -甘露糖基聚糖修饰的特征，可与几种细胞外基质蛋白结合，如层粘连蛋白。破坏α-DG上层粘连蛋白结合聚糖的合成与肌营养不良有关。此外，在包括胰腺导管腺癌（PDAC）在内的许多癌症中经常观察到这种聚糖的缺失，这与预后不良有关。然而，这种聚糖在癌症病理中的意义尚不清楚。本研究旨在阐明层粘连蛋白结合的o -甘露糖基聚糖对PDAC细胞α-DG的生物学意义。由于肿瘤来源的癌细胞系由具有多种特征的细胞组成，我们首先使用MIA PaCa-2（一种常用的未分化PDAC细胞系）获得了几个单细胞来源的克隆，发现不同克隆间层粘连蛋白结合聚糖对α-DG的修饰水平不同。多糖修饰水平与LARGE1的mRNA表达水平密切相关，LARGE1是合成多糖上层粘连蛋白结合结构的酶。我们分析了PDAC细胞的几种特性，如细胞形态、增殖和迁移/入侵能力，并研究了它们与聚糖修饰的相关性。我们发现，α-DG上高水平的层粘连蛋白结合的o -甘露糖聚糖修饰与细胞的细长形态、高侵袭能力和低膜泡活性相关，反之亦然。此外，操纵层粘连蛋白结合的o -甘露糖基聚糖的合成证实了这种聚糖部分地促进了这些特性。总的来说，本研究为层粘胶蛋白结合聚糖在PDAC中对α-DG的作用提供了有价值的见解。

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引用次数: 0

Rapid in vivo loss of non-T-cell binding capacities of ATLG Grafalon® and ATG Thymoglobulin® explains selective effect on T-cell reconstitution after hematopoietic stem cell transplantation ATLG Grafalon®和ATG Thymoglobulin®体内非t细胞结合能力的快速丧失解释了造血干细胞移植后t细胞重建的选择性作用

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 10.1016/j.bbagen.2026.130904

Lisa V.E. Oostenbrink, Anja M. Jansen-Hoogendijk, Monique M. van Ostaijen-ten Dam, Carly Vervat, Cornelia M. Jol-van der Zijde, Maarten J.D. van Tol, Robbert G.M. Bredius, Arjan C. Lankester, Marco W. Schilham, Gertjan Lugthart

Anti-thymocyte globulin (ATG Thymoglobulin®) and anti-T-lymphocyte globulin (ATLG Grafalon®) are commonly used in hematopoietic stem cell transplantation (HSCT) for in vivo T-cell depletion, aiming to reduce graft failure and graft-versus-host disease (GvHD). Despite their widespread use, the precise mechanisms by which ATG/ATLG affect immune recovery post-transplantation remain partially understood. In this study, in 289 pediatric HSCT patients treated with ATG (n = 213) or ATLG (n = 76), the relationship between longitudinal serum levels of the active T-lymphocyte-binding component of ATG/ATLG and immune reconstitution was evaluated. High levels of active ATG/ATLG did not prevent the recovery of neutrophils or NK-cells; however, T-cell recovery was delayed until active ATG/ATLG concentrations fell below 1 AU/mL. This is in apparent contradiction with the fact that ATG/ATLG are known not only to contain antibodies against antigens present on T-cells but also to antigens present on other immune and non-immune cells, including B-, NK-cells, granulocytes, monocytes and hematopoietic stem and progenitor cells (HSPC). To address this, we assessed the binding capacities of ATG and ATLG to immune cell subsets and HSPC both in vitro directly from the vial and in vivo from patients serum samples taken at multiple time points pre- and post-HSCT. Shortly after infusion, we observed a rapid reduction of ATG and ATLG binding to all cell types except for T-cells. This real-life specificity of ATG and ATLG explains their selective impact on T-cell reconstitution. These findings enhance our understanding of the mechanisms of action of ATG and ATLG and may contribute to optimization of these therapies.

抗胸腺细胞球蛋白（ATG Thymoglobulin®）和抗t淋巴细胞球蛋白（ATLG Grafalon®）常用于造血干细胞移植（HSCT）的体内t细胞消耗，旨在减少移植物衰竭和移植物抗宿主病（GvHD）。尽管它们被广泛使用，但ATG/ATLG影响移植后免疫恢复的确切机制仍部分被了解。在本研究中，289例接受ATG （n = 213）或ATLG （n = 76）治疗的儿童HSCT患者，评估了ATG/ATLG活性t淋巴细胞结合成分纵向血清水平与免疫重建之间的关系。高水平的ATG/ATLG活性不妨碍中性粒细胞或nk细胞的恢复；然而，t细胞恢复延迟，直到活性ATG/ATLG浓度低于1 AU/mL。这与已知ATG/ATLG不仅含有针对存在于t细胞上的抗原的抗体，而且还含有存在于其他免疫和非免疫细胞（包括B细胞、nk细胞、粒细胞、单核细胞和造血干细胞和祖细胞（HSPC））上的抗原的抗体的事实明显矛盾。为了解决这个问题，我们评估了ATG和ATLG对免疫细胞亚群和HSPC的结合能力，包括在体外直接从小瓶中提取的能力，以及在体内从hsct前后多个时间点采集的患者血清样本中提取的能力。在输注后不久，我们观察到ATG和ATLG与除t细胞外的所有细胞类型的结合迅速减少。ATG和ATLG在现实生活中的特异性解释了它们对t细胞重构的选择性影响。这些发现增强了我们对ATG和ATLG作用机制的理解，并可能有助于优化这些治疗方法。

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引用次数: 0

Ectonucleotidases: Possible roles in the tumor microenvironment and influence on tumor progression in breast cancer 外核苷酸酶：在乳腺癌肿瘤微环境中的可能作用和对肿瘤进展的影响。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-29 DOI: 10.1016/j.bbagen.2026.130913

Thaís Cristino Rocha-Vieira , José Roberto Meyer-Fernandes

Compared with nontumor tissue, the tumor microenvironment has a higher concentration of extracellular ATP. Extracellular ATP is degraded by the cooperative action of CD39 and ecto-5′-nucleotidase (CD73), thus leading to increases in the concentrations of adenosine and phosphate. This cooperative action can convert a proinflammatory environment characterized by a high concentration of ATP into an anti-inflammatory environment characterized by a high concentration of adenosine. In addition to its role in immune suppression, adenosine induces migration, metastasis and angiogenesis in breast cancer. In breast cancer, extracellular Pi plays an important role in tumor progression by increasing metastatic capacity. Studies have demonstrated that ecto-5′-nucleotidases are associated with chemoresistance and immune suppression through adenosine generation. In addition, ecto-5′-nucleotidases play a role in activating the epithelial-mesenchymal transition. Therefore, ectonucleotidase activity may represent a therapeutic target for the treatment of breast cancer.

与非肿瘤组织相比，肿瘤微环境具有更高的细胞外ATP浓度。细胞外ATP通过CD39和外5′-核苷酸酶（CD73）的协同作用降解，从而导致腺苷和磷酸盐浓度的增加。这种协同作用可以将以高浓度ATP为特征的促炎环境转化为以高浓度腺苷为特征的抗炎环境。腺苷除了在免疫抑制中的作用外，还能诱导乳腺癌的迁移、转移和血管生成。在乳腺癌中，细胞外Pi通过增加转移能力在肿瘤进展中起重要作用。研究表明，胞外5′-核苷酸酶通过腺苷的产生与化学耐药和免疫抑制有关。此外，胞外5′-核苷酸酶在激活上皮-间质转化中起作用。因此，外核苷酸酶活性可能是治疗乳腺癌的一个治疗靶点。

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引用次数: 0

Obese serum factors aggravate DNA damage, alter DNA damage response, and promote proliferation in colon cancer cells 肥胖血清因子加重结肠癌细胞DNA损伤，改变DNA损伤反应，促进细胞增殖。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-27 DOI: 10.1016/j.bbagen.2026.130911

Bhavana Deshmukh, Himanshi Yaduvanshi, Firoz Khan Bhati, Manoj Kumar Bhat

Clinical data indicate a positive association between obesity and DNA damage, which has been implicated in several pathological conditions. Obesity also increases the risk of the development and progression of cancers, including colon cancer. However, the underlying mechanisms linking obesity-induced alterations in the DNA damage response (DDR) to colon cancer remain largely unexplored. The present study aims to investigate the functional status of the cellular DNA damage response in an obese environment and its association with colon cancer. To address this, cells were cultured in media supplemented with serum collected from mice fed a normal-fat diet (ND) and a high-fat diet (HFD). Subsequently, the DNA damage response and associated phenotypic parameters were evaluated.

Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage along with reduced levels of DNA repair molecules, together with activation of the DDR, as indicated by elevated levels of pH2AX, P-p53Ser15, and pchk2 proteins. Moreover, cell growth assays demonstrated rapid proliferation of cells cultured in HFD serum. Furthermore, HFD-fed C57BL6/J mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher incidence of colon polyps compared to ND-fed mice. Interestingly, in ATM knockout mice (ATM, a key DDR-related molecule), a higher occurrence of polyps was detected compared to ATM wild-type mice, suggesting a potential role of ATM in polyp formation. Thus, by perturbing DDR and DNA repair pathways and promoting cell survival, obesity creates a favorable environment for cell proliferation. Collectively, this pre-clinical study enhances our understanding of obesity-altered DDR and its association with cancer cell proliferation.

临床数据表明，肥胖和DNA损伤之间存在正相关关系，这与几种病理状况有关。肥胖还会增加癌症发生和发展的风险，包括结肠癌。然而，将肥胖引起的DNA损伤反应（DDR）改变与结肠癌联系起来的潜在机制在很大程度上仍未被探索。本研究旨在探讨肥胖环境下细胞DNA损伤反应的功能状态及其与结肠癌的关系。为了解决这个问题，细胞在补充了正常脂肪饮食（ND）和高脂肪饮食（HFD）小鼠血清的培养基中培养。随后，评估DNA损伤反应和相关表型参数。实验结果显示，在HFD血清中培养的细胞表现出DNA损伤增加，DNA修复分子水平降低，DDR激活，如pH2AX， P-p53Ser15和pchk2蛋白水平升高。此外，细胞生长试验表明，在HFD血清中培养的细胞增殖迅速。此外，hfd喂养的C57BL6/J小鼠与nd喂养的小鼠相比，给予偶氮氧甲烷/葡聚糖硫酸钠（AOM/DSS）的结肠息肉发生率更高。有趣的是，在ATM敲除小鼠（ATM，一种关键的ddr相关分子）中，与ATM野生型小鼠相比，检测到更高的息肉发生率，这表明ATM在息肉形成中的潜在作用。因此，通过干扰DDR和DNA修复途径，促进细胞存活，肥胖为细胞增殖创造了有利的环境。总的来说，这项临床前研究增强了我们对肥胖改变的DDR及其与癌细胞增殖的关系的理解。

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引用次数: 0

TMED2 promotes thyroid cancer tumorigenesis by being involved in mTORC1-mediated fatty acid metabolism TMED2通过参与mtorc1介导的脂肪酸代谢促进甲状腺癌的肿瘤发生。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-23 DOI: 10.1016/j.bbagen.2026.130910

Jiajun Yin , Shiping Wang , Yang Liu

Background

TMED2, a p24 family member, has been implicated in the progression of multiple cancers. However, its function in thyroid cancer (THCA) is unclear and needs to be clarified.

Methods

TMED2 expression was first explored using single-cell datasets and the TCGA database, followed by validation in THCA tissues and cell lines by immunohistochemistry (IHC), western blot, and qRT-PCR. Survival analysis was performed to evaluate the correlation between TMED2 expression and patient survival. The impact of TMED2 on THCA cells was analyzed using CCK-8, EdU staining, wound healing, Transwell, and flow cytometry assays. The lipid droplet accumulation was detected using BODIPY staining. The expression of key enzymes involved in fatty acid (FA) synthesis was assessed using western blot assay. Rescue experiments were conducted to investigate the mechanism of TMED2. Finally, the role of TMED2 in vivo was assessed in a nude mouse model.

Results

TMED2 expression was significantly upregulated in THCA tissues and four cell lines and was closely related to worse outcomes. Functional experiments revealed that TMED2 enhanced proliferation, migration, invasion, and FA synthesis in THCA cells, while suppressing cell apoptosis. Mechanistically, TMED2 promoted tumor growth and FA synthesis in THCA by affecting the activation of mTORC1 signaling, which was also observed in a xenograft mouse model.

Conclusions

Our results demonstrated that TMED2 may function as an oncogene to support THCA growth by affecting mTORC1-mediated FA synthesis. These findings suggest that TMED2 could serve as a potential target for THCA treatment.

背景：p24家族成员TMED2与多种癌症的进展有关。然而，其在甲状腺癌（THCA）中的作用尚不清楚，需要进一步阐明。方法：首先使用单细胞数据集和TCGA数据库探索TMED2的表达，然后通过免疫组织化学（IHC）、western blot和qRT-PCR在THCA组织和细胞系中进行验证。通过生存分析来评估TMED2表达与患者生存的相关性。通过CCK-8、EdU染色、伤口愈合、Transwell和流式细胞术分析TMED2对THCA细胞的影响。采用BODIPY染色法检测脂滴积累。western blot法检测脂肪酸合成关键酶的表达。通过救援实验探讨TMED2的作用机制。最后，在裸鼠模型中评估TMED2在体内的作用。结果：TMED2在THCA组织和4种细胞系中表达显著上调，并与预后不良密切相关。功能实验显示，TMED2增强THCA细胞的增殖、迁移、侵袭和FA合成，同时抑制细胞凋亡。在机制上，TMED2通过影响mTORC1信号的激活来促进THCA中的肿瘤生长和FA合成，这在异种移植小鼠模型中也被观察到。结论：我们的研究结果表明，TMED2可能作为一种致癌基因，通过影响mtorc1介导的FA合成来支持THCA的生长。这些发现表明TMED2可以作为THCA治疗的潜在靶点。

{"title":"TMED2 promotes thyroid cancer tumorigenesis by being involved in mTORC1-mediated fatty acid metabolism","authors":"Jiajun Yin , Shiping Wang , Yang Liu","doi":"10.1016/j.bbagen.2026.130910","DOIUrl":"10.1016/j.bbagen.2026.130910","url":null,"abstract":"<div><h3>Background</h3><div>TMED2, a p24 family member, has been implicated in the progression of multiple cancers. However, its function in thyroid cancer (THCA) is unclear and needs to be clarified.</div></div><div><h3>Methods</h3><div>TMED2 expression was first explored using single-cell datasets and the TCGA database, followed by validation in THCA tissues and cell lines by immunohistochemistry (IHC), western blot, and qRT-PCR. Survival analysis was performed to evaluate the correlation between TMED2 expression and patient survival. The impact of TMED2 on THCA cells was analyzed using CCK-8, EdU staining, wound healing, Transwell, and flow cytometry assays. The lipid droplet accumulation was detected using BODIPY staining. The expression of key enzymes involved in fatty acid (FA) synthesis was assessed using western blot assay. Rescue experiments were conducted to investigate the mechanism of TMED2. Finally, the role of TMED2 <em>in vivo</em> was assessed in a nude mouse model.</div></div><div><h3>Results</h3><div>TMED2 expression was significantly upregulated in THCA tissues and four cell lines and was closely related to worse outcomes. Functional experiments revealed that TMED2 enhanced proliferation, migration, invasion, and FA synthesis in THCA cells, while suppressing cell apoptosis. Mechanistically, TMED2 promoted tumor growth and FA synthesis in THCA by affecting the activation of mTORC1 signaling, which was also observed in a xenograft mouse model.</div></div><div><h3>Conclusions</h3><div>Our results demonstrated that TMED2 may function as an oncogene to support THCA growth by affecting mTORC1-mediated FA synthesis. These findings suggest that TMED2 could serve as a potential target for THCA treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130910"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046055","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}

引用次数: 0

Involvement of neuropilin-1 in radiation-induced cell death via modulation of DNA double-strand break repair in glioblastoma T98G cells 神经匹林-1通过调节胶质母细胞瘤T98G细胞DNA双链断裂修复参与辐射诱导的细胞死亡。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2026-04-01 Epub Date: 2026-01-15 DOI: 10.1016/j.bbagen.2026.130906

Kaori Tsutsumi , Kouta Kawahara , Mizuki Kojima , Ayu Yuasa , Mitsuki Imazato , Juri Kidachi , Nanoha Yamamoto , Hisashi Nakano

Glioblastoma (GBM) is the most malignant form of brain tumor and is characterized by resistance to chemotherapy, radiotherapy, and combined chemoradiotherapy. Neuropilin-1 (NRP1) is a transmembrane receptor known to play critical roles in angiogenesis, tumor progression, and radioresistance. However, its precise role in radiation-induced cellular responses, particularly in GBM, remains unclear. In this study, we aimed to elucidate the mechanism underlying radiation resistance via NRP1 by examining the effects of NRP1 depletion in the p53-mutant GBM T98G cell line. Short interfering RNA-mediated suppression of NRP1 significantly reduced clonogenic survival following irradiation. Although the expression of caspase-3 and p21 was up-regulated in NRP1-suppressed cells, radiation-induced apoptosis and senescence did not significantly increase. γH2AX foci, a marker of radiation-induced DNA double-strand breaks (DSBs), were comparable between control and NRP1-suppressed cells. However, the DSB repair capacity was reduced in NRP1-suppressed cells, as evidenced by a higher number of unrepaired DSBs 24 h after irradiation. The number of 53BP1 foci, one of an important molecule in non-homologous end joining (NHEJ) of the DNA repair pathways, decreased in NRP1 suppression cells 0.5 h after X-ray irradiation. These changes were also observed in another GBM cell line, LN-18. The phosphorylation status of AKT, a key molecule in the survival pathway, remained unchanged in NRP1-suppressed cells compared to control cells. These findings suggest that NRP1 may regulate radiosensitivity by modulating DNA repair pathways in p53-mutated GBM T98G cells. NRP1 could serve as a potential therapeutic target for improving the response of radioresistant tumors such as GBM.

胶质母细胞瘤（GBM）是脑肿瘤中最恶性的形式，其特点是对化疗、放疗和放化疗联合耐药。神经匹林-1 （NRP1）是一种跨膜受体，已知在血管生成、肿瘤进展和放射耐药中起关键作用。然而，它在辐射诱导的细胞反应中的确切作用，特别是在GBM中，仍不清楚。在本研究中，我们旨在通过检测NRP1缺失对p53突变体GBM T98G细胞系的影响，阐明NRP1辐射抗性的机制。短干扰rna介导的NRP1抑制显著降低辐照后的克隆存活。虽然在nrp1抑制的细胞中caspase-3和p21的表达上调，但辐射诱导的细胞凋亡和衰老并未明显增加。γH2AX焦点是辐射诱导的DNA双链断裂（DSBs）的标记，在对照和nrp1抑制细胞之间具有可比性。然而，在nrp1抑制的细胞中，DSB修复能力降低，辐照后24 h未修复的DSB数量增加。在x射线照射后0.5 h， NRP1抑制细胞的非同源末端连接（non-homologous end joining， NHEJ）的重要分子之一53BP1位点数量减少。在另一种GBM细胞系LN-18中也观察到这些变化。与对照细胞相比，nrp1抑制细胞中AKT的磷酸化状态保持不变，AKT是存活途径的关键分子。这些发现表明NRP1可能通过调节p53突变的GBM T98G细胞的DNA修复途径来调节辐射敏感性。NRP1可以作为改善放射耐药肿瘤（如GBM）疗效的潜在治疗靶点。

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引用次数: 0