Biochimica et biophysica acta. Molecular basis of disease最新文献_第2页

UBE2K promotes breast cancer growth by ubiquitinating and degrading STUB1 to regulate the PKA/CREB1 signaling pathway, forming a feedback loop UBE2K通过泛素化和降解STUB1调控PKA/CREB1信号通路，促进乳腺癌生长，形成反馈回路。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-21 DOI: 10.1016/j.bbadis.2025.168145

Jiancheng Mou , Hongchao Tang , Xiaoge Hu , Zhuotao Yang , Haotian Su , Da Qian , Chenhong Li , Haotian Liu , Zhihao Ye , Mingxing Xu , Shuyan Liu , Qinghui Zheng , Xiaozhen Liu , Xin Zeng , Qiuran Xu , Xuli Meng

Background

Breast cancer (BC) remains one of the major threats to women's health in the 21st century, due to its high incidence and mortality rates. Ubiquitin-conjugating enzymes, as members of the ubiquitin-proteasome system, are responsible for numerous cellular physiological processes. However, ubiquitin-conjugating enzymes may also play unexpected roles in other physiological activities, such as phosphorylation, lactylation, and even methylation. The physiological function of the ubiquitin-conjugating E2 enzyme UBE2K in BC remains unknown. As a result, we looked into UBE2K's physiological role in the malignant development of BC.

Methods

A combination of RT-qPCR, Transwell migration assays, Western blotting, and CCK-8 analysis was employed to confirm the upregulation of UBE2K in BC cells and to assess its role in promoting cell proliferation and migration. Furthermore, using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, we identified and validated CREB1 as a transcription factor for UBE2K for the first time.

Results

We discovered that UBE2K regulates the physiological processes of BC cells via the STUB1/PKA/CREB1/p-CREB1 axis. Moreover, functional rescue experiments ultimately displayed that UBE2K promotes the malignant progression of BC cells by via STUB1/PKA/CREB1/p-CREB1 axis.

Conclusions

In conclusion, the UBE2K/CREB1 positive feedback loop promotes the development of BC, indicating that UBE2K could be a viable therapeutic target for anti-BC.

背景：由于乳腺癌的高发病率和高死亡率，它仍然是21世纪妇女健康的主要威胁之一。泛素偶联酶作为泛素-蛋白酶体系统的成员，负责许多细胞生理过程。然而，泛素偶联酶也可能在其他生理活动中发挥意想不到的作用，如磷酸化、乳酸化甚至甲基化。泛素偶联E2酶UBE2K在BC中的生理功能尚不清楚。因此，我们研究了UBE2K在BC恶性发展中的生理作用。方法：采用RT-qPCR、Transwell迁移实验、Western blotting和CCK-8分析相结合的方法，证实UBE2K在BC细胞中的表达上调，并评估其在促进细胞增殖和迁移中的作用。此外，通过染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测，我们首次鉴定并验证了CREB1是UBE2K的转录因子。结果：我们发现UBE2K通过STUB1/PKA/CREB1/p-CREB1轴调控BC细胞的生理过程。此外，功能修复实验最终显示UBE2K通过STUB1/PKA/CREB1/p-CREB1轴促进BC细胞的恶性进展。结论：综上所述，UBE2K/CREB1正反馈回路促进BC的发展，提示UBE2K可能是抗BC的可行治疗靶点。

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引用次数: 0

Targeting the NLRP3 inflammasome signalling in acute myeloid leukemia: Mechanisms, therapeutics, and future directions 靶向NLRP3炎性小体信号在急性髓性白血病中的作用：机制、治疗方法和未来方向。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-21 DOI: 10.1016/j.bbadis.2025.168143

Sally H. Fayad , Alaa Mohamed Salah , Ayad A. Jaffa , Nadine Darwiche

Acute myeloid leukemia (AML) is one of the most frequent hematological malignancies. It is a complex and aggressive disease of undifferentiated hematopoietic progenitor cells, with high rates of relapse and drug resistance, posing significant clinical challenges. Emerging evidence underscores the critical role of inflammation in AML progression, with inflammasomes—key regulators of the inflammatory response—emerging as pivotal players in disease pathogenesis. Among these, the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome has gained particular attention due to its involvement in promoting leukemogenesis and chemoresistance. While inflammasomes have been previously studied in various cancer types, no comprehensive review to date has specifically addressed the role of the NLRP3 inflammasome in AML and its potential targeted therapy. Focusing on the NLRP3 inflammasome, we explore its contribution to AML pathogenesis and its therapeutic potential. We highlight preclinical natural and synthetic compounds, alongside clinical-stage and clinically approved drugs that target the NLRP3 inflammasome signalling pathway and components. We address the challenges and limitations of these promising compounds and drugs, while highlighting recent advancements such as the synthesis of novel and derivatives designed to improve their efficacy. Finally, we discuss future research directions aimed at deepening our understanding of the NLRP3 inflammasome and identifying novel and improved therapeutic outcomes against AML.

急性髓系白血病（AML）是最常见的血液系统恶性肿瘤之一。它是一种复杂和侵袭性的未分化造血祖细胞疾病，具有高复发率和耐药性，给临床带来了重大挑战。新出现的证据强调了炎症在AML进展中的关键作用，炎症小体-炎症反应的关键调节因子-在疾病发病机制中扮演着关键角色。其中，NOD-、LRR-和含pyrin结构域3 （NLRP3）炎症小体因其参与促进白血病发生和化疗耐药而受到特别关注。虽然炎性小体在各种癌症类型中已经被研究过，但迄今为止还没有全面的综述专门针对NLRP3炎性小体在AML中的作用及其潜在的靶向治疗。以NLRP3炎性小体为重点，探讨其在AML发病机制中的作用及其治疗潜力。我们重点关注临床前天然和合成化合物，以及临床阶段和临床批准的靶向NLRP3炎症小体信号通路和成分的药物。我们解决了这些有前途的化合物和药物的挑战和局限性，同时强调了最近的进展，如新合成和衍生物的设计，以提高其功效。最后，我们讨论了未来的研究方向，旨在加深我们对NLRP3炎症小体的理解，并确定新的和改进的AML治疗结果。

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引用次数: 0

HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis HKDC1促进ORMDL3启动子的H3K18乳酸化，诱导肝硬化肝星状细胞活化

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-18 DOI: 10.1016/j.bbadis.2025.168140

Yanan Zhang , Lei Li , Gaiqin Li , Junyuan Zhu , Zexue Qi , Chunqing Zhang

Purpose

We aimed to investigate the role and possible mechanism of action of hexokinase domain containing 1 (HKDC1) in liver cirrhosis.

Methods

Hepatic stellate cell (HSC) activation model was established in LX-2 cells by transforming growth factor (TGF)-βl stimulation. A mouse model of hepatic fibrosis was established using carbon tetrachloride (CCl₄) stimulation. HKDC1 expression was assessed using qRT-PCR, western blotting, and immunofluorescence. Hematoxylin and eosin (H&E) and Masson staining were used to assess liver injury and fibrosis. Changes in fibrosis markers were assessed using qRT-PCR, western blotting, and immunohistochemical staining. The effect of HKDC1 on glycolysis was evaluated by measuring the levels of extracellular acidification rate (ECAR), oxygen consumption rate (OCR), lactate, and related proteins.

Results

In liver cirrhosis tissues and activated HSCs, HKDC1 expression was upregulated. CCl₄-induced liver injury and fibrosis were inhibited by silencing of Hkdc1 in mice, as evidenced by the decrease of aspartate transaminase (AST), alanine transaminase (ALT), Collagen I, α-SMA, TGF-β1, and TIMP-1. Under TGF-β1 treatment, silencing of HKDC1 inhibited HSC activation and glycolysis, as evidenced by the reduce of Collagen I, α-SMA, TIMP-1, ECAR, lactate, HK2, LDHA, PKM2 and the increase of OCR. Mechanistically, silencing of HKDC1 reduced the levels of ORMDL3 and H3K18la proteins, and HKDC1 increased histone lactylation of the promoter of ORMDL3. ORMDL3 overexpression and lactate eliminated the effects of HKDC1 silencing on LX-2 cell activation.

Conclusion

HKDC1 silencing alleviates liver fibrosis and HSC activation by regulating glycolysis and decreasing histone lactylation of the promoter of ORMDL3.

目的探讨己糖激酶结构域1 （HKDC1）在肝硬化中的作用及其可能机制。方法采用转化生长因子(TGF)-β 1刺激LX-2细胞建立肝星状细胞（HSC）活化模型。采用四氯化碳（CCl4）刺激法建立小鼠肝纤维化模型。采用qRT-PCR、western blotting和免疫荧光检测HKDC1的表达。苏木精和伊红（H&；E）和Masson染色评估肝损伤和纤维化。使用qRT-PCR、western blotting和免疫组织化学染色评估纤维化标志物的变化。通过测量细胞外酸化率（ECAR）、耗氧量（OCR）、乳酸盐和相关蛋白的水平来评估HKDC1对糖酵解的影响。结果在肝硬化组织和活化的造血干细胞中，HKDC1表达上调。沉默Hkdc1可抑制ccl4诱导的小鼠肝损伤和纤维化，表现为天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、I型胶原蛋白、α-SMA、TGF-β1和TIMP-1的降低。TGF-β1处理下，沉默HKDC1抑制HSC活化和糖酵解，表现为胶原I、α-SMA、TIMP-1、ECAR、乳酸、HK2、LDHA、PKM2减少，OCR增加。机制上，HKDC1的沉默降低了ORMDL3和H3K18la蛋白的水平，HKDC1增加了ORMDL3启动子的组蛋白乳酸化。ORMDL3过表达和乳酸消除了HKDC1沉默对LX-2细胞活化的影响。结论hkdc1沉默通过调节ORMDL3启动子的糖酵解和降低组蛋白乳酸化来缓解肝纤维化和HSC活化。

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引用次数: 0

Binding of human low-density lipoproteins to type-I collagen is synergistic with the pro-atherogenic lipoprotein remodeling 人低密度脂蛋白与i型胶原蛋白的结合与促动脉粥样硬化脂蛋白重塑具有协同作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-17 DOI: 10.1016/j.bbadis.2025.168142

Shobini Jayaraman , Kyeongseo Choi , Antonio Pérez , Inka Miñambres , Jose Luis Sánchez-Quesada , Olga Gursky

Low-density lipoprotein (LDL) entrapment in the extracellular matrix of the arterial intima is an established early trigger of atherosclerosis. Though much is known about LDL binding to arterial proteoglycans, the binding to other matrix components remains underexplored. This study focuses on LDL interactions with type-I collagen (Col-I), a major extracellular matrix protein found in atherosclerotic lesions. Human normolipidemic LDL, which has been oxidized or lipolyzed in vitro, and naturally occurring plasma LDL subclasses differing in size and charge are explored, along with LDL from patients with type-2 diabetes or obesity before and after treatment. To understand how these lipoproteins interact with Col-I, we quantify their binding to collagen-coated microwell plates using enzyme-linked immunosorbent assay. The mechanistic underpinnings are probed by a multipronged approach using the methods of chromatography, spectroscopy, microscopy and others. The results reveal that intact LDL binds Col-I in a cooperative dose-dependent manner. The binding is synergistic with pro-atherogenic LDL modifications including aggregation, oxidation and lipolysis. The pro-atherogenic subclasses of small dense LDL and electronegative LDL show enhanced Col-I binding; conversely, Col-I binding induces LDL remodeling to generate smaller and more electronegative particles. This synergy suggests a potential causal role of LDL–Col-I interactions in atherogenesis. Moreover, our results suggest that LDL binding to Col-I provides a biomarker and a sensitive treatment readout for the risk of atherosclerosis in patients with metabolic diseases such as diabetes and obesity.

动脉内膜细胞外基质中的低密度脂蛋白（LDL）被确定为动脉粥样硬化的早期触发因素。尽管人们对LDL与动脉蛋白聚糖的结合了解甚多，但其与其他基质成分的结合仍未得到充分研究。本研究的重点是LDL与i型胶原蛋白（ColI）的相互作用，i型胶原蛋白是动脉粥样硬化病变中发现的主要细胞外基质蛋白。研究了在体外氧化或脂解的人正常血脂LDL，以及在治疗前后2型糖尿病或肥胖患者的LDL的大小和电荷不同的天然血浆LDL亚类。为了了解这些脂蛋白如何与大肠杆菌相互作用，我们使用酶联免疫吸附法定量了它们与胶原包被微孔板的结合。其机制基础是通过使用色谱、光谱学、显微镜和其他方法的多管齐下的方法来探索的。结果表明，完整的LDL以一种剂量依赖的方式与col - 1结合。这种结合与促动脉粥样硬化的LDL修饰有协同作用，包括聚集、氧化和脂解。小密度LDL和电负性LDL的促动脉粥样硬化亚类显示出增强的coli结合；相反，col - 1结合诱导LDL重塑，产生更小、电负性更强的颗粒。这种协同作用提示ldl - col - 1相互作用在动脉粥样硬化发生中的潜在因果作用。此外，我们的研究结果表明，LDL与col - 1的结合为糖尿病和肥胖等代谢性疾病患者的动脉粥样硬化风险提供了一种生物标志物和敏感的治疗读数。

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引用次数: 0

The effects of tissue inflammation on cancer cachexia 组织炎症对癌症恶病质的影响。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-17 DOI: 10.1016/j.bbadis.2025.168144

Benjamin R. Pryce , Haiming L. Kerr

Cancer cachexia is characterized by a significant loss in body weight due to the wasting of skeletal muscle and adipose tissue. Systemic inflammation has long been associated with cachexia, with various tumor secreted factors shown to correlate with as well as cause tissue wasting. In addition to systemic inflammation, it has become increasingly appreciated that inflammation occurs in specific tissues in cancer cachexia, with tissues such as muscle, adipose, liver and brain being affected. While several studies have shown that this local tissue inflammation contributes to cachexia, there is evidence that some aspects of the inflammatory response may play a protective role to mitigate tissue wasting. Here, we will review the findings on local tissue inflammation in cachexia, comparing the impacts of such inflammation on tissue wasting and cachexia progression overall. Furthermore, we discuss the methods used to mitigate inflammation in various tissues and highlight the outcomes on the cachectic phenotype. Collectively, understanding how inflammation contributes to cachexia in each tissue will ultimately influence how therapies can be designed to treat cachexia while minimizing possible adverse side effects.

癌症恶病质的特征是由于骨骼肌和脂肪组织的消耗而导致体重显著下降。长期以来，全身炎症与恶病质有关，各种肿瘤分泌因子被证明与组织消耗相关，也导致组织消耗。除了全身性炎症外，人们越来越认识到炎症发生在癌症恶病质的特定组织中，如肌肉、脂肪、肝脏和大脑等组织受到影响。虽然一些研究表明，这种局部组织炎症有助于恶病质，但有证据表明，炎症反应的某些方面可能在减轻组织浪费方面发挥保护作用。在这里，我们将回顾有关恶病质局部组织炎症的研究结果，比较这种炎症对组织消耗和恶病质进展的总体影响。此外，我们讨论了用于减轻各种组织炎症的方法，并强调了恶病质表型的结果。总的来说，了解炎症如何导致每个组织中的恶病质将最终影响如何设计治疗恶病质的治疗方法，同时最大限度地减少可能的不良副作用。

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引用次数: 0

ATOX1-driven ECM degradation and vascular smooth muscle cell apoptosis accelerate aortic dissection progression atox1驱动的ECM降解和血管平滑肌细胞凋亡加速了主动脉夹层的进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-16 DOI: 10.1016/j.bbadis.2025.168134

Yuling Xie , Xinfan Lin , Xu Han , Xingfeng Chen , Qingsong Wu , Debin Jiang , Linfeng Xie

Background

The development of aortic dissection (AD) is closely associated with extracellular matrix degradation and the apoptosis of vascular smooth muscle cells (VSMCs). Antioxidant-1 (ATOX1), a copper-binding protein, the precise mechanisms by which it contributes to extracellular matrix (ECM) degradation, VSMC apoptosis, and the onset of AD remain to be further elucidated.

Methods and results

Through high-throughput sequencing, we identified a significant increase in the expression of ATOX1 in patients with AD. Further validation using tissue staining, RT-PCR and Western blot revealed that ATOX1 expression was elevated in AD patients, AD mouse models, and in vitro human aortic vascular smooth muscle cells (HAVSMCs) induced by Angiotensin II (AngII). In vitro experiments showed that silencing ATOX1 or pharmacologically inhibiting ATOX1 with DC_AC50 significantly reduced copper ion expression and the secretion of matrix metalloproteinases (MMPs), while alleviating cell apoptosis in HAVSMCs. Targeted knockdown of ATOX1 in smooth muscle cells using adeno-associated virus vector 9 (AAV9) or pharmacological inhibition of ATOX1 effectively slowed the progression of AD in a β-aminopropionitrile (BAPN)-induced mouse model. Additionally, ATOX1 expression is directly regulated by miR-133b, which was found to be significantly downregulated in the serum and aortic tissues of AD patients, exhibiting an inverse correlation with ATOX1 upregulation in AD. MiR-133b mimic successfully reversed the effects of ATOX1-induced MMPs secretion and apoptosis in HAVSMCs. Lastly, overexpression of miR-133b through AAV9 significantly attenuated the progression of BAPN-induced AD in mice.

Conclusions

Our study suggests that inhibiting ATOX1 may reduce ECM degradation and cell apoptosis, thereby slowing the progression of AD, and highlights ATOX1 inhibition as a potential new strategy for AD treatment.

背景：主动脉夹层（AD）的发生与细胞外基质降解和血管平滑肌细胞（VSMCs）凋亡密切相关。抗氧化剂1 （ATOX1）是一种铜结合蛋白，其参与细胞外基质降解、VSMC凋亡和AD发病的确切机制仍有待进一步阐明。方法和结果：通过高通量测序，我们发现ATOX1在AD患者中表达显著增加。通过组织染色、RT-PCR和Western blot进一步验证，发现ATOX1在AD患者、AD小鼠模型和血管紧张素II （AngII）诱导的体外人主动脉血管平滑肌细胞（HAVSMCs）中表达升高。体外实验表明，沉默ATOX1或用DC_AC50药物抑制ATOX1可显著降低hasmcs中铜离子的表达和基质金属蛋白酶（MMPs）的分泌，同时减轻细胞凋亡。在β-氨基丙腈（BAPN）诱导的小鼠模型中，使用腺相关病毒载体9 （AAV9）靶向敲除平滑肌细胞中的ATOX1或药理抑制ATOX1可有效减缓AD的进展。此外，ATOX1的表达受miR-133b的直接调控，在AD患者的血清和主动脉组织中，miR-133b被发现显著下调，与ATOX1在AD中的上调呈负相关。MiR-133b mimic成功逆转了atox1诱导的hasmcs中MMPs分泌和凋亡的影响。最后，通过AAV9过表达miR-133b可显著减弱小鼠bapn诱导的AD的进展。结论：我们的研究表明，抑制ATOX1可能会减少细胞外基质降解和细胞凋亡，从而减缓AD的进展，并强调抑制ATOX1是一种潜在的治疗AD的新策略。

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引用次数: 0

Neutrophil-derived thrombospondin-1 (THBS1) drives type 2 diabetes-induced osteoporosis via CD36-PPARγ-POU2F2 signaling 中性粒细胞衍生的血栓反应蛋白-1 （THBS1）通过CD36-PPARγ-POU2F2信号驱动2型糖尿病诱导的骨质疏松症。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-15 DOI: 10.1016/j.bbadis.2025.168139

Weibo Huang , Chenghao Zhou , Rong Wu , Kangcheng Zhao , Jianfeng Wu , Dianwen Song

Objective

Type 2 diabetes (T2D) is associated with osteoporosis. Although chronic inflammation and immune dysregulation are implicated in T2D-induced bone loss, the specific roles of immune cells remain poorly understood. This study aimed to investigate how neutrophils in T2D contribute to osteoporosis and to identify the underlying molecular mechanisms and potential therapeutic targets.

Methods

We utilized a combination of in vivo and in vitro approaches, including T2D and control mouse models, primary cell cultures, and publicly available single-cell RNA sequencing data from the GEO database. Osteoporosis was assessed through TRAP staining, micro-CT imaging, and quantitative PCR. Molecular interactions were examined using Western blotting, chromatin immunoprecipitation followed by qPCR, and flow cytometry. Additionally, virtual screening was employed to identify potential inhibitors of thrombospondin-1(THBS1).

Results

Neutrophils isolated from T2D mice promoted osteoclast activity and bone loss when transferred into wild-type mice, as evidenced by increased TRAP-positive cells and deteriorated bone microarchitecture. We identified THBS1, a glycoprotein secreted at higher levels by T2D neutrophils, as a mediator of osteoclast differentiation. THBS1 engaged the CD36 receptor on macrophages, activating PPARγ, which transcriptionally upregulates POU2F2—a transcription factor that enhances osteoclastogenesis via c-FOS induction. Genetic ablation of THBS1 attenuated osteoclast formation and bone loss in T2D mice. Virtual screening identified nasunin as a potent THBS1 inhibitor. Treatment with nasunin suppressed the CD36–PPARγ–POU2F2–c-FOS axis, reduced osteoclast differentiation in vitro, and ameliorated T2D-induced osteoporosis in vivo.

Conclusion

Our findings reveal a novel pathway through which neutrophil-derived THBS1 exacerbates diabetic osteoporosis by promoting osteoclastogenesis via CD36–PPARγ–POU2F2 signaling.

目的：2型糖尿病（T2D）与骨质疏松有关。尽管慢性炎症和免疫失调与t2d诱导的骨质流失有关，但免疫细胞的具体作用仍然知之甚少。本研究旨在探讨T2D中性粒细胞如何促进骨质疏松症，并确定潜在的分子机制和潜在的治疗靶点。方法：我们结合了体内和体外方法，包括T2D和对照小鼠模型，原代细胞培养，以及GEO数据库中公开的单细胞RNA测序数据。通过TRAP染色、显微ct成像和定量PCR评估骨质疏松症。分子间相互作用采用Western blotting、染色质免疫沉淀（随后采用qPCR）和流式细胞术检测。此外，虚拟筛选用于确定血栓反应蛋白-1（THBS1）的潜在抑制剂。结果：从T2D小鼠中分离的中性粒细胞在转移到野生型小鼠时促进破骨细胞活性和骨质流失，表现为trap阳性细胞增加和骨微结构恶化。我们发现THBS1是一种由T2D中性粒细胞分泌的较高水平的糖蛋白，是破骨细胞分化的介质。THBS1参与巨噬细胞上的CD36受体，激活PPARγ，其转录上调pou2f2 -一种通过c-FOS诱导促进破骨细胞发生的转录因子。THBS1基因消融术可减轻T2D小鼠破骨细胞的形成和骨质流失。虚拟筛选证实nasunin是一种有效的THBS1抑制剂。纳苏宁治疗抑制CD36-PPARγ-POU2F2-c-FOS轴，减少体外破骨细胞分化，改善体内t2d诱导的骨质疏松症。结论：我们的研究结果揭示了中性粒细胞来源的THBS1通过CD36-PPARγ-POU2F2信号通路促进破骨细胞生成，从而加剧糖尿病骨质疏松症的新途径。

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引用次数: 0

CD4+ T-cell-derived small extracellular vesicles induce the apoptosis of renal tubular epithelial cells in diabetic nephropathy by regulating mitochondrial dynamics CD4+ t细胞来源的细胞外小泡通过调节线粒体动力学诱导糖尿病肾病肾小管上皮细胞凋亡。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-15 DOI: 10.1016/j.bbadis.2025.168131

Qianqian Han , Yutong Zou , Qing Yang , Enrong Ran , Ziyao Li , Fang Liu

CD4+ T cells play a critical role in diabetic nephropathy (DN) progression. High-glucose (HG) conditions induce small extracellular vesicle (sEV) cargo loading disorders, but whether CD4+ T cells mediate renal injury via sEVs remains unclear. In vitro, a transformed C3H mouse kidney-1 (TCMK-1)/CD4+ T-cell coculture model revealed that high-glucose (HG) conditions increased CD4+ T-cell-induced lactate dehydrogenase release, reactive oxygen species production, apoptosis of TCMK-1 cells, and mitochondrial dysfunction, as confirmed by enzyme-linked immunosorbent assays, flow cytometry, Western blotting (WB), and transmission electron microscopy (TEM). Notably, compared with those under normal glucose conditions, CD4+ T cells under HG conditions exacerbated these effects more significantly. In vivo, CD4+ T cells were isolated from the blood of C57BL/6J (control) mice and db/db (experimental) mice using magnetic beads, and their sEVs were extracted from the culture medium. These sEVs were injected into corresponding C57BL/6J or db/db mice, with saline-injected mice used as blank controls. Compared with control mice, mice injected with db/db mouse CD4+ T-cell-derived sEVs (both C57BL/6J and db/db recipients) exhibited significant increases in serum creatinine levels and proteinuria, as well as more severe renal pathological injury. TEM, flow cytometry and WB analyses revealed disordered mitochondrial dynamics in renal tubular epithelial cells (RTECs), marked by reduced membrane potential and imbalanced Drp1/Mfn1/Mfn2 expression. Collectively, these findings indicate that CD4+ T cells exacerbate renal injury and disrupt mitochondrial homeostasis in RTECs by releasing sEVs under HG conditions, highlighting the CD4+ T-cell-sEV axis as a potential diagnostic and therapeutic target for DN.

CD4+ T细胞在糖尿病肾病（DN）进展中起关键作用。高糖（HG）条件诱导小细胞外囊泡（sEV）货物装载障碍，但CD4+ T细胞是否通过sEV介导肾损伤尚不清楚。体外，转化的C3H小鼠肾-1 (TCMK-1)/CD4+ t细胞共培养模型显示，高糖（HG）条件增加了CD4+ t细胞诱导的乳酸脱氢酶释放、活性氧产生、TCMK-1细胞凋亡和线粒体功能障碍，酶联免疫吸附试验、流式细胞术、Western blotting （WB）和透射电镜（TEM）证实了这一点。值得注意的是，与正常血糖条件下相比，HG条件下CD4+ T细胞更明显地加剧了这些作用。在体内，采用磁珠法从C57BL/6J（对照）小鼠和db/db（实验）小鼠血液中分离CD4+ T细胞，并从培养液中提取其sev。将这些sev注射到相应的C57BL/6J或db/db小鼠体内，以盐水注射小鼠作为空白对照。与对照小鼠相比，注射db/db小鼠CD4+ t细胞衍生sev的小鼠（C57BL/6J和db/db受体）血清肌酐水平和蛋白尿显著升高，肾脏病理损伤更严重。TEM、流式细胞术和WB分析显示，肾小管上皮细胞（RTECs）线粒体动力学紊乱，表现为膜电位降低和Drp1/Mfn1/Mfn2表达不平衡。总的来说，这些发现表明，CD4+ T细胞在HG条件下通过释放sev加剧肾损伤，破坏rtec中的线粒体稳态，突出了CD4+ T细胞- sev轴作为DN的潜在诊断和治疗靶点。

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引用次数: 0

Ubiquitin-specific peptidase 40 promotes cellular proliferation and inhibits apoptosis through deubiquitination-mediated stabilization of c-MYC in acute myeloid leukemia 在急性髓性白血病中，泛素特异性肽酶40通过去泛素化介导的c-MYC稳定促进细胞增殖和抑制凋亡。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-15 DOI: 10.1016/j.bbadis.2025.168138

Wen Fu , Qiaoliang Wu , Yanru Yao , Yingsen Sun , Huafang Wang , Jing Jie , Xiaoyan Zheng , Lina Wang , Xiaoge Hu , Xiangmin Tong , Qiuran Xu

Background

Ubiquitin-specific peptidase 40(USP40), a member of the deubiquitinase family, regulates numerous cellular processes. Recent studies have increasingly highlighted the involvement of USP40 in cancer development. However, the precise mechanism through which USP40 influences acute myeloid leukemia (AML) progression remains poorly understood.

Methods

The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression.

Results

USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin–proteasome pathway.

Conclusion

USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.

背景：泛素特异性肽酶40（USP40）是去泛素酶家族的一员，调节许多细胞过程。最近的研究越来越强调USP40在癌症发展中的作用。然而，USP40影响急性髓性白血病（AML）进展的确切机制仍然知之甚少。方法：采用基因表达谱交互分析、逆转录定量聚合酶链反应（RT-qPCR）和western blotting （WB）检测AML组织和细胞系中USP40的表达水平。Kaplan-Meier绘图仪用于评估AML患者USP40表达与预后之间的关系。采用细胞计数试剂盒- 8,5 -乙基-2'-脱氧尿苷掺入、细胞凋亡实验和裸鼠皮下肿瘤模型研究USP40表达对体外和体内AML细胞增殖和凋亡的影响。采用WB、RT-qPCR、免疫荧光法、共免疫沉淀法、环己亚胺追踪法等方法探讨USP40与c-MYC的关系。我们进一步进行了拯救实验，以评估USP40-c-MYC轴在AML进展中的功能贡献。结果：与正常对照相比，USP40在AML组织和细胞系中过表达，且与不良预后相关。USP40通过促进增殖和抑制细胞凋亡加速AML进展。在机制上，USP40通过选择性去除k48连接的多泛素链来去泛素化c-MYC，从而阻止其通过泛素-蛋白酶体途径降解。结论：USP40通过去泛素化c-MYC加速AML进展，凸显了USP40-c-MYC轴作为AML治疗的潜在治疗靶点。

{"title":"Ubiquitin-specific peptidase 40 promotes cellular proliferation and inhibits apoptosis through deubiquitination-mediated stabilization of c-MYC in acute myeloid leukemia","authors":"Wen Fu , Qiaoliang Wu , Yanru Yao , Yingsen Sun , Huafang Wang , Jing Jie , Xiaoyan Zheng , Lina Wang , Xiaoge Hu , Xiangmin Tong , Qiuran Xu","doi":"10.1016/j.bbadis.2025.168138","DOIUrl":"10.1016/j.bbadis.2025.168138","url":null,"abstract":"<div><h3>Background</h3><div>Ubiquitin-specific peptidase 40(USP40), a member of the deubiquitinase family, regulates numerous cellular processes. Recent studies have increasingly highlighted the involvement of USP40 in cancer development. However, the precise mechanism through which USP40 influences acute myeloid leukemia (AML) progression remains poorly understood.</div></div><div><h3>Methods</h3><div>The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression.</div></div><div><h3>Results</h3><div>USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin–proteasome pathway.</div></div><div><h3>Conclusion</h3><div>USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168138"},"PeriodicalIF":4.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

INSR/AKT1 axis promotes cells proliferation and migration in acute myeloid leukemia INSR/AKT1轴促进急性髓系白血病细胞增殖和迁移。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-13 DOI: 10.1016/j.bbadis.2025.168132

Liman Lin , Chunle Zhao , Xiaoya Cai , Aiguo Liu , Min Xiao , Liting Chen , Dengju Li

Chemotherapy resistance represents a major challenge in relapsed and refractory acute myeloid leukemia (AML). Therefore, it is necessary to investigate the mechanisms underlying chemotherapy resistance in AML. INSR not only highly expressed in AML cells treated with chidamide, but also elevated in AML patients. Subsequent overexpression and knockdown experiments of INSR in AML cells demonstrated that INSR facilitates cell cycle transition from G1 to S phase and promotes AML cell proliferation. Furthermore, INSR upregulates vimentin and N-cadherin expression, thereby enhancing cell invasion and migration. By integrating transcriptome sequencing data with gene expression profile interactive analysis, we discovered that AKT1 expression levels were positively correlated with INSR expression, while AKT1 expression exhibited a negative correlation with the prognosis of AML patients. AKT1 expression inhibition reduced the proliferation and migratory activity of AML cells. Additionally, suppressing AKT1 expression diminished the impact of INSR on promoting AML cells proliferation, invasion, and migration. This study indicates that INSR expression is elevated in AML cells after treating with chidamide and that INSR promotes AML cells proliferation and migration by upregulating AKT1 expression.

化疗耐药是复发和难治性急性髓性白血病（AML）的主要挑战。因此，有必要研究AML化疗耐药的机制。INSR不仅在奇达胺处理的AML细胞中高表达，而且在AML患者中也升高。随后在AML细胞中进行的INSR过表达和敲低实验表明，INSR促进细胞周期从G1期向S期过渡，促进AML细胞增殖。此外，INSR上调vimentin和N-cadherin的表达，从而增强细胞的侵袭和迁移。通过整合转录组测序数据和基因表达谱交互分析，我们发现AKT1表达水平与INSR表达呈正相关，而AKT1表达与AML患者的预后呈负相关。抑制AKT1表达可降低AML细胞的增殖和迁移活性。此外，抑制AKT1表达降低了INSR对促进AML细胞增殖、侵袭和迁移的影响。本研究表明，经奇达胺处理后，AML细胞中INSR表达升高，INSR通过上调AKT1表达促进AML细胞增殖和迁移。

{"title":"INSR/AKT1 axis promotes cells proliferation and migration in acute myeloid leukemia","authors":"Liman Lin , Chunle Zhao , Xiaoya Cai , Aiguo Liu , Min Xiao , Liting Chen , Dengju Li","doi":"10.1016/j.bbadis.2025.168132","DOIUrl":"10.1016/j.bbadis.2025.168132","url":null,"abstract":"<div><div>Chemotherapy resistance represents a major challenge in relapsed and refractory acute myeloid leukemia (AML). Therefore, it is necessary to investigate the mechanisms underlying chemotherapy resistance in AML. INSR not only highly expressed in AML cells treated with chidamide, but also elevated in AML patients. Subsequent overexpression and knockdown experiments of INSR in AML cells demonstrated that INSR facilitates cell cycle transition from G1 to S phase and promotes AML cell proliferation. Furthermore, INSR upregulates vimentin and N-cadherin expression, thereby enhancing cell invasion and migration. By integrating transcriptome sequencing data with gene expression profile interactive analysis, we discovered that AKT1 expression levels were positively correlated with INSR expression, while AKT1 expression exhibited a negative correlation with the prognosis of AML patients. AKT1 expression inhibition reduced the proliferation and migratory activity of AML cells. Additionally, suppressing AKT1 expression diminished the impact of INSR on promoting AML cells proliferation, invasion, and migration. This study indicates that INSR expression is elevated in AML cells after treating with chidamide and that INSR promotes AML cells proliferation and migration by upregulating AKT1 expression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168132"},"PeriodicalIF":4.2,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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