关键词： Cell differentiation   Periodontal ligament   Bone morphogenetic protein 2   Mesenchymal stem cells   Bone regeneration   Multivariate Analysis  

摘要： Understanding the molecular mechanisms regulating osteo/cementogenic differentiation is critical for optimizing cell-based strategies in periodontal regeneration. This study employed multivariate statistical modeling to investigate, in vitro, the interaction between bone morphogenetic protein 2 (BMP2) and asporin (ASPN) in human periodontal ligament stem cells (hPDLSCs) and its impact on mineralization potential. Four primary hPDLSC populations-two with high osteo/cementogenic potential (HOP) and two with low potential (LOP)-were cultured under standard (SDM) and osteo/cementogenic (OM) conditions. Mineralization was assessed using Alizarin Red Staining (AR-S) and alkaline phosphatase (ALP) activity, while gene expression of ASPN, BMP2, osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). BMP2 protein levels were measured using the Luminex system. Data analysis incorporated Principal Component Analysis (PCA), Linear Discriminant Analysis (LDA), Pearson correlations, correlation networks, and multivariate regression models in RStudio. HOP cells exhibited higher mineralization and BMP2 expression compared to LOP cells (p < 0.05). ASPN negatively correlated with BMP2 expression and mineralization, particularly in LOP cells (p < 0.01), reinforcing its inhibitory role. Multivariate modeling identified BMP2 as a key positive regulator of osteo/cementogenesis, while ASPN emerged as a significant inhibitory factor (p < 0.001). This study highlights the potential of multivariate models as powerful tools for uncovering molecular interactions and identifying novel therapeutic targets, paving the way for advancements in periodontal regeneration and cell-based therapies.

摘要： Fibrosis is an important feature of adipose tissue in obese individuals;nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.

关键词： 颞下颌关节紊乱病   Asporin   酶联免疫吸附试验   生物学标志物  

摘要： 目的探讨颞下颌关节紊乱病(temporomandibular joint disorders,TMD)患者关节滑液中无孢蛋白(Asporin)水平的变化及其临床意义。方法随机入选2021年1月至2023年12月因激发性疼痛及张口受限于承德医学院附属医院口腔科就诊的TMD患者48例作为TMD组,同时选取健康志愿者48例作为对照组。采用酶联免疫吸附实验(ELISA)法检测两组关节滑液中Asporin水平,比较两组滑液Asporin水平的差异,并分析其与TMD临床症状的相关性。结果TMD组滑液Asporin水平显著高于对照组,差异有统计学意义(P<0.05)。滑液中Asporin水平与TMD患者的疼痛程度呈正相关(Rs=0.825,P<0.001),与张口度呈负相关(Rs=-0.945,P<0.001)。结论TMD患者滑液中Asporin水平明显升高,TMD患者滑液中Asporin水平与TMD临床症状具有相关性,为TMD诊断和病情评估提供依据。

关键词： ASPN   Prostate cancer   Docetaxel chemoresistance   Metastasis   Wnt/β-catenin signaling  

摘要： Aims Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/β-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/β-catenin signaling pathway in docetaxel resistance and metastasis of PCa. Methods The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments. Results In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGFβ and interacts with STMN1. ASPN increases the expression of β-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/β-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells. Conclusions Our findings identify ASPN as a novel upstream regulatory factor of Wnt/β-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/β-catenin axis could be a promising strategy for PCa intervention.

关键词： ASPN   Prostate cancer   Docetaxel chemoresistance   Metastasis   Wnt/(3-catenin signaling  

摘要： Aims: Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/(3-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/(3-catenin signaling pathway in docetaxel resistance and metastasis of PCa. Methods: The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments. Results: In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGF(3 and interacts with STMN1. ASPN increases the expression of (3-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/(3-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells. Conclusions: Our findings identify ASPN as a novel upstream regulatory factor of Wnt/(3-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/(3-catenin axis could be a promising strategy for PCa intervention.

摘要： Abstract Coronary heart disease (CHD) remains a top cause of mortality across the globe. Both occlusive and non-occlusive ischemic events result in hypoxic conditions in the myocardium, which leads to stress and apoptosis of cardiomyocytes. We hav...

关键词： fetal-like cellular reprogramming   regeneration   aging   mesenchyme   asporin   intestinal stem cells   extracellular matrix   TGF-β signaling   CD44   Wnt signaling  

摘要： Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor b (TGF-b)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.

关键词： 冠心病   慢性心力衰竭   松弛素-2   Asporin   磷脂酰肌醇蛋白聚糖   病情严重程度  

摘要： 目的探究冠心病(CHD)合并慢性心力衰竭(CHF)患者血清松弛素-2(relaxin-2)、Asporin、磷脂酰肌醇蛋白聚糖(glypican-4)水平变化及其与病情严重程度的相关性。方法选取2021年6月至2023年9月在四川省南充市中医医院确诊为CHD合并CHF患者92例作为CHD-CHF组,另选取同期在四川省南充市中医医院进行诊治的92例CHD患者作为CHD组。根据纽约心脏病协会心功能分级将CHD合并CHF患者分为心功能Ⅰ~Ⅱ级组(24例),心功能Ⅲ级组(41例),心功能Ⅳ组(27例)。采用酶联免疫吸附试验检测血清relaxin-2、Asporin、glypican-4水平。采用Spearman相关分析血清relaxin-2、Asporin、glypican-4水平与心功能分级的相关性;采用Pearson相关分析血清relaxin-2、Asporin、glypican-4水平与心功能相关指标的相关性。绘制受试者工作特征(ROC)曲线评估血清relaxin-2、Asporin、glypican-4单独及联合检测对CHD合并CHF病情严重程度的诊断价值。结果CHD-CHF组血清relaxin-2水平低于CHD组,Asporin、glypican-4水平均高于CHD组,差异均有统计学意义(P<0.05)。心功能Ⅳ级组、心功能Ⅲ级组、心功能Ⅰ~Ⅱ级组血清relaxin-2依次升高,Asporin、glypican-4水平均依次降低,差异均有统计学意义(P<0.05)。心功能Ⅳ级组、心功能Ⅲ级组、心功能Ⅰ~Ⅱ级组左室舒张末期内径(LVEDD)、左室前后径(LAD)均依次降低,左室射血分数(LVEF),左室相对室壁厚度(RWT)均依次升高,差异均有统计学意义(P<0.05)。Spearman相关分析结果显示,血清relaxin-2水平与心功能分级呈负相关(P<0.05),血清Asporin、glypican-4水平与心功能分级均呈正相关(P<0.05)。Pearson相关分析结果显示,血清relaxin-2水平与LVEDD、LAD均呈负相关(P<0.05),与LVEF、RWT均呈正相关(P<0.05);血清Asporin、glypican-4水平与心功能分级、LVEDD、LAD均呈正相关(P<0.05),与LVEF、RWT均呈负相关(P<0.05)。ROC曲线分析结果显示,血清relaxin-2、Asporin、glypican-4单独及联合检测诊断CHD合并CHF病情严重程度的曲线下面积(AUC)分别为0.757、0.771、0.776、0.845,3项联合诊断的AUC大于3项单独诊断的AUC(Z=2.329、2.119、2.068,P<0.05)。结论CHD合并CHF患者血清relaxin-2水平降低,Asporin、glypican-4水平升高,与患者心功能分级显著相关,可作为临床评估CHD合并CHF患者病情严重程度的生物指标。

关键词： ASPN   CAF   collagen   extracellular matrix   MDA-MB-231   metastasis   tumor microenvironment  

摘要： Background: Migrating strategies of the triple-negative breast cancer (TNBC) together with its role in the establishment of tumor microenvironment (TME), supporting metastasis, have been extensively studied. Extracellular matrix (ECM) is a major player for the TME, establishing the 3D spatial networks with interconnected pores necessary for the mechano-physiological function of the cells. Certain collagen aligners and cross-linkers which are necessary for the formation and the stabilization of ECM networks, however, have not been studied either in normal or in abnormal tissues. Complexities in cell-cell and cell-matrix interactions, and different in types and ratios of ECM proteins in a TME challenge to reveal the precise function of a particular protein that is exhibited by special cells and if specifically present in insignificant amount. Cancer-associated fibroblasts (CAFs) predominantly occupy the major stroma of a solid tumor where they deposit extracellular proteins in the excessive amount compared to other tumor-associated cells. For example, the TNBC tumor itself is positive for asporin (ASPN) since CAFs are major ASPN exhibitors. However, the TNBC cells express it insignificantly. Objective: The increase in ECM and its networks suppresses the metastasis. Methods: Here, we studied the expression of collagen type I and ASPN in CAFS and MDA-MB-231 (MM231), and evaluated the role of ASPN in collagen alignment and crosslinking. Results: TNBC cells have an insignificant expression of ASPN and scanty collagen fibers, some of which aggregate to form the stiff deranged fibers, forming large-size pores in ECM of cancer-cell-dominant outer core of TNBC that support cancer cell invasion and metastasis. Exogenous ASPN and fibroblast-ASPN supported for the collagen alignment and crosslinking that established the small-size pores in the ECM, inhibiting the cancer cell invasion. Conclusions: The collagen aligner and the cross-linker, ASPN increases the ECM networks and dec