International Journal of Biochemistry & Cell Biology最新文献_第4页

β-Tricalcium phosphate nanoparticles induce macrophage polarization to M1-type through mitochondrial oxidative stress activation β-磷酸三钙纳米颗粒通过线粒体氧化应激激活诱导巨噬细胞向m1型极化

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-12-01 Epub Date: 2025-09-25 DOI: 10.1016/j.biocel.2025.106868

Yunbing Chen , Xinping Li , Hongyi Yang, Gaoying Ran, Lifang Zhang, Shuguang Zeng

β-Tricalcium phosphate (β-TCP), frequently employed for bone tissue regeneration, can induce inflammation during the initial phases of implantation within the organism. However, mechanisms by which β-TCP nanoparticles (NPs) cause this inflammatory response is rarely reported. This project aims to investigate the causes of the macrophage inflammatory response induced by β-TCP NPs. Here, macrophage-like RAW264.7 cells were co-cultured with conditioned medium containing β-TCP NPs to identify the pathways through which β-TCP NPs influence inflammation and polarization of macrophages. This effect is achieved by modulating mitochondrial oxidative stress in the immune microenvironment. The results demonstrated that β-TCP NPs caused mitochondrial swelling, increased intracellular calcium ions, reduced mitochondrial membrane potential, as well as decreased the level of adenosine triphosphate (ATP) and translocase of outer mitochondrial membrane 20 (TOMM20). These NPs further lead to mitochondrial oxidative damage. These alterations promoted the polarization of macrophage to M1-type. Exogenous mitochondrial-targeted antioxidants could block this M1-type macrophage polarization. The findings of this work suggest that β-TCP NPs induce macrophage inflammation and contribute to M1 macrophage polarization, primarily through the activation of mitochondrial oxidative stress. These insights could guide the development of improved β-TCP formulations to mitigate inflammatory responses in bone regeneration applications.

β-磷酸三钙（β-TCP）常用于骨组织再生，可在生物体内植入的初始阶段诱导炎症。然而，β-TCP纳米颗粒（NPs）引起这种炎症反应的机制很少报道。本项目旨在探讨β-TCP NPs诱导巨噬细胞炎症反应的原因。本研究将巨噬细胞样RAW264.7细胞与含有β-TCP NPs的条件培养基共培养，以确定β-TCP NPs影响巨噬细胞炎症和极化的途径。这种效果是通过调节免疫微环境中的线粒体氧化应激来实现的。结果表明，β-TCP NPs引起线粒体肿胀，增加细胞内钙离子，降低线粒体膜电位，降低线粒体外膜20转位酶（TOMM20）和三磷酸腺苷（ATP）水平。这些NPs进一步导致线粒体氧化损伤。这些改变促进巨噬细胞向m1型极化。外源性线粒体靶向抗氧化剂可阻断这种m1型巨噬细胞极化。本研究结果表明，β-TCP NPs主要通过激活线粒体氧化应激诱导巨噬细胞炎症并促进M1巨噬细胞极化。这些见解可以指导改进β-TCP配方的发展，以减轻骨再生应用中的炎症反应。

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引用次数: 0

Escin alleviates DNCB-induced atopic dermatitis-like symptoms by promoting autophagy activation and tight junction barrier restoration Escin通过促进自噬激活和紧密连接屏障恢复来缓解dncb诱导的特应性皮炎样症状。

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-12-01 Epub Date: 2025-09-22 DOI: 10.1016/j.biocel.2025.106865

Zhenxing Liu , Jingye Zhao , Lei Zhang , Xiaoting Wu , Jiamiao Liu , Yuanrui Mei , Shuyan Liu , Jieru Lin , Hongyan Li , Xiaoye Qi , Fuping Lu , Huabing Zhao , Aipo Diao

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by impaired skin barrier function and immune dysregulation. Autophagy, a lysosome-dependent degradation pathway essential for removing unnecessary components, plays a crucial role in maintaining cellular homeostasis. Defective autophagy has been implicated in AD pathogenesis, and enhancing autophagic activity represents a viable therapeutic strategy. This study investigated the potential of the natural saponin escin to ameliorate AD through autophagy activation. We demonstrated that escin induced autophagy in HaCaT keratinocytes and mitigated tight junction (TJ) barrier disruption in an AD-like cell model stimulated with IL-4 and IL-13. Notably, silencing ATG7, an essential autophagy-related protein, abrogated the barrier-restorative effects of escin. Furthermore, in a 2,4-dinitrochlorobenzene (DNCB)-induced murine model of AD, escin treatment ameliorated AD-like skin lesions, reduced mast cell infiltration, and decreased cutaneous levels of the pro-inflammatory cytokines IL-4, IL-13, and IFN-γ. Escin administration also restored the epidermal expression of key TJ proteins, Claudin-1 and ZO-1. Mechanistically, escin promoted the nuclear translocation of transcription factor EB (TFEB) and upregulated the expression of genes involved in autophagy and lysosome biogenesis. These protective effects were associated with the activation of the AMPK-mTORC1-TFEB signaling pathway. Collectively, our findings indicate that escin enhances autophagy and restores skin barrier function, highlighting its potential as a novel therapeutic agent for AD treatment.

特应性皮炎（AD）是一种以皮肤屏障功能受损和免疫失调为特征的慢性炎症性皮肤病。自噬是一种依赖于溶酶体的降解途径，对去除不必要的成分至关重要，在维持细胞稳态中起着至关重要的作用。自噬缺陷与AD的发病机制有关，增强自噬活性是一种可行的治疗策略。本研究探讨了天然皂苷叶香素通过自噬激活改善AD的潜力。在IL-4和IL-13刺激的ad样细胞模型中，escin诱导HaCaT角质形成细胞自噬，并减轻紧密连接（TJ）屏障破坏。值得注意的是，沉默ATG7（一种重要的自噬相关蛋白）可以消除escin的屏障修复作用。此外，在2,4-二硝基氯苯（DNCB）诱导的AD小鼠模型中，escin治疗改善了AD样皮肤病变，减少了肥大细胞浸润，降低了促炎细胞因子IL-4、IL-13和IFN-γ的皮肤水平。Escin也恢复了表皮关键TJ蛋白Claudin-1和ZO-1的表达。机制上，escin促进了转录因子EB （TFEB）的核易位，上调了自噬和溶酶体生物发生相关基因的表达。这些保护作用与AMPK-mTORC1-TFEB信号通路的激活有关。总之，我们的研究结果表明，叶皂苷可以增强自噬并恢复皮肤屏障功能，这突出了它作为一种新的治疗阿尔茨海默病的药物的潜力。

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引用次数: 0

The DNA damage response in myogenic C2C7 cells depends on the characteristics of ionizing particles 肌源性C2C7细胞的DNA损伤反应取决于电离粒子的特性。

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-12-01 Epub Date: 2025-10-14 DOI: 10.1016/j.biocel.2025.106872

Haser H. Sutcu , Arthur Thomas--Joyeux , Mikaël Cardot-Martin , Delphine Dugué , François Vianna , Yann Perrot , Mohamed A. Benadjaoud , Marc Benderitter , Céline Baldeyron

DNA integrity and stability are vital for proper cellular activity. Nevertheless, to treat cancer patients, DNA is the main target for inducing tumoral cell death. Nowadays, cancer treatment is improving by the development of new technologies, protocols and strategies. Amongst them, the charged particle radiotherapies are becoming prevalent. However, tumor-neighboring healthy tissues are still exposed to ionizing radiation (IR) and subject to late side effects. Skeletal muscle is one of those tissues most likely to be affected. To decipher the DNA damage response (DDR) of skeletal muscle cells, myogenic cells, we irradiated them with microbeams of protons or α-particles and followed the accumulation of DDR proteins at localized irradiation sites. Thereby, we showed that myoblasts, proliferating myogenic cells, repair local IR-induced DNA damage through both non-homologous end-joining and homologous recombination with different recruitment dynamics depending on the characteristics of ionizing particles (type, energy deposition and time after irradiation), whereas myotubes, post-mitotic myogenic cells, display globally reduced DNA damage response.

DNA的完整性和稳定性对正常的细胞活动至关重要。然而，在治疗癌症患者时，DNA是诱导肿瘤细胞死亡的主要靶点。如今，随着新技术、新方案和新策略的发展，癌症治疗正在不断改进。其中，带电粒子放射治疗越来越流行。然而，肿瘤邻近的健康组织仍然暴露于电离辐射（IR）并受到后期副作用的影响。骨骼肌是最容易受到影响的组织之一。为了研究骨骼肌细胞的DNA损伤反应（DDR），我们用质子或α-粒子微束照射骨骼肌细胞，并在局部照射部位观察DDR蛋白的积累。因此，我们发现，肌母细胞，增殖性肌原细胞，通过非同源末端连接和同源重组修复局部ir诱导的DNA损伤，并根据电离粒子的特征（类型、能量沉积和照射后时间）具有不同的招募动力学，而肌管，有丝分裂后的肌原细胞，显示出整体降低的DNA损伤反应。

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引用次数: 0

Pyruvate kinase M2 (PKM2) regulates rheumatoid arthritis by mediating glycolysis reprogramming through the Akt/mTOR pathway 丙酮酸激酶M2 （PKM2）通过Akt/mTOR通路介导糖酵解重编程调控类风湿关节炎。

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-12-01 Epub Date: 2025-10-06 DOI: 10.1016/j.biocel.2025.106870

Hai-yang Liao , Guo-hua Zhang , Jian-xiong Zheng , Jin-yue Lu , Jia-yao Hao , Min Tan , Zhan-dong Wang , Hai-li Shen

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Fibroblast-like synovial cells (FLSs) are the main effector cells in the synovial microenvironment that cause chronic swelling and joint injury, and their enhanced glycolytic metabolism can lead to persistent joint injury. As a key regulatory enzyme in glycolysis, pyruvate kinase M2 (PKM2) plays a crucial role in the pathogenesis of RA. However, the exact mechanism by which PKM2 induces the inflammatory response of RA-FLSs through enhanced glucose metabolism and its impact on the pathogenic behaviour of cells remain unclear. This study detected the expression of PKM2 in synovial tissues and RA-FLSs of patients with RA and explored the effect of PKM2 on collagen-induced arthritis (CIA) rats. The results showed that PKM2 was upregulated in the synovial tissue of RA and RA-FLSs. PKM2 could promote glucose uptake, ATP and lactic acid production, and extracellular acidification rate in RA-FLSs, thereby promoting the release of pro-inflammatory cytokines such as TNF-α, interleukin-1 β (IL-1β), and IL-6. However, inhibiting PKM2 can reverse these changes. In in vivo experiments, inhibition of PKM2 could significantly improve the clinical arthritis symptoms of CIA rats (reduce plantar swelling and arthritis score), down-regulate the expression of pro-inflammatory cytokines, and inhibit bone erosion in CIA rats, reducing inflammatory cell infiltration, synovial hyperplasia and joint destruction. Furthermore, inhibiting PKM2 can suppress the phosphorylated expression of Akt and mTOR proteins, thereby inhibiting glycolytic reprogramming. Our research results indicate that PKM2 mediates glycolytic reprogramming to induce the release of RA-FLSs inflammatory cytokines by activating the Akt/mTOR signaling pathway, thereby promoting the progression of RA. Therefore, PKM2 may be a candidate target for the treatment of RA. Targeting PKM2 to regulate glycolytic reprogramming can provide a new idea for the treatment of RA.

类风湿性关节炎（RA）是一种慢性自身免疫性疾病，以持续滑膜炎症和进行性关节破坏为特征。成纤维细胞样滑膜细胞（FLSs）是滑膜微环境中引起慢性肿胀和关节损伤的主要效应细胞，其糖酵解代谢的增强可导致持续性关节损伤。丙酮酸激酶M2 （pyruvate kinase M2, PKM2）作为糖酵解的关键调控酶，在RA的发病过程中起着至关重要的作用。然而，PKM2通过增强葡萄糖代谢诱导RA-FLSs炎症反应的确切机制及其对细胞致病行为的影响尚不清楚。本研究检测了PKM2在RA患者滑膜组织和RA- flss中的表达，探讨PKM2对CIA大鼠的影响。结果显示，RA和RA- flss滑膜组织中PKM2表达上调。PKM2可以促进RA-FLSs的葡萄糖摄取、ATP和乳酸生成以及细胞外酸化速率，从而促进促炎细胞因子如TNF-α、白细胞介素-1β (IL-1β)和IL-6的释放。然而，抑制PKM2可以逆转这些变化。在体内实验中，抑制PKM2可显著改善CIA大鼠的临床关节炎症状（减轻足底肿胀和关节炎评分），下调促炎细胞因子的表达，抑制CIA大鼠骨侵蚀，减轻炎症细胞浸润、滑膜增生和关节破坏。此外，抑制PKM2可以抑制Akt和mTOR蛋白的磷酸化表达，从而抑制糖酵解重编程。我们的研究结果表明，PKM2通过激活Akt/mTOR信号通路介导糖酵解重编程，诱导RA- flss炎性细胞因子的释放，从而促进RA的进展。因此，PKM2可能是治疗RA的候选靶点。靶向PKM2调控糖酵解重编程可为类风湿关节炎的治疗提供新的思路。

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引用次数: 0

ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy 通过PI3K/AKT/ mtor介导的自噬，ATP1B4作为糖尿病肌少症肌肉萎缩的候选上游调节因子

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-12-01 Epub Date: 2025-09-27 DOI: 10.1016/j.biocel.2025.106869

Tingting Duan , Shumin Jia , Dan Zhou , Liqun Zhao

Objective

This study aimed to elucidate the regulatory role of the muscle-specific gene ATP1B4 in skeletal muscle metabolism and mitophagy in diabetic sarcopenia (DS) rats.

Methods

Differentially expressed genes were screened from the GEO dataset GSE7014, and ATP1B4 was identified as a candidate gene associated with DS. A DS rat model was established via high-fat diet feeding and streptozotocin injection. ATP1B4 expression was modulated through lentiviral overexpression or knockdown. Additionally, PI3K/AKT/mTOR pathway activators (SC79, leucine) and inhibitors (LY294002, MK-2206) were administered. Protein expression of ATP1B4, phosphorylated PI3K/AKT/mTOR components, and autophagy markers (LC3-II, DRP1, ATG9, MFN2) was assessed via Western blotting, immunohistochemistry, and immunofluorescence. Skeletal muscle function and structure were evaluated using behavioral tests (treadmill and inclined plane) and histopathological staining (H&E, Masson, PAS).

Results

Bioinformatic analysis of the GSE7014 dataset identified ATP1B4 as a skeletal muscle-related differentially expressed gene enriched in extracellular matrix and metabolic pathways. In DS rats, ATP1B4 expression was upregulated, coinciding with suppression of PI3K/AKT/mTOR signaling and activation of mitophagy markers (LC3-II, DRP1, ATG9). Overexpression of ATP1B4 exacerbated hyperglycemia, muscle atrophy, collagen accumulation, and glycogen deposition, while knockdown reversed these effects. Activation of the PI3K/AKT/mTOR pathway improved muscle function and histological architecture, normalized autophagy, and reduced pathological features. However, co-overexpression of ATP1B4 eliminated the protective effects of pathway activation. Conversely, dual intervention with ATP1B4 knockdown and PI3K activation restored skeletal muscle integrity and autophagy flux. Importantly, ATP1B4 expression remained unchanged following pathway modulation, supporting its unidirectional upstream regulatory role in DS.

Conclusion

ATP1B4 may aggravate diabetic sarcopenia by acting as an upstream suppressor of the PI3K/AKT/mTOR pathway.

目的：研究肌肉特异性基因ATP1B4在糖尿病性肌肉减少症（DS）大鼠骨骼肌代谢和线粒体自噬中的调控作用。方法：从GEO数据集GSE7014中筛选差异表达基因，确定ATP1B4为与DS相关的候选基因。采用高脂饲料喂养和注射链脲佐菌素建立DS大鼠模型。ATP1B4的表达通过慢病毒过表达或敲低来调节。此外，给予PI3K/AKT/mTOR通路激活剂（SC79、亮氨酸）和抑制剂（LY294002、MK-2206）。通过Western blotting、免疫组织化学和免疫荧光检测ATP1B4、磷酸化PI3K/AKT/mTOR组分和自噬标志物（LC3-II、DRP1、ATG9、MFN2）的蛋白表达。采用行为测试（跑步机和斜面）和组织病理学染色（H&E, Masson， PAS）评估骨骼肌功能和结构。结果：GSE7014数据集的生物信息学分析鉴定ATP1B4是骨骼肌相关的差异表达基因，富集于细胞外基质和代谢途径。在DS大鼠中，ATP1B4表达上调，同时抑制PI3K/AKT/mTOR信号传导和激活线粒体自噬标志物（LC3-II, DRP1, ATG9）。ATP1B4过表达加重了高血糖、肌肉萎缩、胶原积累和糖原沉积，而敲低则逆转了这些作用。激活PI3K/AKT/mTOR通路可改善肌肉功能和组织结构，使自噬正常化，并减少病理特征。然而，ATP1B4的共过表达消除了通路激活的保护作用。相反，ATP1B4敲低和PI3K激活的双重干预可以恢复骨骼肌的完整性和自噬通量。重要的是，ATP1B4的表达在通路调节后保持不变，支持其在DS中的单向上游调控作用。结论：ATP1B4可能作为上游PI3K/AKT/mTOR通路的抑制因子而加重糖尿病肌少症。

{"title":"ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy","authors":"Tingting Duan , Shumin Jia , Dan Zhou , Liqun Zhao","doi":"10.1016/j.biocel.2025.106869","DOIUrl":"10.1016/j.biocel.2025.106869","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to elucidate the regulatory role of the muscle-specific gene ATP1B4 in skeletal muscle metabolism and mitophagy in diabetic sarcopenia (DS) rats.</div></div><div><h3>Methods</h3><div>Differentially expressed genes were screened from the GEO dataset GSE7014, and ATP1B4 was identified as a candidate gene associated with DS. A DS rat model was established via high-fat diet feeding and streptozotocin injection. ATP1B4 expression was modulated through lentiviral overexpression or knockdown. Additionally, PI3K/AKT/mTOR pathway activators (SC79, leucine) and inhibitors (LY294002, MK-2206) were administered. Protein expression of ATP1B4, phosphorylated PI3K/AKT/mTOR components, and autophagy markers (LC3-II, DRP1, ATG9, MFN2) was assessed via Western blotting, immunohistochemistry, and immunofluorescence. Skeletal muscle function and structure were evaluated using behavioral tests (treadmill and inclined plane) and histopathological staining (H&E, Masson, PAS).</div></div><div><h3>Results</h3><div>Bioinformatic analysis of the GSE7014 dataset identified ATP1B4 as a skeletal muscle-related differentially expressed gene enriched in extracellular matrix and metabolic pathways. In DS rats, ATP1B4 expression was upregulated, coinciding with suppression of PI3K/AKT/mTOR signaling and activation of mitophagy markers (LC3-II, DRP1, ATG9). Overexpression of ATP1B4 exacerbated hyperglycemia, muscle atrophy, collagen accumulation, and glycogen deposition, while knockdown reversed these effects. Activation of the PI3K/AKT/mTOR pathway improved muscle function and histological architecture, normalized autophagy, and reduced pathological features. However, co-overexpression of ATP1B4 eliminated the protective effects of pathway activation. Conversely, dual intervention with ATP1B4 knockdown and PI3K activation restored skeletal muscle integrity and autophagy flux. Importantly, ATP1B4 expression remained unchanged following pathway modulation, supporting its unidirectional upstream regulatory role in DS.</div></div><div><h3>Conclusion</h3><div>ATP1B4 may aggravate diabetic sarcopenia by acting as an upstream suppressor of the PI3K/AKT/mTOR pathway.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"189 ","pages":"Article 106869"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193857","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

Syndecan-2 positively regulates Wnt/β-catenin signaling in breast cancer cells Syndecan-2正调控乳腺癌细胞中Wnt/β-catenin信号

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-11-01 Epub Date: 2025-08-25 DOI: 10.1016/j.biocel.2025.106853

Leyli Naraghi , Alexey Koval , Vladimir L. Katanaev , S.Mahmoud A Najafi

Syndecans are a family of four-member transmembrane heparan sulfate proteoglycans that bind to various extracellular biomolecules, such as Wnt ligands, via their heparan sulfate chains, thereby controlling a variety of cellular processes. When dysregulated, syndecans can affect tumorigenesis and cancer progression by modulating key signaling pathways involved in the regulation of biological functions. Aberrant activation of Wnt/β-catenin signaling is a hallmark of many human tumors, including breast cancer. Studying the interplay between syndecans and Wnt signaling in human cancers is beneficial for identifying new therapeutic strategies, understanding tumor behavior and improving patient outcomes. Syndecan-2 is predominantly expressed by mesenchymal cells, and its overexpression in tumors of epithelial origin appears to induce aggressive behavior. Here, by measuring β-catenin cytoplasmic stabilization and transcriptional activity, we show that syndecan-2 expression significantly enhances the sensitivity of HEK293T cells and BT-20 triple-negative breast cancer cells to Wnt3a-induced activation of Wnt/β-catenin signaling. In addition, CRISPR/Cas9-mediated deletion of SDC2, the gene encoding syndecan-2, reduced β-catenin transcriptional activity in BT-20 cells in response to Wnt3a stimulation. This reduction was rescued by the re-expression of SDC2. Collectively, our results demonstrate that syndecan-2 is a positive regulator of canonical Wnt signaling. These results also suggest that syndecan-2 is a potential clinical target for inhibiting the progression of some human cancers.

Syndecans是一个四成员的跨膜硫酸肝素蛋白聚糖家族，通过其硫酸肝素链与各种细胞外生物分子（如Wnt配体）结合，从而控制多种细胞过程。当失调时，syndecans可以通过调节参与生物功能调节的关键信号通路来影响肿瘤发生和癌症进展。Wnt/β-连环蛋白信号的异常激活是包括乳腺癌在内的许多人类肿瘤的标志。研究人类癌症中syndecans和Wnt信号之间的相互作用有助于确定新的治疗策略，了解肿瘤行为和改善患者预后。Syndecan-2主要由间充质细胞表达，其在上皮源性肿瘤中的过度表达似乎会诱导侵袭性行为。本文通过测量β-catenin细胞质稳定性和转录活性，我们发现syndecan-2的表达显著增强了HEK293T细胞和BT-20三阴性乳腺癌细胞对wnt3a诱导的Wnt/β-catenin信号激活的敏感性。此外，CRISPR/ cas9介导的SDC2（编码syndecan-2的基因）的缺失，在Wnt3a刺激下降低了BT-20细胞中β-catenin的转录活性。SDC2的重新表达挽救了这种减少。总之，我们的研究结果表明syndecan-2是典型Wnt信号的正调节因子。这些结果还表明syndecan-2是抑制某些人类癌症进展的潜在临床靶点。

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引用次数: 0

Anti-cancer effect of Loranthus micranthus via downregulation of inflammation, tryptophan catabolism and kynurenine synthesis 微月桂通过下调炎症、色氨酸分解代谢和犬尿氨酸合成的抗癌作用

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-11-01 Epub Date: 2025-08-23 DOI: 10.1016/j.biocel.2025.106852

Azubuike P. Ebokaiwe , Lingyu Li , Ting Peng , Emmanuel M. Njoya , Zongyuan Zhou , Euslar Nnenna Onu , Guolin Zhang , Wang Fei

New therapeutic approaches are essential in the fight against breast cancer, which remains one of the top causes of mortality globally. Innovative and efficient methods of treating and preventing cancer has become expedient since its incidence rates are rising globally. Combining herbal extracts and chemotherapy have drawn a lot of attention in recent times as a cutting-edge cancer prevention approach. The wild parasitic plant Loranthus micranthus is extensively distributed throughout the world and is well-known for its therapeutic uses. Previous preclinical investigations indicated that the leaves and stem extracts of L. micranthus had the potential to suppress breast cancer. Investigating the anticancer effects of L. micranthus extracts through network pharmacology analysis, in vitro and in vivo experiments is the goal of the current study. Network pharmacology analysis revealed 207 targets and 30 bioactive phytoconstituents of L. micranthus associated with the metabolism of breast cancer. L. micranthus controlled the metabolism of tryptophan and nitrogen in breast cancer, according to KEGG analysis and in silico models. The results of the experiment showed that L. micranthus significantly reduced the synthesis of kynurenine in interferon-γ (IFN-γ)-stimulated breast cancer cells, downregulated important proteins involved in tryptophan catabolism, and produced no cytotoxic effects in human breast cancer cells (MCF 7 and MDA-MB 231) at the administered doses. The viability of T cells co-cultured with IFN-γ-treated breast cancer cells was also markedly enhanced by L. micranthus pre-treatment. The in vivo investigation showed a similar outcome, with L. micranthus treatment suppressing the inflammatory response, IDO activity/expression, lowering kynurenine levels, blocking CTLA-4 immune checkpoint and finally increasing the CD4⁺ T cell population in rats with DMBA-induced breast cancer.

新的治疗方法对防治乳腺癌至关重要，乳腺癌仍然是全球死亡的主要原因之一。由于全球癌症发病率不断上升，创新和有效的治疗和预防癌症的方法已成为权宜之计。近年来，将草药提取物和化疗结合起来作为一种尖端的癌症预防方法备受关注。野生寄生植物微兰花（Loranthus microranthus）广泛分布于世界各地，以其治疗用途而闻名。先前的临床前研究表明，微兰花叶和茎提取物具有抑制乳腺癌的潜力。通过网络药理学分析、体外和体内实验来研究微牛蒡提取物的抗癌作用是当前研究的目标。网络药理学分析揭示了微兰花与乳腺癌代谢相关的207个靶点和30个生物活性成分。根据KEGG分析和计算机模型，微乳杆菌控制着乳腺癌中色氨酸和氮的代谢。实验结果表明，微乳草显著降低干扰素-γ (IFN-γ)刺激的乳腺癌细胞中犬尿氨酸的合成，下调参与色氨酸分解代谢的重要蛋白，并且在给药剂量下对人乳腺癌细胞（mcf7和MDA-MB 231）没有细胞毒性作用。与IFN-γ处理过的乳腺癌细胞共培养的T细胞活力也明显增强。体内研究显示了类似的结果，微乳草治疗抑制炎症反应，IDO活性/表达，降低犬尿氨酸水平，阻断CTLA-4免疫检查点，最终增加dba诱导的乳腺癌大鼠的CD4+ T细胞群。

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引用次数: 0

Antigen-presenting cells orchestrate mixed inflammatory endotypes in atopic dermatitis 抗原呈递细胞在特应性皮炎中协调混合炎症内型。

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-11-01 Epub Date: 2025-08-15 DOI: 10.1016/j.biocel.2025.106850

Shan Wang , Jiahao Huang , Fangping He , Jiaxiao Lin, Xinyu Zheng, Na Zhang, Ailin Tao

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a complex pathogenesis involving aberrant activation of multiple immune responses. In recent years, targeted biologics have demonstrated significant efficacy in treating moderate to severe AD due to their precise mechanisms. However, the complex inflammatory profile of AD poses challenges for single-target biologics, leading to suboptimal therapeutic responses. By investigating the upstream induction mechanisms of mixed immune endotypes of AD, our study examined the roles of three types of skin antigen-presenting cells (APCs) in inducing distinct inflammatory responses in AD pathogenesis, utilizing animal models and genetically deficient mice. Our findings revealed that epidermal Langerhans cells primarily recognize allergens, induce Th2 inflammation, and promote IgE production. Nlrp3 contributes to macrophage activation by the AD lesion microbiota, driving Th17 inflammation and IgG1 production. The STING pathway facilitates dendritic cell activation, exacerbates the overall inflammatory process across mixed immune endotypes of AD, and the production of IgG2a and IgG1. In summary, our study conducted a comprehensive analysis of the upstream key antigen-presenting cells and their regulatory pathways that contribute to the progression of AD-associated immune endotypes. This research provides valuable insights into upstream mechanisms for controlling AD mixed inflammatory processes and offers strategic directions for developing combination therapies targeting multiple inflammatory pathways.

特应性皮炎（AD）是一种慢性炎症性皮肤病，其发病机制复杂，涉及多种免疫反应的异常激活。近年来，靶向生物制剂由于其精确的作用机制，在治疗中重度AD方面显示出显著的疗效。然而，阿尔茨海默病复杂的炎症特征给单靶点生物制剂带来了挑战，导致治疗反应不理想。通过研究AD混合免疫内型的上游诱导机制，我们利用动物模型和基因缺陷小鼠，研究了三种类型的皮肤抗原呈递细胞（APCs）在AD发病机制中诱导不同炎症反应的作用。我们的研究结果表明，表皮朗格汉斯细胞主要识别过敏原，诱导Th2炎症，促进IgE的产生。Nlrp3有助于AD病变微生物群激活巨噬细胞，驱动Th17炎症和IgG1的产生。STING通路促进了树突状细胞的激活，加剧了AD混合免疫内型的整体炎症过程，并促进了IgG2a和IgG1的产生。综上所述，我们的研究全面分析了上游关键抗原呈递细胞及其调控途径，这些途径有助于ad相关免疫内型的进展。本研究为控制AD混合炎症过程的上游机制提供了有价值的见解，并为开发针对多种炎症途径的联合治疗提供了战略方向。

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引用次数: 0

Heterozygous Kctd5 knockout mice exhibit abnormal lipid metabolism 杂合子Kctd5敲除小鼠表现出异常的脂质代谢

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-11-01 Epub Date: 2025-08-20 DOI: 10.1016/j.biocel.2025.106851

Qiao Ling , Manqi Cao , Hua-an Zhang , Xinjie Li , Wenhao Wang , Zhuohua Wang , Qingrong Sun , Zhijuan Liang , Weiyi Huang , Mengxuan Wang , Xin Li , Chuwen Lin , Xuan Jiang , Ji-An Pan , Xiaoxue Peng

The KCTD gene family is conserved across species, yet the knowledge of its function is limited. Recently, increasing studies focused on KCTD5 emerged. The functions of KCTD5 and its associations with various diseases were revealed. However, the function of KCTD5 in vivo has remained elusive. We generated Kctd5^+/- mice with the Kctd5 gene’s exon 2 deleted using CRISPR/Cas9 technology. Breeding experiments on Kctd5^+/- mice showed that only Kctd5^+/- and Kctd5^+/+ mice could be born normally, while Kctd5^-/- embryos died in early embryonic development. Compared to Kctd5^+/+ mice, Kctd5^+/- mice have a shorter lifespan and exhibit spleen enlargement, abnormal blood cell counts, and metabolic disorders, including elevated cholesterol and triglyceride levels. Genome-wide gene expression analysis revealed that KCTD5 may affect the PPAR signaling pathway and subsequent the expression of Apo family genes, thereby regulating lipid metabolism. In summary, our study identified a previously unrecognized role of KCTD5 in regulating lipid metabolism and KCTD5 deficiency-induced animal phenotype, and revealed multiple correlations between KCTD5 and various molecules in mice.

KCTD基因家族是跨物种保守的，但对其功能的了解有限。近年来，对KCTD5的研究越来越多。揭示了KCTD5的功能及其与多种疾病的关系。然而，KCTD5在体内的功能仍然是未知的。我们使用CRISPR/Cas9技术生成了Kctd5基因外显子2缺失的Kctd5+/-小鼠。Kctd5+/-小鼠的育种实验表明，只有Kctd5+/-和Kctd5+/+小鼠能够正常出生，而Kctd5-/-胚胎在胚胎发育早期死亡。与Kctd5+/+小鼠相比，Kctd5+/-小鼠寿命较短，脾脏肿大，血细胞计数异常，代谢紊乱，包括胆固醇和甘油三酯水平升高。全基因组基因表达分析显示，KCTD5可能影响PPAR信号通路，进而影响Apo家族基因的表达，从而调节脂质代谢。综上所述，我们的研究发现了KCTD5在调节脂质代谢和KCTD5缺陷诱导的动物表型中的先前未被认识到的作用，并揭示了KCTD5与小鼠各种分子之间的多重相关性。

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引用次数: 0

Substrate stiffness modulates osteogenic differentiation of BMMSCs via the hedgehog signaling pathway 底物硬度通过Hedgehog信号通路调节BMMSCs的成骨分化。

IF 2.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-10-01 Epub Date: 2025-07-23 DOI: 10.1016/j.biocel.2025.106840

Chengyang Sun , Mengying Jin , Ying Lian , Aodi Jiang , Hongfeng Zhai

Substrate stiffness is a critical biophysical cue regulating mesenchymal stem cell (MSC) fate, yet the underlying mechanisms remain incompletely understood. Here, we investigated how substrate stiffness modulates the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) and the involvement of the Hedgehog (Hh) signaling pathway in this process. Polydimethylsiloxane (PDMS) substrates with tunable stiffness (soft: 32.73 ± 3.74 kPa; medium: 57.59 ± 5.65 kPa; stiff: 147.4 ± 11.04 kPa) were fabricated and functionalized with arginine-glycine-aspartic acid (RGD) peptides to mimic the mechanical microenvironment of bone tissue. BMMSCs cultured on stiff substrates exhibited enhanced cell spreading and proliferation compared to those on soft substrates. Osteogenic induction experiments revealed that stiff substrates significantly upregulated alkaline phosphatase (ALP) expression and calcium nodule formation after 7 and 21 days, respectively. Mechanistically, the Hh pathway was activated on stiff substrates at day 3. Inhibition of Hh signaling using GANT61 impeded stiffness-induced effects, reducing cell spreading, proliferation, and osteogenic differentiation. These findings demonstrate that substrate stiffness promotes BMMSCs osteogenesis in a Hh signaling-dependent manner, providing new insights into the mechanobiology of bone regeneration and informing the design of stiffness-optimized biomaterials for tissue engineering applications.

基质硬度是调节间充质干细胞（MSC）命运的关键生物物理线索，但其潜在机制尚不完全清楚。在这里，我们研究了底物硬度如何调节骨髓间充质干细胞（BMMSCs）的成骨分化以及Hedgehog （Hh）信号通路在这一过程中的参与。硬度可调的聚二甲基硅氧烷（PDMS）衬底(软：32.73±3.74 kPa；介质：57.59±5.65 kPa；采用精氨酸-甘氨酸-天冬氨酸（RGD）多肽对其进行功能化，模拟骨组织的机械微环境。与在软基质上培养的骨髓间充质干细胞相比，在硬基质上培养的骨髓间充质干细胞表现出更强的细胞扩散和增殖。成骨诱导实验显示，在7天和21天后，硬底物分别显著上调碱性磷酸酶（ALP）的表达和钙结节的形成。机械上，Hh通路在第3天在坚硬底物上被激活。使用GANT61抑制Hh信号会阻碍僵硬诱导的效应，减少细胞扩散、增殖和成骨分化。这些发现表明，基质刚度以Hh信号依赖的方式促进BMMSCs成骨，为骨再生的机械生物学提供了新的见解，并为组织工程应用中刚度优化的生物材料的设计提供了信息。

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引用次数: 0