Biochimica et biophysica acta. Molecular cell research最新文献_第5页

Escitalopram disrupts PDK1–Akt signaling in B cells through a structure-dependent mechanism independent of SERT Escitalopram通过独立于SERT的结构依赖机制破坏B细胞中的PDK1-Akt信号。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-09 DOI: 10.1016/j.bbamcr.2025.120086

Yu-Lun Tseng , Meng-Ling Chiang

The PI3K–Akt pathway is a central regulator of survival and growth signals across receptor systems, controlled at the membrane-proximal PDK1–Akt signaling node. Although selective serotonin reuptake inhibitors (SSRIs) primarily target the serotonin transporter (SERT), evidence suggests additional effects on intracellular signaling. Escitalopram, a widely used SSRI, was previously shown to inhibit Syk phosphorylation in platelets, raising the possibility of SERT-independent effects on kinase cascades. Here, we investigated whether escitalopram and related compounds interfere with PI3K–Akt signaling in Ramos B lymphoma cells stimulated through the B cell receptor (BCR). Escitalopram and its enantiomer R-citalopram selectively reduced phosphorylation of Akt and its downstream effector FoxO1 while sparing upstream Syk and parallel ERK and PLC–PKC pathways. To localize the site of interference, we combined analyses of PDK1-dependent targets with a PTEN-inhibition model. Escitalopram suppressed PLK1 and S6K1 phosphorylation without altering mTORC2 autophosphorylation, and it also reduced H₂O₂-induced Akt phosphorylation. These complementary results point to a downstream site of interference at the level of PDK1–Akt complex formation, beyond PI3K and PIP3 availability. By contrast, the structurally related analog N-methyl-citalopram showed no effect, reinforcing a structure-dependent mechanism of interference with PDK1–Akt signaling. Functionally, escitalopram enhanced apoptosis in BCR-stimulated cells. Similar inhibition under insulin and SDF-1 stimulation indicates a generalized, receptor-independent effect. These findings reveal a noncanonical, SERT-independent mechanism by which escitalopram disrupts PDK1–Akt activation, with potential relevance to the broader intracellular effects of SSRI treatment.

PI3K-Akt通路是跨受体系统的生存和生长信号的中枢调节因子，受膜-近端PDK1-Akt信号传导节点控制。虽然选择性5 -羟色胺再摄取抑制剂（SSRIs）主要靶向5 -羟色胺转运体（SERT），但有证据表明对细胞内信号传导有其他作用。Escitalopram是一种广泛使用的SSRI，先前被证明可以抑制血小板中的Syk磷酸化，这增加了sert不依赖于激酶级联反应的可能性。在这里，我们研究了艾司西酞普兰及其相关化合物是否通过B细胞受体（BCR）刺激Ramos B淋巴瘤细胞干扰PI3K-Akt信号。艾司西酞普兰及其对映体r -西酞普兰选择性地降低Akt及其下游效应物fox01的磷酸化，同时保留上游的Syk和平行的ERK和PLC-PKC通路。为了定位干扰位点，我们将pdk1依赖靶点的分析与pten抑制模型相结合。艾司西酞普兰抑制PLK1和S6K1磷酸化，但不改变mTORC2的自磷酸化，还能降低h2o2诱导的Akt磷酸化。这些互补的结果指出了PDK1-Akt复合物形成水平的下游干扰位点，超出了PI3K和PIP3的可用性。相比之下，结构相关的类似物n -甲基西酞普兰没有效果，这加强了对PDK1-Akt信号通路干扰的结构依赖机制。在功能上，艾司西酞普兰促进bcr刺激细胞的凋亡。胰岛素和SDF-1刺激下的类似抑制表明了一种广泛的、不依赖于受体的作用。这些发现揭示了escitalopram破坏PDK1-Akt活化的非规范、sert独立机制，可能与SSRI治疗更广泛的细胞内效应相关。

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引用次数: 0

Developmental spatiotemporal switching of the germline-specific subunits of heterodimeric NAC protein in Drosophila melanogaster 黑腹果蝇异二聚体NAC蛋白种系特异性亚基的发育时空开关。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-09 DOI: 10.1016/j.bbamcr.2025.120085

Elena A. Mikhaleva , Natalia V. Akulenko , Oxana M. Olenkina , Yuri A. Abramov , Sergey A. Lavrov , Thoomas A. Leinsoo , Sofia V. Marfina , Georgij Arapidi , Victoria Shender , Sergei S. Ryazansky , Galina L. Kogan , Vladimir A. Gvozdev

The ribosome-associated αβ heterodimeric ubiquitously expressed NAC protein is involved in protein homeostasis in eukaryotes. We previously reported that the germline-specific α and β subunits (gNACαβ) differ from ubiquitously expressed paralogs by the presence of extended intrinsically disordered regions. The embryonic precursors of the germline (pole cells) express both α and β gNAC subunits. CRISPR/Cas9-mediated knockout of the gNAC α- subunit gene resulted in the death of pole cells progenitors, implicating gNAC as an essential component of the germ plasm responsible for the germline development. Immunofluorescence detection was used to track changes in the expression of α- and β-subunits of gNAC during development. The bright fluorescence of the α-subunit in the germarium strongly decreases during oocyte specification and is replaced by the onset of increased β-subunit fluorescence, especially in the posterior part of mature oocytes, in the germ plasm region, where NACα-subunit fluorescent signal is absent. The visualized switches of gNAC subunits presence, as well as detection of separate cytoplasmic fluorescent puncta for α and β gNAC subunits in a germline cells (elongating spermatids in testis or embryonic pole cells), are explained by transient formation the hybrid NAC heterodimers composed of α or β germline subunit and a ubiquitous partner. The formation of hybrids, demonstrated by mass spectrometry analysis in testes, indicates a programed spatiotemporal functioning of both the ubiquitous and germline-specific NAC paralogs to support the germline-specific proteostasis.

核糖体相关αβ异二聚体普遍表达的NAC蛋白参与真核生物的蛋白稳态。我们之前报道了种系特异性α和β亚基（gNACαβ）与普遍表达的相似物的不同之处在于存在扩展的内在无序区域。胚系的胚胎前体细胞（极细胞）同时表达α和β gNAC亚基。CRISPR/ cas9介导的敲除gNAC α-亚基基因导致极细胞祖细胞死亡，这表明gNAC是负责种系发育的种质的重要组成部分。采用免疫荧光法跟踪gNAC在发育过程中α-和β-亚基的表达变化。在卵母细胞分化过程中，胚芽中α-亚基的明亮荧光强烈减弱，取而代之的是β-亚基荧光开始增强，尤其是在成熟卵母细胞后部，在质区，nac α-亚基荧光信号缺失。gNAC亚基存在的可视化开关，以及在生殖系细胞（睾丸或胚胎极细胞中的细长精子）中检测到α和β gNAC亚基的分离细胞质荧光点，可以通过由α或β生殖系亚基和无处不在的伴侣组成的杂交NAC异源二聚体的瞬时形成来解释。睾丸质谱分析表明，杂种的形成表明，普遍存在的NAC和种系特异性的NAC相似物具有程序化的时空功能，以支持种系特异性的蛋白质静止。

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引用次数: 0

ATR-FTIR spectroscopy as a reliable analytical tool in cancer research: Tracking glycosylation-induced protein and lipid alteration in extracellular vesicles ATR-FTIR光谱在癌症研究中的可靠分析工具：追踪细胞外囊泡中糖基化诱导的蛋白质和脂质改变。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-04 DOI: 10.1016/j.bbamcr.2025.120082

Magdalena Wilczak , Andrzej Wróbel , Magdalena Surman , Martyna Durak-Kozica , Ewa Ł. Stępień , Małgorzata Przybyło

The rising incidence of cancer creates an urgent need to develop faster methods for early detection. Fourier Transform Infrared Spectroscopy (FTIR) spectroscopy is a promising technique to analyse molecular content in biological samples. FTIR has also been used to study structural changes in extracellular vesicles (EVs), revealing alterations in protein secondary structure, protein-to-lipid ratio, and protein phosphorylation levels. We investigated how changes in glycosylation, which naturally occur during tumor progression, affect the previously mentioned parameters and whether these cellular changes are reflected in EV composition. The WM266–4 melanoma cell line, treated with two glycosylation inhibitors, was used as a model. After treatment, EVs were isolated and ATR-FTIR measurements were performed, followed by a comprehensive analysis of the data. Significant differences in protein and lipid content were observed between EV populations treated with glycosylation inhibitors, with greater changes in EVs compared to cells. Glycosylation inhibitors also increased the level of phosphorylated proteins in EVs. Our findings showed that changes in EVs were more dynamic than at the cellular level cells. The presented analysis shows that subtle molecular changes can significantly impact EV cargo and properties. FTIR is a powerful tool for detecting these changes and may aid future cancer diagnostics.

癌症发病率不断上升，迫切需要开发更快的早期检测方法。傅里叶变换红外光谱（FTIR）是一种很有前途的分析生物样品中分子含量的技术。FTIR也被用于研究细胞外囊泡（EVs）的结构变化，揭示蛋白质二级结构、蛋白脂比和蛋白质磷酸化水平的变化。我们研究了在肿瘤进展过程中自然发生的糖基化变化如何影响上述参数，以及这些细胞变化是否反映在EV组成中。用两种糖基化抑制剂处理的WM266-4黑色素瘤细胞系作为模型。治疗后，分离EVs，进行ATR-FTIR测量，然后对数据进行综合分析。在糖基化抑制剂处理的EV群体之间，观察到蛋白质和脂质含量的显著差异，与细胞相比，EV的变化更大。糖基化抑制剂也增加了ev中磷酸化蛋白的水平。我们的研究结果表明，电动汽车的变化比细胞水平的变化更具动态性。分析表明，微小的分子变化会显著影响电动汽车的载货量和性能。FTIR是检测这些变化的有力工具，可能有助于未来的癌症诊断。

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引用次数: 0

Endothelial ANGPT2 impairs cardiomyocyte calcium homeostasis via ITGB3 receptor in murine sepsis-related cardiomyopathy 内皮ANGPT2通过ITGB3受体在小鼠败血症相关心肌病中损害心肌细胞钙稳态。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-04 DOI: 10.1016/j.bbamcr.2025.120083

Yi-Ni Lu , Wen-Xue Liu , Xiao-Han Wang , Xiong Zhang , Yu-Fen Zheng , Tian-Yin Wang , Feng Chen , Feng Yu

Sepsis-related cardiomyopathy (SCM) is a life-threatening complication of sepsis, characterized by cardiac dysfunction. Although angiopoietin 2 (ANGPT2) is pivotal in the pathological progress of several diseases, its functional involvement in the pathogenesis of SCM remains uncharacterized. In this study, we demonstrated that ANGPT2 is a key regulator of SCM progression, bridging the functional homeostasis between vascular endothelial cells (ECs) and cardiomyocytes. Bioinformatics analysis of a SCM-related gene set derived from public databases revealed that ANGPT2 is a critical regulatory node. Serum ANGPT2 levels correlated with elevated creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) in vivo. Abnormal cardiac function was observed in cecal ligation and puncture (CLP)-induced sepsis mouse model and adeno-associated virus 9-mediated endothelial cell-specific ANGPT2-overexpressing (AAV9-Angpt2) mice, primarily characterized by reduced left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Additionally, integrin β1 (ITGB1) and integrin β3 (ITGB3) were upregulated, along with dysregulation of calcium signaling-associated proteins in cardiac tissue. Notably, AAV9-Angpt2 mice exhibited exacerbated CLP-induced cardiac dysfunction. In vitro experiments showed that ANGPT2 significantly reduced the beating frequency of primary neonatal mouse cardiomyocytes (NMCMs), and disrupted intracellular calcium homeostasis in adult mouse cardiomyocytes (AMCMs). Mechanistically, ANGPT2 activates and binds to the extracellular domains of ITGB3, thereby triggering ryanodine receptor 2 (RYR2) phosphorylation and upregulating the reticulum calcium ATPase 2 (ATP2a2) and phospholamban (PLN) expression, while simultaneously suppressing PLN phosphorylation. ITGB3-specific siRNA significantly attenuated the effects of ANGPT2 on calcium signaling proteins and intracellular calcium homeostasis. Collectively, these results suggest that the ANGPT2-ITGB3 signaling axis plays an important role in the pathogenesis of SCM in mice and may support this pathway as a potential therapeutic target during sepsis in humans.

败血症相关性心肌病（SCM）是一种危及生命的败血症并发症，以心功能障碍为特征。尽管血管生成素2 （ANGPT2）在几种疾病的病理进展中起关键作用，但其在SCM发病机制中的功能参与尚不清楚。在这项研究中，我们证明了ANGPT2是SCM进展的关键调节因子，在血管内皮细胞（ECs）和心肌细胞之间的功能稳态之间架起桥梁。生物信息学分析来自公共数据库的scm相关基因集显示，ANGPT2是一个关键的调控节点。体内血清ANGPT2水平与肌酸激酶- mb （CK-MB）和心肌肌钙蛋白I （cTnI）升高相关。在阑尾结扎穿刺（CLP）诱导的脓毒症小鼠模型和腺相关病毒9介导的内皮细胞特异性angpt2过表达（AAV9-Angpt2）小鼠中观察到异常心功能障碍，主要表现为左心室舒张末期容积（LVEDV）和左心室收缩末期容积（LVESV）降低。此外，整合素β1 （ITGB1）和整合素β3 （ITGB3）上调，并伴有心脏组织钙信号相关蛋白的失调。值得注意的是，AAV9-Angpt2小鼠表现出加重的clp诱导的心功能障碍。体外实验表明，ANGPT2显著降低初生小鼠心肌细胞（NMCMs）的搏动频率，并破坏成年小鼠心肌细胞（AMCMs）的细胞内钙稳态。在机制上，ANGPT2激活并结合ITGB3的胞外结构域，从而触发红嘌呤受体2 （RYR2）磷酸化，上调网状钙atp酶2 （ATP2a2）和磷蛋白（PLN）表达，同时抑制PLN磷酸化。itgb3特异性siRNA显著减弱ANGPT2对钙信号蛋白和细胞内钙稳态的影响。总之，这些结果表明ANGPT2-ITGB3信号轴在小鼠SCM的发病机制中起重要作用，并可能支持该途径作为人类败血症的潜在治疗靶点。

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引用次数: 0

Frequent EPHA2 receptor mutations in cholangiocarcinoma disrupt receptor forward signaling supporting a tumor suppressor role 胆管癌中频繁的EPHA2受体突变破坏了支持肿瘤抑制作用的受体正向信号传导。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-03 DOI: 10.1016/j.bbamcr.2025.120081

Evodie Koutouan , Alejandro Lillo , Ayano Kabashima , Jack W. Sample , Danielle Carlson , Rondell Graham , Rory L. Smoot , Elena B. Pasquale

Although EPHA2 is a receptor tyrosine kinase widely expressed in many cancers, it exhibits a uniquely high frequency of coding sequence mutations in cholangiocarcinoma, a cancer of the biliary tract with dismal prognosis. EPHA2 is extensively studied, but very little is known about the role of EPHA2 cancer mutations. To define the functional significance of EPHA2 mutations in biliary tract cancers, we generated representative EPHA2 mutants and monitored major receptor autophosphorylation sites as indicators of kinase activity-dependent signal transduction (known as forward signaling). We found that missense mutations in the ligand-binding domain abrogate ephrinA ligand binding, while missense mutations in the kinase domain abrogate kinase activity. The effects of missense mutations in other domains were less pronounced and varied depending on the phosphosite. The majority of the EPHA2 mutations are nonsense or frame-shift mutations that introduce early stop codons. They generate EPHA2 truncated forms that lack an intact kinase domain or, in some cases, most of the coding sequence. Several EPHA2 mutants tested inhibited tyrosine phosphorylation of co-expressed EPHA2 wild-type, indicating the ability to exert dominant negative effects. We show that EPHA2 forward signaling in cholangiocytes inhibits the ERK oncogenic pathway and cell proliferation, suggesting that loss-of-function mutations facilitate tumor development in the biliary tract. Indeed, an EPHA2 kinase-inactive mutant, but not EPHA2 wild-type, induced proliferative masses consistent with well differentiated cholangiocarcinoma in a validated mouse model of cholangiocarcinogenesis. Thus, EPHA2 has the attributes of a driver gene with tumor suppressor activity in biliary tract cancers.

虽然EPHA2是一种在许多癌症中广泛表达的受体酪氨酸激酶，但它在胆管癌中表现出独特的高频率编码序列突变，胆管癌是一种预后不良的胆道癌症。EPHA2被广泛研究，但对EPHA2癌症突变的作用知之甚少。为了确定EPHA2突变在胆道癌症中的功能意义，我们生成了具有代表性的EPHA2突变体，并监测了主要受体自磷酸化位点作为激酶活性依赖性信号转导（称为正向信号转导）的指标。我们发现配体结合域的错义突变取消了ephrinA配体结合，而激酶结构域的错义突变取消了激酶活性。错义突变在其他结构域的影响不太明显，并根据磷的不同而变化。大多数EPHA2突变是无义突变或引入早期终止密码子的移帧突变。它们产生EPHA2截断形式，缺乏完整的激酶结构域，或者在某些情况下，缺乏大部分编码序列。几个EPHA2突变体被测试抑制了共表达EPHA2野生型的酪氨酸磷酸化，表明能够发挥显性的负面作用。我们发现，胆管细胞中的EPHA2正向信号传导抑制ERK致癌途径和细胞增殖，这表明功能缺失突变促进了胆道肿瘤的发展。事实上，EPHA2激酶失活突变体，而不是EPHA2野生型，在经过验证的小鼠胆管癌发生模型中诱导增殖肿块与高分化胆管癌一致。因此，EPHA2在胆道肿瘤中具有肿瘤抑制活性的驱动基因的属性。

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引用次数: 0

EZH2-mediated hypermethylation of H3K27me3 downregulates claudin-4 and upregulates the Wnt/β-catenin signaling pathway in hepatocellular carcinoma metastasis ezh2介导的H3K27me3高甲基化下调claudin-4并上调肝癌转移过程中Wnt/β-catenin信号通路。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-02 DOI: 10.1016/j.bbamcr.2025.120076

Smriti Verma , Manisha Yadav , Shobhit Verma , Anurag Kumar Srivastava , Madhav Nilakanth Mugale

Enhancer of zeste homolog 2 (EZH2) is often overexpressed in malignant tumors and plays a key role in metastasis by trimethylating lysine 27 on histone H3 (H3K27me3). However, the exact mechanism by which EZH2 facilitates metastasis in the diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR)-induced hepatocellular carcinoma (HCC) model remains unexplored. In this study, we demonstrated that EZH2 expression is elevated in HCC and is associated with metastasis to lung tissue, with poor overall survival outcomes. EZH2 overexpression in HCC liver tissues inhibited claudin-4 gene expression and promoted the activation of the Wnt/β-catenin signaling pathway. β-catenin signaling activates Lymphoid Enhancer-Binding Factor 1(LEF-1) transcription factors that regulate the expression of genes involved in epithelia-to-mesenchymal transition (EMT) and metastasis. EZH2 overexpression significantly elevates H3K27me3 at the promoter, suppressing claudin-4 expression. This leads to increased levels of Matrix metalloproteinase-9 (MMP-9) and vimentin, enhancing the invasion, migration, and metastasis of hepatocellular carcinoma (HCC) cells. However, inhibiting EZH2 with tazemetostat subsequently enhanced claudin-4 expression by reducing Wnt/β-catenin signaling activity and inhibiting EMT-inducing factors.

zeste同源物增强子2 （Enhancer of zeste homolog 2, EZH2）在恶性肿瘤中经常过表达，并通过组蛋白H3 （H3K27me3）上赖氨酸27的三甲基化在转移中起关键作用。然而，EZH2在二乙基亚硝胺（DEN）和n -亚硝基somoroline （NMOR）诱导的肝细胞癌（HCC）模型中促进转移的确切机制尚不清楚。在这项研究中，我们证明了EZH2在HCC中的表达升高，并与肺组织转移有关，总体生存结果较差。HCC肝组织中EZH2过表达抑制claudin-4基因表达，促进Wnt/β-catenin信号通路的激活。β-catenin信号通路激活淋巴细胞增强因子结合因子1（LEF-1）转录因子，而LEF-1转录因子调节上皮间质转化（EMT）和转移相关基因的表达。EZH2过表达显著提高启动子处的H3K27me3，抑制claudin-4的表达。这导致基质金属蛋白酶-9 （MMP-9）和波形蛋白水平升高，增强肝细胞癌（HCC）细胞的侵袭、迁移和转移。然而，他zemetostat抑制EZH2随后通过降低Wnt/β-catenin信号活性和抑制emt诱导因子增强了cludin -4的表达。

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引用次数: 0

Adipose-derived stem cells (ADSCs)-derived DKK1 promotes cutaneous wound healing by inducing M2 macrophage polarization via PI3K/AKT and JNK activation 脂肪源性干细胞（ADSCs）衍生的DKK1通过激活PI3K/AKT和JNK诱导M2巨噬细胞极化，从而促进皮肤伤口愈合。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-11-01 DOI: 10.1016/j.bbamcr.2025.120077

Daiming Liu , Ning Liu , Xinxuan Liu , Yi Liu , Hongjia Zhang , Zhuoqian Zhou , Jiawang Zheng , Yi Tian

Wound healing requires the coordinated resolution of inflammation and tissue regeneration, whereby the role played by macrophage polarization is critical. This study investigates whether adipose-derived stem cells (ADSCs) promote wound repair through paracrine dickkopf-related protein 1 (DKK1) and explores their regulatory mechanism on macrophage polarization. In a murine full-thickness skin wound model, ADSCs treatment significantly enhanced re-epithelialization, collagen deposition, and Ki67 expression levels, while reducing local inflammatory cytokines and promoting M2 macrophage polarization. In vitro, ADSCs suppressed proinflammatory cytokines and induced M2 markers in LPS/IFN-γ-stimulated macrophages, an effect that was attenuated upon DKK1 knockdown. Mechanistically, DKK1 enhanced PI3K/AKT and JNK pathway activation both in macrophages and wound tissue. DKK1-deficient ADSCs showed a diminished ability to promote wound healing, reduce inflammation, and modulate macrophage phenotypes. These findings identify DKK1 as a key paracrine mediator of ADSCs-driven immunomodulation and tissue regeneration, thereby providing new insights into optimizing stem cell-based therapies for wound healing.

伤口愈合需要炎症和组织再生的协调解决，巨噬细胞极化的作用是至关重要的。本研究探讨脂肪源性干细胞（ADSCs）是否通过旁分泌dickkopf相关蛋白1 （DKK1）促进伤口修复，并探讨其对巨噬细胞极化的调控机制。在小鼠全层皮肤创面模型中，ADSCs处理显著提高了再上皮化、胶原沉积和Ki67表达水平，同时降低了局部炎症因子，促进了M2巨噬细胞极化。在体外，ADSCs抑制LPS/IFN-γ刺激的巨噬细胞中的促炎细胞因子和诱导的M2标记物，这种作用在DKK1敲除后减弱。在机制上，DKK1增强了巨噬细胞和伤口组织中PI3K/AKT和JNK通路的激活。缺乏dkk1的ADSCs显示促进伤口愈合、减少炎症和调节巨噬细胞表型的能力减弱。这些发现确定了DKK1是adscs驱动的免疫调节和组织再生的关键旁分泌介质，从而为优化基于干细胞的伤口愈合治疗提供了新的见解。

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引用次数: 0

13th Tuscany Retreat on Cancer Research and Apoptosis: Genetic profiling, resistance mechanisms and novel treatment concepts in cancer and neurodegeneration 第十三届托斯卡纳癌症研究与细胞凋亡学术研讨会：癌症和神经退行性疾病的基因分析、耐药机制和新的治疗理念。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-30 DOI: 10.1016/j.bbamcr.2025.120079

Femke Speelman-Rooms , Olga Troitskaya , Hannah Coxhead , Claire Naveh , Konstantinos Kelepouras , Marta Manik , Annalena Renner , Dhairya Rajguru , Jelena Budimir , Fatma Isil Yapici , Ophélie Champion

The 13th edition of the Tuscany Retreat on Cancer Research and Apoptosis was convened on August 23rd to 30th, 2025, continuing its tradition as a biennial forum for scientific exchange. The Retreat brought together leading investigators focused on cancer biology, programmed cell death, and neurodegenerative disorders. Presentations and discussions encompassed diverse themes, including mechanisms of therapeutic resistance, advances in molecular signaling networks, and the identification of novel cellular targets. All topics were unified by their relevance to the regulation of programmed cell death and the pathological consequences of its disruption. Through this review, we intend to convey the essence of the scientific exchanges and to summarize the major take-home messages derived from the Retreat.

第13届托斯卡纳癌症研究与细胞凋亡会议于2025年8月23日至30日召开，延续了其两年一次的科学交流论坛的传统。这次会议汇集了癌症生物学、程序性细胞死亡和神经退行性疾病的主要研究人员。演讲和讨论涵盖了多种主题，包括治疗耐药机制、分子信号网络的进展以及新细胞靶点的鉴定。所有主题都是统一的，因为它们与程序性细胞死亡的调节及其破坏的病理后果有关。通过这篇综述，我们打算传达科学交流的精髓，并总结从务虚会中获得的主要信息。

引用次数: 0

O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway DDX46的o - glcn酰化通过激活PI3K/Akt信号通路促进肝细胞癌的进展。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-30 DOI: 10.1016/j.bbamcr.2025.120080

Qiujie Wang, Yuanyuan Liu, Kai Wang, Ailong Huang, Ni Tang, Pai Peng

O-linked-β-N-acetylglucosamine (O-GlcNAc) modification, also known as O-GlcNAcylation, is a dynamic and reversible protein modification. Aberrant O-GlcNAcylation are associated with the pathogenesis of cancers. DEAD-box helicase 46 (DDX46) is an ATP-dependent RNA helicase associated with cancer development; however, its role and regulation in hepatocellular carcinoma (HCC) remain unclear. In this study, we observed that the level of O-GlcNAcylation of DDX46 was significantly elevated in HCC mouse models and patients. In addition, direct OGT-DDX46 interaction facilitates O-GlcNAcylation at the Ser257 site. Mechanically, we discovered that O-GlcNAcylation enhances the stability of DDX46 by impeding ubiquitin-mediated degradation. Increased expression of DDX46 activates the PI3K/Akt signaling pathway, promoting the proliferation and invasion of HCC. Taken together, our study highlights the critical role of DDX46 O-GlcNAcylation in HCC progression, thus proposing targeted disruption of this cascade as a novel therapeutic strategy for HCC treatment.

O-linked-β- n -乙酰氨基葡萄糖（O-GlcNAc）修饰，又称O-GlcNAc酰化，是一种动态可逆的蛋白质修饰。异常的o - glcn酰化与癌症的发病机制有关。DEAD-box解旋酶46 （DDX46）是一种与癌症发展相关的atp依赖性RNA解旋酶；然而，其在肝细胞癌（HCC）中的作用和调控尚不清楚。在本研究中，我们观察到DDX46的o - glcnac酰化水平在HCC小鼠模型和患者中显著升高。此外，直接OGT-DDX46相互作用促进了Ser257位点的o - glcn酰化。机械地，我们发现o - glcn酰化通过阻碍泛素介导的降解来增强DDX46的稳定性。DDX46表达增加激活PI3K/Akt信号通路，促进HCC的增殖和侵袭。综上所述，我们的研究强调了DDX46 o - glcn酰化在HCC进展中的关键作用，因此提出了靶向破坏该级联作为HCC治疗的新治疗策略。

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引用次数: 0

Basic leucine zipper ATF-like transcription factor (Batf) aggravates central sensitization in nitroglycerin-induced chronic migraine mouse model 碱性亮氨酸拉链atf样转录因子（Batf）在硝酸甘油诱导的慢性偏头痛小鼠模型中加重中枢致敏

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-29 DOI: 10.1016/j.bbamcr.2025.120078

Yanhong Liu , Xiaoyu Tong

Chronic migraine (CM) is a widespread neurological disorder with heterogeneous underlying causes. Basic leucine zipper ATF-like transcription factor (Batf) can amplify neuroinflammatory responses, but therapeutic strategies targeting Batf in CM remain unclear. Here, we investigated the role of Batf in a nitroglycerin (NTG)-induced CM mouse model and lipopolysaccharide (LPS)-induced BV-2 cells. Batf and Iba-1 expression were enhanced in the trigeminal nucleus caudalis (TNC) of NTG-induced mice. Batf knockdown mitigated NTG-induced central sensitization, decreased CGRP and c-Fos expression, and inhibited Iba-1, iNOS, IL-18, and IL-1β expression in TNC of NTG-induced mice. Furthermore, the NLRP3 inflammasome in TNC of NTG-induced mice was inhibited by Batf knockdown. Our results suggested that Batf knockdown attenuated central sensitization through mediating microglial activation via the NLRP3 inflammasome in the TNC of CM mice. Batf might be a candidate for migraine treatment.

慢性偏头痛（CM）是一种广泛的神经系统疾病与异质性的潜在原因。碱性亮氨酸拉链atf样转录因子（Batf）可以放大神经炎症反应，但针对Batf的CM治疗策略尚不清楚。在这里，我们研究了Batf在硝酸甘油（NTG）诱导的CM小鼠模型和脂多糖（LPS）诱导的BV-2细胞中的作用。ntg诱导小鼠三叉神经尾核（TNC）中Batf和Iba-1表达增强。Batf敲低可减轻ntg诱导的中枢致敏，降低CGRP和c-Fos的表达，抑制ntg诱导小鼠TNC中Iba-1、iNOS、IL-18和IL-1β的表达。此外，ntg诱导小鼠TNC中NLRP3炎性体被Batf敲低抑制。我们的研究结果表明，在CM小鼠的TNC中，Batf敲除通过介导NLRP3炎性体的小胶质细胞激活来减弱中枢致敏。蝙蝠可能是治疗偏头痛的候选药物。

引用次数: 0