首页 > 最新文献

Chemical Biology & Drug Design最新文献

英文 中文
Targeting the Autophagy–Apoptosis Axis in Osteosarcoma: Therapeutic Potential of Biocompounds: A Review 针对骨肉瘤的自噬-凋亡轴:生物化合物的治疗潜力:综述
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-28 DOI: 10.1111/cbdd.70257
Oznur Bayraktar Ekmekcigil, Secil Eroglu, Shiv Bharadwaj, Ammad Ahmad Farooqi, Devrim Gozuacik, Ozlem Kutlu

Osteosarcoma is a prevalent form of cancer that develops in growing bones. The precise cause of this multifaceted disease remains uncertain. Yet, genetic, genomic and proteomic research has enhanced our understanding of the disruption in its molecular signaling pathways. In this review, we attempted to highlight the regulation of autophagy pathways by a range of biocompounds (chemical compounds of biological origin) in osteosarcoma. Autophagy is a degradation mechanism, maintaining cellular homeostasis under basal and stress conditions. However, the role of autophagy is variable in cancer. There is a delicate balance between autophagy and apoptosis, and disruption of this balance is one of the causes of tumor formation and development. Autophagy and apoptosis can reciprocally activate or inhibit each other. Thus, autophagy works synergistically or antagonistically with apoptosis. In osteosarcoma, different biocompounds involve in the regulation of autophagy and/or apoptosis, triggering cellular signaling pathways, convenient or inconvenient for growth, proliferation, invasion and metastasis of cancer cells in a tumor. Also, some of the biocompounds have been shown to affect the therapeutic response of osteosarcoma cells. Therefore, biocompounds are promising candidates for the regulation of autophagy and may play critical roles in the crosstalk between autophagy and apoptosis in osteosarcoma.

骨肉瘤是生长中的骨骼中常见的一种癌症。这种多方面疾病的确切病因仍不确定。然而,遗传学、基因组学和蛋白质组学的研究增强了我们对其分子信号通路中断的理解。在这篇综述中,我们试图强调骨肉瘤中一系列生物化合物(生物来源的化学化合物)对自噬途径的调节。自噬是一种降解机制,在基础和应激条件下维持细胞稳态。然而,自噬在癌症中的作用是可变的。自噬和细胞凋亡之间存在着微妙的平衡,这种平衡的破坏是肿瘤形成和发展的原因之一。自噬和凋亡可以相互激活或相互抑制。因此,自噬与细胞凋亡具有协同或拮抗作用。在骨肉瘤中,不同的生物化合物参与调节自噬和/或凋亡,触发细胞信号通路,方便或不方便肿瘤中癌细胞的生长、增殖、侵袭和转移。此外,一些生物化合物已被证明可以影响骨肉瘤细胞的治疗反应。因此,生物化合物是调控骨肉瘤细胞自噬的有希望的候选物质,并可能在骨肉瘤细胞自噬和细胞凋亡之间的相互作用中发挥关键作用。
{"title":"Targeting the Autophagy–Apoptosis Axis in Osteosarcoma: Therapeutic Potential of Biocompounds: A Review","authors":"Oznur Bayraktar Ekmekcigil,&nbsp;Secil Eroglu,&nbsp;Shiv Bharadwaj,&nbsp;Ammad Ahmad Farooqi,&nbsp;Devrim Gozuacik,&nbsp;Ozlem Kutlu","doi":"10.1111/cbdd.70257","DOIUrl":"https://doi.org/10.1111/cbdd.70257","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteosarcoma is a prevalent form of cancer that develops in growing bones. The precise cause of this multifaceted disease remains uncertain. Yet, genetic, genomic and proteomic research has enhanced our understanding of the disruption in its molecular signaling pathways. In this review, we attempted to highlight the regulation of autophagy pathways by a range of biocompounds (chemical compounds of biological origin) in osteosarcoma. Autophagy is a degradation mechanism, maintaining cellular homeostasis under basal and stress conditions. However, the role of autophagy is variable in cancer. There is a delicate balance between autophagy and apoptosis, and disruption of this balance is one of the causes of tumor formation and development. Autophagy and apoptosis can reciprocally activate or inhibit each other. Thus, autophagy works synergistically or antagonistically with apoptosis. In osteosarcoma, different biocompounds involve in the regulation of autophagy and/or apoptosis, triggering cellular signaling pathways, convenient or inconvenient for growth, proliferation, invasion and metastasis of cancer cells in a tumor. Also, some of the biocompounds have been shown to affect the therapeutic response of osteosarcoma cells. Therefore, biocompounds are promising candidates for the regulation of autophagy and may play critical roles in the crosstalk between autophagy and apoptosis in osteosarcoma.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prediction of Breast Cancer Lymph Node Metastasis by a Nomogram Model Integrating Pathomics, Radiomics, and Immunoscore 结合病理、放射组学和免疫评分的Nomogram模型预测乳腺癌淋巴结转移。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-20 DOI: 10.1111/cbdd.70244
Tian Xu, Jingyao Feng, Kun Zhang, Liugang Gao, Jianlin Wang

This study aimed to develop a noninvasive nomogram that integrates deep learning-pathomics, radiomics, and immunoscore to predict lymph node metastasis (LNM) in breast cancer. Pathological features from 1133 TCGA-BRCA slides were extracted via ResNet50 and Lasso. Radiomics features from 137 MRI images (TCIA) were analyzed using pyradiomics. Immunoscore was calculated via ESTIMATE. A nomogram was constructed and validated with 10-fold cross-validation. The pathomics model achieved an AUC of 0.65 (95% CI: 0.61–0.68), sensitivity 0.62, specificity 0.67; radiomics 0.61 (95% CI: 0.50–0.72), sensitivity 0.59, specificity 0.63; and the combined nomogram 0.69 (95% CI: 0.59–0.79), sensitivity 0.66, specificity 0.71. Radiomics score was the strongest predictor. The nomogram provides a reliable noninvasive tool for predicting lymph node involvement, potentially reducing unnecessary biopsies.

本研究旨在开发一种整合了深度学习-病理学、放射组学和免疫评分的无创nomographic,以预测乳腺癌的淋巴结转移(LNM)。通过ResNet50和Lasso提取1133例TCGA-BRCA切片的病理特征。应用放射组学对137张MRI影像(TCIA)的放射组学特征进行分析。免疫评分通过ESTIMATE计算。构建nomogram并进行10倍交叉验证。病理模型的AUC为0.65 (95% CI: 0.61-0.68),敏感性0.62,特异性0.67;放射组学0.61 (95% CI: 0.50-0.72),敏感性0.59,特异性0.63;联合nomogram 0.69 (95% CI: 0.59-0.79), sensitivity 0.66, specificity 0.71。放射组学评分是最强的预测因子。nomographic为预测淋巴结受累提供了可靠的无创工具,可能减少不必要的活组织检查。
{"title":"Prediction of Breast Cancer Lymph Node Metastasis by a Nomogram Model Integrating Pathomics, Radiomics, and Immunoscore","authors":"Tian Xu,&nbsp;Jingyao Feng,&nbsp;Kun Zhang,&nbsp;Liugang Gao,&nbsp;Jianlin Wang","doi":"10.1111/cbdd.70244","DOIUrl":"10.1111/cbdd.70244","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to develop a noninvasive nomogram that integrates deep learning-pathomics, radiomics, and immunoscore to predict lymph node metastasis (LNM) in breast cancer. Pathological features from 1133 TCGA-BRCA slides were extracted via ResNet50 and Lasso. Radiomics features from 137 MRI images (TCIA) were analyzed using pyradiomics. Immunoscore was calculated via ESTIMATE. A nomogram was constructed and validated with 10-fold cross-validation. The pathomics model achieved an AUC of 0.65 (95% CI: 0.61–0.68), sensitivity 0.62, specificity 0.67; radiomics 0.61 (95% CI: 0.50–0.72), sensitivity 0.59, specificity 0.63; and the combined nomogram 0.69 (95% CI: 0.59–0.79), sensitivity 0.66, specificity 0.71. Radiomics score was the strongest predictor. The nomogram provides a reliable noninvasive tool for predicting lymph node involvement, potentially reducing unnecessary biopsies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tetramethylpyrazine Targets HDAC6-Mediated PINK1 Degradation to Alleviate Chronic Intermittent Hypoxia-Induced Injury in Human Bronchial Epithelial Cells (16HBE) Tetramethylpyrazine靶向hdac6介导的PINK1降解以减轻慢性间歇性缺氧诱导的人支气管上皮细胞损伤(16HBE)。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-18 DOI: 10.1111/cbdd.70236
Yanjie Chen, Hongye Chen, Zhixiong Huang, Mulan Deng, Xin Zheng, Qihui Chen

Obstructive sleep apnea (OSA) is characterized by recurrent chronic intermittent hypoxia (CIH), which induces oxidative stress, inflammatory responses, and mitochondrial damage in bronchial epithelial cells. Tetramethylpyrazine (TMP) has been shown to exert lung-protective effects in other pathological models, but its role in mitigating CIH-induced 16HBE cell injury and the underlying molecular mechanisms have not been previously investigated. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy is a critical endogenous mechanism that defends against CIH-induced epithelial damage. However, whether TMP alleviates CIH-induced injury by regulating the PINK1 pathway remains unknown. CIH significantly reduced 16HBE cell viability, increased apoptosis rate, elevated inflammatory responses (IL-6 and TNF-α levels upregulated), and oxidative stress (ROS and MDA levels increased), and inhibited mitophagy (reduced PINK1 and LC3-II/LC3-I ratio, increased p62). TMP treatment improved cell viability in a dose-dependent manner; notably, 20 μg/mL TMP reversed CIH-induced apoptosis, inflammation, and oxidative stress, accompanied by upregulated PINK1 and restored mitophagy. Moreover, HDAC6 knockdown mimicked TMP's benefits (enhanced PINK1 and mitophagy, reduced injury), while concurrent PINK1 silencing reversed this effect. TMP protected 16HBE cells from CIH-induced injury by inhibiting HDAC6-mediated PINK1 deacetylation. This mechanism stabilized PINK1 protein, enhanced mitophagy, and thereby suppressed apoptosis, oxidative stress, and inflammation, identifying the HDAC6/PINK1 axis as a key regulatory pathway in CIH-induced cell injury.

阻塞性睡眠呼吸暂停(OSA)以复发性慢性间歇性缺氧(CIH)为特征,可诱导支气管上皮细胞的氧化应激、炎症反应和线粒体损伤。川芎嗪(Tetramethylpyrazine, TMP)已在其他病理模型中显示出肺保护作用,但其在减轻cih诱导的16HBE细胞损伤中的作用及其分子机制尚未被研究。pten诱导的推定激酶1 (PINK1)介导的线粒体自噬是防御cih诱导的上皮损伤的关键内源性机制。然而,TMP是否通过调节PINK1通路减轻cih诱导的损伤尚不清楚。CIH显著降低16HBE细胞活力,增加凋亡率,提高炎症反应(IL-6和TNF-α水平上调)和氧化应激(ROS和MDA水平升高),抑制线粒体自噬(PINK1和LC3-II/LC3-I比值降低,p62升高)。TMP处理以剂量依赖的方式提高细胞活力;值得注意的是,20 μg/mL TMP可逆转cih诱导的细胞凋亡、炎症和氧化应激,并伴有PINK1的上调,恢复线粒体自噬。此外,HDAC6敲低模仿TMP的益处(增强PINK1和线粒体自噬,减少损伤),而同时PINK1沉默逆转了这一作用。TMP通过抑制hdac6介导的PINK1去乙酰化,保护16HBE细胞免受cih诱导的损伤。该机制稳定了PINK1蛋白,增强了线粒体自噬,从而抑制了细胞凋亡、氧化应激和炎症,确定了HDAC6/PINK1轴是cih诱导细胞损伤的关键调控途径。
{"title":"Tetramethylpyrazine Targets HDAC6-Mediated PINK1 Degradation to Alleviate Chronic Intermittent Hypoxia-Induced Injury in Human Bronchial Epithelial Cells (16HBE)","authors":"Yanjie Chen,&nbsp;Hongye Chen,&nbsp;Zhixiong Huang,&nbsp;Mulan Deng,&nbsp;Xin Zheng,&nbsp;Qihui Chen","doi":"10.1111/cbdd.70236","DOIUrl":"10.1111/cbdd.70236","url":null,"abstract":"<div>\u0000 \u0000 <p>Obstructive sleep apnea (OSA) is characterized by recurrent chronic intermittent hypoxia (CIH), which induces oxidative stress, inflammatory responses, and mitochondrial damage in bronchial epithelial cells. Tetramethylpyrazine (TMP) has been shown to exert lung-protective effects in other pathological models, but its role in mitigating CIH-induced 16HBE cell injury and the underlying molecular mechanisms have not been previously investigated. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy is a critical endogenous mechanism that defends against CIH-induced epithelial damage. However, whether TMP alleviates CIH-induced injury by regulating the PINK1 pathway remains unknown. CIH significantly reduced 16HBE cell viability, increased apoptosis rate, elevated inflammatory responses (IL-6 and TNF-α levels upregulated), and oxidative stress (ROS and MDA levels increased), and inhibited mitophagy (reduced PINK1 and LC3-II/LC3-I ratio, increased p62). TMP treatment improved cell viability in a dose-dependent manner; notably, 20 μg/mL TMP reversed CIH-induced apoptosis, inflammation, and oxidative stress, accompanied by upregulated PINK1 and restored mitophagy. Moreover, <i>HDAC6</i> knockdown mimicked TMP's benefits (enhanced PINK1 and mitophagy, reduced injury), while concurrent <i>PINK1</i> silencing reversed this effect. TMP protected 16HBE cells from CIH-induced injury by inhibiting HDAC6-mediated PINK1 deacetylation. This mechanism stabilized PINK1 protein, enhanced mitophagy, and thereby suppressed apoptosis, oxidative stress, and inflammation, identifying the HDAC6/PINK1 axis as a key regulatory pathway in CIH-induced cell injury.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Daucosterol Targets PFKFB3 to Mitigates Sepsis-Induced Acute Lung Injury by Inhibiting Glycolysis and M1 Macrophage Polarization 桃甾醇通过抑制糖酵解和M1巨噬细胞极化,靶向PFKFB3减轻败血症诱导的急性肺损伤
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-18 DOI: 10.1111/cbdd.70243
Lulu Wang, Jingmin Zhou, Chuanfu Sun, Yuan Liu, Yingzhi Wang, Xianjin Zhang

Acute lung injury (ALI) is a severe inflammatory condition often triggered by infections. Glycolysis and macrophage polarization play critical roles in ALI pathogenesis. This study investigates the effects of Daucosterol on lipopolysaccharide (LPS)-stimulated lung injury and its potential mechanisms. In this research, BEAS-2B lung epithelial cells and MH-S alveolar macrophages were exposed to LPS and various concentrations of Daucosterol. Cell viability was assessed using CCK-8 assay. Glycolytic activity was evaluated by detecting ATP production, lactate level, and extracellular acidification rate. Macrophage polarization was assessed using flow cytometry. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were detected by enzyme-linked immunosorbent assay. Gene expression was evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting. A cecal ligation and puncture (CLP)-induced ALI mouse model was used to validate the protective effect of Daucosterol in vivo. Results showed that Daucosterol prevented the reduction in cell viability in LPS-stimulated BEAS-2B cells. In MH-S macrophages, Daucosterol inhibited LPS-induced glycolysis and M1 polarization while promoting M2 polarization. Mechanistically, Daucosterol reversed the LPS-induced upregulation of PFKFB3. Overexpression of PFKFB3 counteracted the inhibitory effects of Daucosterol on glycolysis and M1 polarization. In vivo, Daucosterol significantly alleviated CLP-induced ALI by improving lung histopathology, reducing pulmonary edema, enhancing oxygenation, inhibiting myeloperoxidase and caspase-3 activity, and decreasing TNF-α and IL-6 levels in bronchoalveolar lavage fluid. In conclusion, Daucosterol targets PFKFB3 to mitigate sepsis-induced ALI by inhibiting glycolysis and M1 macrophage polarization, offering a potential therapeutic strategy for ALI.

急性肺损伤(ALI)是一种严重的炎症,通常由感染引起。糖酵解和巨噬细胞极化在ALI发病机制中起关键作用。本研究探讨了大豆甾醇对脂多糖(LPS)刺激的肺损伤的影响及其可能的机制。本研究将BEAS-2B肺上皮细胞和MH-S肺泡巨噬细胞分别暴露于LPS和不同浓度的桃甾醇中。采用CCK-8法测定细胞活力。通过检测ATP产量、乳酸水平和细胞外酸化速率来评估糖酵解活性。流式细胞术检测巨噬细胞极化。采用酶联免疫吸附法检测肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6水平。采用逆转录-定量聚合酶链反应和免疫印迹法检测基因表达。采用盲肠结扎穿刺(CLP)诱导的ALI小鼠模型,在体内验证大豆甾醇的保护作用。结果表明,大豆甾醇能抑制lps刺激的BEAS-2B细胞活力的降低。在MH-S巨噬细胞中,桃油甾醇抑制lps诱导的糖酵解和M1极化,促进M2极化。在机制上,桃油甾醇逆转了lps诱导的PFKFB3的上调。PFKFB3的过表达抵消了豆甾醇对糖酵解和M1极化的抑制作用。在体内,桃甾醇通过改善肺组织病理学、减轻肺水肿、增强氧合、抑制髓过氧化物酶和caspase-3活性、降低支气管肺泡灌洗液中TNF-α和IL-6水平,显著缓解clp诱导的ALI。总之,Daucosterol靶向PFKFB3通过抑制糖酵解和M1巨噬细胞极化来减轻败血症诱导的ALI,为ALI提供了一种潜在的治疗策略。
{"title":"Daucosterol Targets PFKFB3 to Mitigates Sepsis-Induced Acute Lung Injury by Inhibiting Glycolysis and M1 Macrophage Polarization","authors":"Lulu Wang,&nbsp;Jingmin Zhou,&nbsp;Chuanfu Sun,&nbsp;Yuan Liu,&nbsp;Yingzhi Wang,&nbsp;Xianjin Zhang","doi":"10.1111/cbdd.70243","DOIUrl":"10.1111/cbdd.70243","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute lung injury (ALI) is a severe inflammatory condition often triggered by infections. Glycolysis and macrophage polarization play critical roles in ALI pathogenesis. This study investigates the effects of Daucosterol on lipopolysaccharide (LPS)-stimulated lung injury and its potential mechanisms. In this research, BEAS-2B lung epithelial cells and MH-S alveolar macrophages were exposed to LPS and various concentrations of Daucosterol. Cell viability was assessed using CCK-8 assay. Glycolytic activity was evaluated by detecting ATP production, lactate level, and extracellular acidification rate. Macrophage polarization was assessed using flow cytometry. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were detected by enzyme-linked immunosorbent assay. Gene expression was evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting. A cecal ligation and puncture (CLP)-induced ALI mouse model was used to validate the protective effect of Daucosterol in vivo. Results showed that Daucosterol prevented the reduction in cell viability in LPS-stimulated BEAS-2B cells. In MH-S macrophages, Daucosterol inhibited LPS-induced glycolysis and M1 polarization while promoting M2 polarization. Mechanistically, Daucosterol reversed the LPS-induced upregulation of PFKFB3. Overexpression of PFKFB3 counteracted the inhibitory effects of Daucosterol on glycolysis and M1 polarization. In vivo, Daucosterol significantly alleviated CLP-induced ALI by improving lung histopathology, reducing pulmonary edema, enhancing oxygenation, inhibiting myeloperoxidase and caspase-3 activity, and decreasing TNF-α and IL-6 levels in bronchoalveolar lavage fluid. In conclusion, Daucosterol targets PFKFB3 to mitigate sepsis-induced ALI by inhibiting glycolysis and M1 macrophage polarization, offering a potential therapeutic strategy for ALI.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Network Pharmacology-Based Analysis and In Vitro Experiments Validation Reveal Tormentic Acid Induces Apoptosis via PI3K/AKT/HSP90 Pathway in HepG2 Cells 基于网络药理学的分析和体外实验验证表明,拷问酸通过PI3K/AKT/HSP90通路诱导HepG2细胞凋亡。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-16 DOI: 10.1111/cbdd.70239
Jingyang Lu, Yue Qiu, Facheng Bai, Lijun Pang, Junjie Tan, Jun Deng, Yeting Lin, Jinbin Wei, Dandan Wang

Tormentic acid (TA) has demonstrated potential anti-hepatocellular carcinoma (HCC) effects. This study aimed to explore the anti-HCC effect and underlying mechanisms of TA via network pharmacology, molecular docking, molecular dynamics simulation and in vitro experiments. In this study, HCC-related genes were obtained from the GeneCards OMIM, and GEO databases. The targets of TA were collected from Swiss Target Prediction, TargetNet, and the PharmMapper database. A protein–protein interaction network of TA anti-HCC target genes was constructed using the STRING database and visualized by Cytoscape. The potential anti-HCC targets of TA were then identified through GO and KEGG pathway enrichment analyses using the DAVID database. Molecular docking and molecular dynamics simulation were performed to evaluate the binding affinity and structural stability of TA-target complexes. For the in vitro experiments, the CCK-8 assay was employed to assess the effects of TA on HepG2 cell viability. Apoptosis in HepG2 cells was detected via flow cytometry. Western blotting was used to elucidate the underlying molecular mechanisms of TA. Integrating network pharmacology and bioinformatics analyses revealed that the anti-HCC effect of TA was closely associated with apoptosis and the PI3K/AKT/HSP90 pathway. Molecular docking and molecular dynamics simulation demonstrated that TA-target protein complexes maintained marked structural stability and exhibited favorable kinetic properties. In vitro experiments showed that TA significantly inhibited the proliferation of HepG2 cells and induced apoptosis. Western blot results further indicated that TA treatment increased the expression of Bax while decreasing the expression levels of PI3K, AKT, HSP90, and Bcl-2. TA suppressed the proliferation of HepG2 cells and induced apoptosis, possibly by regulating the PI3K/AKT/HSP90 signaling pathway.

折磨酸(TA)已被证明具有潜在的抗肝细胞癌(HCC)作用。本研究旨在通过网络药理学、分子对接、分子动力学模拟和体外实验等手段探讨TA的抗hcc作用及其机制。在本研究中,从GeneCards OMIM和GEO数据库中获得了hcc相关基因。TA的靶标收集自Swiss Target Prediction、TargetNet和PharmMapper数据库。利用STRING数据库构建TA抗hcc靶基因的蛋白-蛋白相互作用网络,并利用Cytoscape进行可视化。然后使用DAVID数据库通过GO和KEGG途径富集分析确定TA的潜在抗hcc靶点。通过分子对接和分子动力学模拟来评价ta靶配合物的结合亲和力和结构稳定性。体外实验采用CCK-8法评价TA对HepG2细胞活力的影响。流式细胞术检测HepG2细胞的凋亡情况。Western blotting用于阐明TA的潜在分子机制。结合网络药理学和生物信息学分析发现,TA的抗hcc作用与细胞凋亡和PI3K/AKT/HSP90通路密切相关。分子对接和分子动力学模拟表明,ta靶蛋白复合物保持了显著的结构稳定性和良好的动力学性质。体外实验表明,TA能显著抑制HepG2细胞的增殖,诱导细胞凋亡。Western blot结果进一步表明,TA处理增加了Bax的表达,降低了PI3K、AKT、HSP90和Bcl-2的表达水平。TA抑制HepG2细胞增殖,诱导凋亡,可能通过调控PI3K/AKT/HSP90信号通路实现。
{"title":"Network Pharmacology-Based Analysis and In Vitro Experiments Validation Reveal Tormentic Acid Induces Apoptosis via PI3K/AKT/HSP90 Pathway in HepG2 Cells","authors":"Jingyang Lu,&nbsp;Yue Qiu,&nbsp;Facheng Bai,&nbsp;Lijun Pang,&nbsp;Junjie Tan,&nbsp;Jun Deng,&nbsp;Yeting Lin,&nbsp;Jinbin Wei,&nbsp;Dandan Wang","doi":"10.1111/cbdd.70239","DOIUrl":"10.1111/cbdd.70239","url":null,"abstract":"<div>\u0000 \u0000 <p>Tormentic acid (TA) has demonstrated potential anti-hepatocellular carcinoma (HCC) effects. This study aimed to explore the anti-HCC effect and underlying mechanisms of TA via network pharmacology, molecular docking, molecular dynamics simulation and in vitro experiments. In this study, HCC-related genes were obtained from the GeneCards OMIM, and GEO databases. The targets of TA were collected from Swiss Target Prediction, TargetNet, and the PharmMapper database. A protein–protein interaction network of TA anti-HCC target genes was constructed using the STRING database and visualized by Cytoscape. The potential anti-HCC targets of TA were then identified through GO and KEGG pathway enrichment analyses using the DAVID database. Molecular docking and molecular dynamics simulation were performed to evaluate the binding affinity and structural stability of TA-target complexes. For the in vitro experiments, the CCK-8 assay was employed to assess the effects of TA on HepG2 cell viability. Apoptosis in HepG2 cells was detected via flow cytometry. Western blotting was used to elucidate the underlying molecular mechanisms of TA. Integrating network pharmacology and bioinformatics analyses revealed that the anti-HCC effect of TA was closely associated with apoptosis and the PI3K/AKT/HSP90 pathway. Molecular docking and molecular dynamics simulation demonstrated that TA-target protein complexes maintained marked structural stability and exhibited favorable kinetic properties. In vitro experiments showed that TA significantly inhibited the proliferation of HepG2 cells and induced apoptosis. Western blot results further indicated that TA treatment increased the expression of Bax while decreasing the expression levels of PI3K, AKT, HSP90, and Bcl-2. TA suppressed the proliferation of HepG2 cells and induced apoptosis, possibly by regulating the PI3K/AKT/HSP90 signaling pathway.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, Synthesis, and Anticancer Assessment of Benzylated Pyrrole-Based Pyrido[2,3-d]Pyrimidines as Thymidylate Synthase Inhibitors 基于苯基吡咯的吡啶[2,3-d]嘧啶类胸苷酸合成酶抑制剂的设计、合成及抗癌评价。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-16 DOI: 10.1111/cbdd.70240
Adarsh Kumar, Sonu Rajput, Ankit Kumar Singh, Vineet Prajapati, Amita Verma, Prateek Pathak, Umashanker Navik, Jurica Novak, Pradeep Kumar

Globally, colorectal cancer (CRC) is the second most common cause of cancer-related deaths and the third most common cancer. Thymidylate synthase (TS), a key enzyme involved in DNA biosynthesis, has emerged as a promising molecular target for anticancer therapy. In the present study, we designed and synthesized a series of 22 benzylated pyrrole-based pyrido[2,3-d]pyrimidines using Claisen Schmidt and Michael addition reactions, and evaluated their anticancer potential against four human cancer cell lines: HCT 116 (colorectal), A549 (lung), MCF-7 (breast), and MDA-MB-231 (triple-negative breast cancer) as well as for TS inhibitory potential. Compounds 1c and 2i exhibited potent TS inhibition with IC50 values of 11.50 ± 1.08 nM and 17.12 ± 0.91 nM, respectively, comparable to the standard drug raltitrexed (IC50 = 12.51 ± 0.91 nM). Molecular docking studies revealed stronger binding affinities of these compounds compared to raltitrexed, involving key interactions with the catalytic residue Cys195 of TS. Additionally, compounds 1c and 2i exhibited good stability in 300 ns molecular dynamics simulations along with acceptable drug-like properties and oral bioavailability. These findings suggest that compounds 1c and 2i are promising lead candidates for the development of TS inhibitors.

在全球范围内,结直肠癌(CRC)是癌症相关死亡的第二大常见原因,也是第三大常见癌症。胸苷酸合成酶(Thymidylate synthase, TS)是参与DNA生物合成的关键酶,已成为抗癌治疗的一个有前景的分子靶点。本研究采用Claisen Schmidt和Michael加成反应,设计合成了一系列22种基于苯基吡罗的吡多[2,3-d]嘧啶,并评估了它们对四种人类癌细胞系:HCT 116(结直肠癌)、A549(肺癌)、MCF-7(乳腺癌)和MDA-MB-231(三阴性乳腺癌)的抗癌潜力以及TS抑制潜力。化合物1c和2i表现出较强的TS抑制作用,IC50值分别为11.50±1.08 nM和17.12±0.91 nM,与标准药物雷曲塞(IC50 = 12.51±0.91 nM)相当。分子对接研究表明,与雷曲塞相比,这些化合物具有更强的结合亲和力,包括与TS催化残基Cys195的关键相互作用。此外,化合物1c和2i在300 ns分子动力学模拟中表现出良好的稳定性,具有可接受的药物样特性和口服生物利用度。这些发现表明,化合物1c和2i是开发TS抑制剂的有希望的主要候选者。
{"title":"Design, Synthesis, and Anticancer Assessment of Benzylated Pyrrole-Based Pyrido[2,3-d]Pyrimidines as Thymidylate Synthase Inhibitors","authors":"Adarsh Kumar,&nbsp;Sonu Rajput,&nbsp;Ankit Kumar Singh,&nbsp;Vineet Prajapati,&nbsp;Amita Verma,&nbsp;Prateek Pathak,&nbsp;Umashanker Navik,&nbsp;Jurica Novak,&nbsp;Pradeep Kumar","doi":"10.1111/cbdd.70240","DOIUrl":"10.1111/cbdd.70240","url":null,"abstract":"<div>\u0000 \u0000 <p>Globally, colorectal cancer (CRC) is the second most common cause of cancer-related deaths and the third most common cancer. Thymidylate synthase (TS), a key enzyme involved in DNA biosynthesis, has emerged as a promising molecular target for anticancer therapy. In the present study, we designed and synthesized a series of 22 benzylated pyrrole-based pyrido[2,3-<i>d</i>]pyrimidines using Claisen Schmidt and Michael addition reactions, and evaluated their anticancer potential against four human cancer cell lines: HCT 116 (colorectal), A549 (lung), MCF-7 (breast), and MDA-MB-231 (triple-negative breast cancer) as well as for TS inhibitory potential. Compounds 1c and 2i exhibited potent TS inhibition with IC<sub>50</sub> values of 11.50 ± 1.08 nM and 17.12 ± 0.91 nM, respectively, comparable to the standard drug raltitrexed (IC<sub>50</sub> = 12.51 ± 0.91 nM). Molecular docking studies revealed stronger binding affinities of these compounds compared to raltitrexed, involving key interactions with the catalytic residue Cys195 of TS. Additionally, compounds 1c and 2i exhibited good stability in 300 ns molecular dynamics simulations along with acceptable drug-like properties and oral bioavailability. These findings suggest that compounds 1c and 2i are promising lead candidates for the development of TS inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
EIF2AK2 Globally Binds and Regulates the Expression and Alternative Splicing of T2D-Related Genes in INS1 Cell EIF2AK2在INS1细胞中结合并调控t2d相关基因的表达和选择性剪接
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-13 DOI: 10.1111/cbdd.70242
Lili Ning, Tong Liu, Yuanyuan Lv, Yan Cheng, Maoguang Yang, Hanqing Cai

This study aimed to investigate the impact of the RNA-binding protein eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) gene, also known as PKR, on the condition of islet beta cells. In this study, EIF2AK2 was overexpressed in INS1 cells, and transcriptome data following EIF2AK2 overexpression were obtained using RNA-seq technology. Additionally, potential target genes that bind to EIF2AK2 were identified through iRIP-seq technology. The proteins interacting with EIF2AK2 were characterized using co-immunoprecipitation (CO-IP) combined with mass spectrometry to elucidate the molecular regulatory mechanisms of EIF2AK2 in INS1 cells. RNA-seq results indicated that in INS1 cells overexpressing EIF2AK2, 1171 genes were differentially expressed, and 2161 alternative splicing events were significantly altered. iRIP-seq data demonstrated that reads from the immunoprecipitated samples were significantly enriched in the intronic and coding sequence (CDS) regions. EIF2AK2 preferentially binds to the GCGGCGG motif in RNA. Comprehensive analysis suggests that EIF2AK2 may directly bind to and regulate the expression of Dusp8, Btg1, and Prkce, thereby affecting pancreatic islet cell functions. Furthermore, EIF2AK2 may influence islet cell function by modulating the alternative splicing of Zfr and Pias2. Additionally, combined with Co-IP mass spectrometry data, it was discovered that EIF2AK2 can interact with 649 proteins, including various differentially expressed RNA-binding proteins, transcription factors, and histones, which may be associated with diabetes. Our results indicate that EIF2AK2 may regulate the expression or alternative splicing of mRNA related to type 2 diabetes through direct or indirect binding. Additionally, it may influence the progression of type 2 diabetes by interacting with other proteins. We propose that EIF2AK2 plays a significant role in diabetic islet beta cells, and its aberrant regulatory pattern is closely associated with the onset and progression of type 2 diabetes.

本研究旨在探讨rna结合蛋白真核翻译起始因子2- α激酶2 (EIF2AK2)基因(也称为PKR)对胰岛β细胞状况的影响。本研究中,EIF2AK2在INS1细胞中过表达,利用RNA-seq技术获得了EIF2AK2过表达后的转录组数据。此外,通过iip -seq技术鉴定了与EIF2AK2结合的潜在靶基因。采用共免疫沉淀(CO-IP)结合质谱法对与EIF2AK2相互作用的蛋白进行表征,阐明EIF2AK2在INS1细胞中的分子调控机制。RNA-seq结果显示,在过表达EIF2AK2的INS1细胞中,1171个基因发生了差异表达,2161个选择性剪接事件发生了显著改变。iip -seq数据显示,免疫沉淀样品的reads在内含子和编码序列(CDS)区域显著富集。EIF2AK2优先结合RNA中的GCGGCGG基序。综合分析,EIF2AK2可能直接结合并调控Dusp8、Btg1和Prkce的表达,从而影响胰岛细胞功能。此外,EIF2AK2可能通过调节Zfr和Pias2的选择性剪接来影响胰岛细胞功能。此外,结合Co-IP质谱数据,发现EIF2AK2可与649种蛋白相互作用,包括各种差异表达的rna结合蛋白、转录因子和组蛋白,这些蛋白可能与糖尿病有关。我们的研究结果表明,EIF2AK2可能通过直接或间接结合调节2型糖尿病相关mRNA的表达或选择性剪接。此外,它可能通过与其他蛋白质相互作用影响2型糖尿病的进展。我们认为EIF2AK2在糖尿病胰岛β细胞中发挥重要作用,其异常调控模式与2型糖尿病的发生和进展密切相关。
{"title":"EIF2AK2 Globally Binds and Regulates the Expression and Alternative Splicing of T2D-Related Genes in INS1 Cell","authors":"Lili Ning,&nbsp;Tong Liu,&nbsp;Yuanyuan Lv,&nbsp;Yan Cheng,&nbsp;Maoguang Yang,&nbsp;Hanqing Cai","doi":"10.1111/cbdd.70242","DOIUrl":"10.1111/cbdd.70242","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to investigate the impact of the RNA-binding protein eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) gene, also known as PKR, on the condition of islet beta cells. In this study, EIF2AK2 was overexpressed in INS1 cells, and transcriptome data following EIF2AK2 overexpression were obtained using RNA-seq technology. Additionally, potential target genes that bind to EIF2AK2 were identified through iRIP-seq technology. The proteins interacting with EIF2AK2 were characterized using co-immunoprecipitation (CO-IP) combined with mass spectrometry to elucidate the molecular regulatory mechanisms of EIF2AK2 in INS1 cells. RNA-seq results indicated that in INS1 cells overexpressing EIF2AK2, 1171 genes were differentially expressed, and 2161 alternative splicing events were significantly altered. iRIP-seq data demonstrated that reads from the immunoprecipitated samples were significantly enriched in the intronic and coding sequence (CDS) regions. EIF2AK2 preferentially binds to the GCGGCGG motif in RNA. Comprehensive analysis suggests that EIF2AK2 may directly bind to and regulate the expression of Dusp8, Btg1, and Prkce, thereby affecting pancreatic islet cell functions. Furthermore, EIF2AK2 may influence islet cell function by modulating the alternative splicing of Zfr and Pias2. Additionally, combined with Co-IP mass spectrometry data, it was discovered that EIF2AK2 can interact with 649 proteins, including various differentially expressed RNA-binding proteins, transcription factors, and histones, which may be associated with diabetes. Our results indicate that EIF2AK2 may regulate the expression or alternative splicing of mRNA related to type 2 diabetes through direct or indirect binding. Additionally, it may influence the progression of type 2 diabetes by interacting with other proteins. We propose that EIF2AK2 plays a significant role in diabetic islet beta cells, and its aberrant regulatory pattern is closely associated with the onset and progression of type 2 diabetes.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145967872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring the Therapeutic Potential of Oridonin in the Treatment of Laryngeal Cancer: A Comprehensive Strategy Involving Network Pharmacology, Molecular Docking, Dynamic Simulation, and Experimental Verification 探索冬凌草苷治疗喉癌的潜力:网络药理学、分子对接、动态模拟和实验验证的综合策略。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-12 DOI: 10.1111/cbdd.70222
Rui Zhang, Lei Ren, Jiabin Hou, Chun Yang, Yang Sun, Fei Sun, Bo Yue

Laryngeal cancer (LC) is one of the most common malignant tumors of the head and neck, with high morbidity and mortality rates worldwide. Oridonin (Ori), a natural tetracyclic diterpenoid, exhibits notable anti-tumor properties. However, its efficacy and underlying mechanism in LC remain to be elucidated. This study employed comprehensive network pharmacology, molecular docking, and molecular dynamic simulation to investigate the molecular targets and mechanisms underlying the anti-LC effects of Ori, followed by in vitro validation of its key mechanisms. A total of 172 potential therapeutic targets of Ori for LC were identified. GO and KEGG analyses indicated that Ori's anti-LC mechanism primarily involved the PI3K-Akt, Ras, MAPK, and Rap1 signaling pathways. The PPI network and molecular docking analyses revealed that AKT1, EGFR, and MAPK1 are potential core targets of Ori. Additionally, molecular dynamics simulations and bioinformatics analyses further confirmed that these proteins are key candidate targets. In vitro, Ori inhibited the proliferation of LC Hep-2 and TU212 cells, induced apoptosis, arrested the cell cycle at the G1 phase, and suppressed migration and invasion. WB assays further showed that Ori significantly downregulated p-AKT expression in the PI3K/AKT pathway. These findings indicate that Ori represents a promising therapeutic candidate for LC.

喉癌(LC)是头颈部最常见的恶性肿瘤之一,在世界范围内具有很高的发病率和死亡率。oriidonin (Ori)是一种天然的四环二萜类化合物,具有显著的抗肿瘤作用。然而,其在LC中的作用及其机制尚不清楚。本研究采用综合网络药理学、分子对接、分子动力学模拟等方法研究Ori抗lc作用的分子靶点和机制,并对其关键机制进行体外验证。共鉴定出172个Ori对LC的潜在治疗靶点。GO和KEGG分析表明,Ori的抗lc机制主要涉及PI3K-Akt、Ras、MAPK和Rap1信号通路。PPI网络和分子对接分析显示,AKT1、EGFR和MAPK1是Ori潜在的核心靶点。此外,分子动力学模拟和生物信息学分析进一步证实了这些蛋白是关键的候选靶点。在体外,Ori可抑制LC Hep-2和TU212细胞的增殖,诱导凋亡,使细胞周期停留在G1期,抑制迁移和侵袭。WB分析进一步显示,Ori显著下调PI3K/AKT通路中p-AKT的表达。这些发现表明Ori是一种很有希望的治疗LC的候选药物。
{"title":"Exploring the Therapeutic Potential of Oridonin in the Treatment of Laryngeal Cancer: A Comprehensive Strategy Involving Network Pharmacology, Molecular Docking, Dynamic Simulation, and Experimental Verification","authors":"Rui Zhang,&nbsp;Lei Ren,&nbsp;Jiabin Hou,&nbsp;Chun Yang,&nbsp;Yang Sun,&nbsp;Fei Sun,&nbsp;Bo Yue","doi":"10.1111/cbdd.70222","DOIUrl":"10.1111/cbdd.70222","url":null,"abstract":"<div>\u0000 \u0000 <p>Laryngeal cancer (LC) is one of the most common malignant tumors of the head and neck, with high morbidity and mortality rates worldwide. Oridonin (Ori), a natural tetracyclic diterpenoid, exhibits notable anti-tumor properties. However, its efficacy and underlying mechanism in LC remain to be elucidated. This study employed comprehensive network pharmacology, molecular docking, and molecular dynamic simulation to investigate the molecular targets and mechanisms underlying the anti-LC effects of Ori, followed by in vitro validation of its key mechanisms. A total of 172 potential therapeutic targets of Ori for LC were identified. GO and KEGG analyses indicated that Ori's anti-LC mechanism primarily involved the PI3K-Akt, Ras, MAPK, and Rap1 signaling pathways. The PPI network and molecular docking analyses revealed that AKT1, EGFR, and MAPK1 are potential core targets of Ori. Additionally, molecular dynamics simulations and bioinformatics analyses further confirmed that these proteins are key candidate targets. In vitro, Ori inhibited the proliferation of LC Hep-2 and TU212 cells, induced apoptosis, arrested the cell cycle at the G1 phase, and suppressed migration and invasion. WB assays further showed that Ori significantly downregulated p-AKT expression in the PI3K/AKT pathway. These findings indicate that Ori represents a promising therapeutic candidate for LC.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Paeoniflorin Alleviates Pulmonary Arterial Hypertension by Suppressing TRIM24-Mediated SIRT1 Ubiquitination and NLRP3 Inflammasome Activation 芍药苷通过抑制trim24介导的SIRT1泛素化和NLRP3炎性体激活来缓解肺动脉高压。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-12 DOI: 10.1111/cbdd.70238
Jinbo Zhang, Wenxin Zhang, Bingbing Fan, Zhiyong Yang, Zhengkun Tian, Chunhe Wang, Lizhen Shang, Zhenghui Zhang

This study aimed to investigate the molecular mechanism by which tripartite motif-containing 24 (TRIM24) regulates the ubiquitination of sirtuin 1 (SIRT1) and to explore the protective effect of paeoniflorin (PF) on pulmonary arterial hypertension (PAH). Bioinformatics analysis identified TRIM24 and SIRT1 as key targets of PF. A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx). These model rats were then treated with PF and/or subjected to overexpression of TRIM24 or SIRT1. TRIM24 and SIRT1 expression were assessed by reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry. Lung vascular remodeling was evaluated by hemodynamic analysis and hematoxylin–eosin (HE) staining. Inflammatory cytokine levels (interleukin-1β, interleukin-6, tumor necrosis factor-α) in lung tissues were measured. In vitro, hypoxia-exposed human pulmonary artery endothelial cells (HPAECs) were used to evaluate PF effects on cell viability (CCK-8), migration (scratch assay), and protein expression (Western blot). Ubiquitination and protein stability assays demonstrated that TRIM24 promoted SIRT1 protein degradation. TRIM24 inhibited SIRT1-mediated autophagy, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Conversely, SIRT1 upregulation enhanced autophagy and suppressed NLRP3 activation. PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis.

本研究旨在探讨TRIM24调控sirtuin 1 (SIRT1)泛素化的分子机制,探讨芍药苷(PF)对肺动脉高压(PAH)的保护作用。生物信息学分析发现TRIM24和SIRT1是PF的关键靶点,并通过注射SU5416 (Su)联合慢性缺氧(Hx)建立PAH大鼠模型。然后用PF处理这些模型大鼠和/或使TRIM24或SIRT1过表达。采用逆转录定量PCR (RT-qPCR)和免疫组织化学检测TRIM24和SIRT1的表达。采用血流动力学分析和苏木精-伊红(HE)染色评价肺血管重构。检测肺组织炎性细胞因子(白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α)水平。在体外,我们使用缺氧暴露的人肺动脉内皮细胞(HPAECs)来评估PF对细胞活力(CCK-8)、迁移(划痕法)和蛋白表达(Western blot)的影响。泛素化和蛋白稳定性实验表明TRIM24促进SIRT1蛋白降解。TRIM24抑制sirt1介导的自噬,从而激活nod样受体家族pyrin结构域- 3 (NLRP3)炎性体。相反,SIRT1上调可增强自噬并抑制NLRP3的激活。PF通过下调TRIM24和保持SIRT1功能减轻PAH和内皮功能障碍。这些发现揭示了PF通过TRIM24/SIRT1/NLRP3轴保护PAH的新机制。
{"title":"Paeoniflorin Alleviates Pulmonary Arterial Hypertension by Suppressing TRIM24-Mediated SIRT1 Ubiquitination and NLRP3 Inflammasome Activation","authors":"Jinbo Zhang,&nbsp;Wenxin Zhang,&nbsp;Bingbing Fan,&nbsp;Zhiyong Yang,&nbsp;Zhengkun Tian,&nbsp;Chunhe Wang,&nbsp;Lizhen Shang,&nbsp;Zhenghui Zhang","doi":"10.1111/cbdd.70238","DOIUrl":"10.1111/cbdd.70238","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to investigate the molecular mechanism by which tripartite motif-containing 24 (TRIM24) regulates the ubiquitination of sirtuin 1 (SIRT1) and to explore the protective effect of paeoniflorin (PF) on pulmonary arterial hypertension (PAH). Bioinformatics analysis identified TRIM24 and SIRT1 as key targets of PF. A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx). These model rats were then treated with PF and/or subjected to overexpression of TRIM24 or SIRT1. TRIM24 and SIRT1 expression were assessed by reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry. Lung vascular remodeling was evaluated by hemodynamic analysis and hematoxylin–eosin (HE) staining. Inflammatory cytokine levels (interleukin-1β, interleukin-6, tumor necrosis factor-α) in lung tissues were measured. In vitro, hypoxia-exposed human pulmonary artery endothelial cells (HPAECs) were used to evaluate PF effects on cell viability (CCK-8), migration (scratch assay), and protein expression (Western blot). Ubiquitination and protein stability assays demonstrated that TRIM24 promoted SIRT1 protein degradation. TRIM24 inhibited SIRT1-mediated autophagy, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Conversely, SIRT1 upregulation enhanced autophagy and suppressed NLRP3 activation. PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Benzimidazole-Urea Phenylalanine Hybrids as Dual-Acting Antimicrobial and Anticancer Agents: In Silico and Biological Evaluation 新型苯并咪唑-尿素苯丙氨酸复合物作为双作用抗菌和抗癌剂:硅和生物评价。
IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-05 DOI: 10.1111/cbdd.70229
Tuğçe Deniz Karaca, İrfan Çapan, Yusuf Sert, Hüseyin Balcı, Arzu Aysan, İrfan Koca

The emergence of multidrug-resistant microorganisms and the limited therapeutic options for hepatocellular carcinoma (HCC) highlight the urgent need for new molecular scaffolds with dual pharmacological potential. In this study, a novel series of benzimidazole-urea phenylalanine hybrids was designed and synthesized using a rational structure-based approach to integrate antimicrobial and anticancer functionalities within a single pharmacophore. All synthesized compounds were characterized by spectroscopic methods and evaluated for their antimicrobial and cytotoxic activities. Among the series, CPN305 exhibited the most potent cytotoxicity against hepatocellular carcinoma cell lines (PLC/PRF/5 and HuH7) while maintaining minimal toxicity toward normal human fibroblasts (BJ-1). Additionally, the compound demonstrated promising antimicrobial efficacy against Staphylococcus aureus. Molecular docking simulations revealed favorable binding interactions within the Hsp90 active site, supporting the observed in vitro anticancer effects, while ADME predictions indicated desirable physicochemical and pharmacokinetic properties. Collectively, these findings suggest that the benzimidazole-urea phenylalanine scaffold represents a promising lead framework for further structural optimization and mechanistic exploration as a dual-acting antimicrobial and anticancer agent.

耐多药微生物的出现和有限的肝细胞癌(HCC)治疗方案突出了对具有双重药理潜力的新型分子支架的迫切需求。在这项研究中,设计和合成了一系列新的苯并咪唑-尿素苯丙氨酸杂交体,采用基于合理结构的方法将抗菌和抗癌功能整合在一个药效团中。所有合成的化合物都用光谱方法进行了表征,并对其抗菌和细胞毒活性进行了评价。在该系列中,CPN305对肝癌细胞系(PLC/PRF/5和HuH7)表现出最强的细胞毒性,而对正常人成纤维细胞(BJ-1)保持最小的毒性。此外,该化合物对金黄色葡萄球菌具有良好的抗菌作用。分子对接模拟显示Hsp90活性位点内有利的结合相互作用,支持观察到的体外抗癌作用,而ADME预测显示了理想的物理化学和药代动力学特性。总之,这些发现表明,苯并咪唑-尿素苯丙氨酸支架作为一种双作用抗菌剂和抗癌剂,具有进一步结构优化和机制探索的前景。
{"title":"Novel Benzimidazole-Urea Phenylalanine Hybrids as Dual-Acting Antimicrobial and Anticancer Agents: In Silico and Biological Evaluation","authors":"Tuğçe Deniz Karaca,&nbsp;İrfan Çapan,&nbsp;Yusuf Sert,&nbsp;Hüseyin Balcı,&nbsp;Arzu Aysan,&nbsp;İrfan Koca","doi":"10.1111/cbdd.70229","DOIUrl":"10.1111/cbdd.70229","url":null,"abstract":"<div>\u0000 \u0000 <p>The emergence of multidrug-resistant microorganisms and the limited therapeutic options for hepatocellular carcinoma (HCC) highlight the urgent need for new molecular scaffolds with dual pharmacological potential. In this study, a novel series of benzimidazole-urea phenylalanine hybrids was designed and synthesized using a rational structure-based approach to integrate antimicrobial and anticancer functionalities within a single pharmacophore. All synthesized compounds were characterized by spectroscopic methods and evaluated for their antimicrobial and cytotoxic activities. Among the series, CPN305 exhibited the most potent cytotoxicity against hepatocellular carcinoma cell lines (PLC/PRF/5 and HuH7) while maintaining minimal toxicity toward normal human fibroblasts (BJ-1). Additionally, the compound demonstrated promising antimicrobial efficacy against <i>Staphylococcus aureus</i>. Molecular docking simulations revealed favorable binding interactions within the Hsp90 active site, supporting the observed in vitro anticancer effects, while ADME predictions indicated desirable physicochemical and pharmacokinetic properties. Collectively, these findings suggest that the benzimidazole-urea phenylalanine scaffold represents a promising lead framework for further structural optimization and mechanistic exploration as a dual-acting antimicrobial and anticancer agent.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Chemical Biology & Drug Design
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1