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MCM4 Promotes the Progression of Malignant Melanoma by Activating the PI3K/AKT Pathway. MCM4 通过激活 PI3K/AKT 通路促进恶性黑色素瘤的进展
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-11-06 DOI: 10.1002/tox.24433
Xuewei Zhang, Mingming Dong, Guoxing Zheng, Meng Sun, Chuzhao Zhang, Zibin Zhou, Shijie Tang

This study aims to elucidate the role of minichromosome maintenance protein 4 (MCM4) in malignant melanoma (MM) and explore the underlying mechanism. Initially, data from The Cancer Genome Atlas (TCGA) database and the Molecular Signature Database (MSigDB) were used to investigate the biological impact of MCM4 on MM. Further, a prognostic model using Cox regression analysis was developed to predict the overall survival (OS) rate in the MM patients. The effects of MCM4 on the proliferation, migration, and invasion abilities of MM (B16F0 and A375) cells were demonstrated using the CCK-8, colony formation, EDU, wound scratch, and Transwell assays. In subcutaneous tumor models in C57BL/6 mice in vivo, the expression levels of MCM4 in MM cells and tumors were detected using Western blot and immunofluorescence approaches. The bioinformatics analysis indicated that MCM4 was expressed higher in MM tissues than in the normal tissues (p < 0.05). The established OS prediction model could significantly contribute to devising follow-up strategies and treating MM patients. MCM4 knockdown resulted in reduced proliferation, migration, and invasion abilities of MM cells, which were reversed by MCM4 overexpression (p < 0.05). Moreover, MCM4 could activate the phosphatidylinositol 3'-kinase (PI3K)/AKT pathway in MM cells. The PI3K inhibitor (LY294002) could reverse the effects of MCM4 on MM cells. MCM4 could substantially prompt the tumor growth of MM in mice through the PI3K/AKT pathway in vivo. In summary, MCM4 prompted the development and metastasis of MM by activating the PI3K/AKT pathway.

本研究旨在阐明迷你染色体维护蛋白4(MCM4)在恶性黑色素瘤(MM)中的作用并探索其潜在机制。最初,研究人员利用癌症基因组图谱(TCGA)数据库和分子特征数据库(MSigDB)中的数据研究了MCM4对MM的生物学影响。此外,还利用 Cox 回归分析建立了一个预后模型,以预测 MM 患者的总生存率(OS)。利用 CCK-8、集落形成、EDU、伤口划痕和 Transwell 试验证明了 MCM4 对 MM(B16F0 和 A375)细胞增殖、迁移和侵袭能力的影响。在 C57BL/6 小鼠皮下肿瘤模型中,使用 Western 印迹和免疫荧光方法检测了 MM 细胞和肿瘤中 MCM4 的表达水平。生物信息学分析表明,MCM4 在 MM 组织中的表达高于正常组织(p
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引用次数: 0
SERPING1 Reduces Cell Migration via ERK-MMP2-MMP-9 Cascade in Sorafenib- Resistant Hepatocellular Carcinoma. SERPING1 通过 ERK-MMP2-MMP-9 级联降低索拉非尼耐药肝细胞癌的细胞迁移率
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-30 DOI: 10.1002/tox.24434
Ching-Chuan Hsieh, Yuh-Harn Wu, Yi-Li Chen, Chun-I Wang, Chao-Jen Li, I-Hsiu Liu, Chen-Wei Chou, Yang-Hsiang Lin, Po-Shuan Huang, Te-Chia Huang, Cheng-Yi Chen

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence-free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib-resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP-2 and MMP-9 activity and enhanced the expression of p-ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p-ERK-MMP-2-MMP-9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC.

肝细胞癌(HCC)是最常见的原发性肝脏恶性肿瘤,死亡率在台湾所有恶性肿瘤中排名第二。索拉非尼(Sorafenib)是一种多重酪氨酸激酶抑制剂,可通过不同途径抑制肿瘤细胞增殖和肿瘤周围血管生成。然而,接受索拉非尼治疗的晚期HCC患者的生存结果仍不令人满意。遗憾的是,迄今为止还没有适用于临床的生物标志物来预测索拉非尼对HCC的治疗效果。我们发现,丝氨酸肽酶抑制剂 G 族成员 1(SERPING1)与 HCC 患者的总生存率和无复发生存率高度相关,并且与多个临床参数高度相关。索拉非尼增加了 SERPING1 在 HCC 细胞提取物和条件培养基中的表达,在耐索拉非尼的 HepG2 和 Huh7 细胞中也观察到了这一现象。索拉非尼降低了细胞活力和迁移,这与 SERPING1 在 HCC 进展中的作用相似。此外,索拉非尼还能抑制 HCC 细胞中 MMP-2 和 MMP-9 的活性,并增强 p-ERK 的表达。总之,索拉非尼可能通过上调SERPING1,通过p-ERK-MMP-2-MMP-9级联反应来降低HCC癌的进展。本研究探讨了 SERPING1 的作用和分子机制,以及其作为预测 HCC 患者索拉非尼耐药和进展的标志物的价值。本研究的结果有助于深入了解 SERPING1 在 HCC 索拉非尼耐药中的作用,可用于开发早期诊断和预后评估方法,并建立专门治疗 HCC 的新型治疗靶点。
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引用次数: 0
Correction to "Inflammatory Response and Endothelial Dysfunction in the Hearts of Mice Co-Exposed to SO2, NO2, and PM2.5". 更正 "共同暴露于二氧化硫、二氧化氮和 PM2.5 的小鼠心脏的炎症反应和内皮功能障碍"。
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-29 DOI: 10.1002/tox.24432
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引用次数: 0
Nimbolide Induces Cell Apoptosis via Mediating ER Stress-Regulated Apoptotic Signaling in Human Oral Squamous Cell Carcinoma. Nimbolide 通过介导 ER 应激调节的人口腔鳞状细胞癌细胞凋亡信号诱导细胞凋亡
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-27 DOI: 10.1002/tox.24436
Bou-Yue Peng, Chia-Yu Wu, Chia-Jung Lee, Tsung-Ming Chang, Ya-Ting Tsao, Ju-Fang Liu

Human oral squamous cell carcinoma (OSCC) poses a significant health challenge in Asia, with current therapeutic strategies failing to improve the survival rates for OSCC patients sufficiently. To elucidate the effects of Nimbolide on OSCC cell proliferation and apoptosis, we performed a series of experiments, including cell proliferation assays, annexin V/PI assays, and cell cycle analysis. We further investigated nimbolide's role in modulating endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and mitochondrial dysfunction using flow cytometry. Additionally, Western blotting was used to detect apoptosis-related protein expression. Our findings reveal that nimbolide exerts its anti-proliferative effects on OSCC cells by inducing apoptosis. The nimbolide increased intracellular ROS levels and acceleration of cellular calcium accumulation, respectively promoting endoplasmic reticulum stress and cancer cell apoptosis. Furthermore, nimbolide activates the caspase cascade by altering the mitochondrial membrane potential and apoptotic protein expression, thereby inhibiting the viability of tumor cells. Our data show that Nimbolide suppresses tumor growth through the induction of ROS production, ER stress, and mitochondrial dysfunction, resulting in apoptosis in OSCC cells. Overall, our study highlights nimbolide as a potential natural compound for OSCC therapy.

人类口腔鳞状细胞癌(OSCC)是亚洲面临的一项重大健康挑战,目前的治疗策略未能充分提高OSCC患者的生存率。为了阐明宁波利对 OSCC 细胞增殖和凋亡的影响,我们进行了一系列实验,包括细胞增殖实验、附件素 V/PI 实验和细胞周期分析。我们还利用流式细胞术进一步研究了宁博莱特在调节内质网(ER)应激、活性氧(ROS)生成和线粒体功能障碍方面的作用。此外,还使用 Western 印迹法检测与细胞凋亡相关的蛋白质表达。我们的研究结果表明,宁波利通过诱导细胞凋亡对 OSCC 细胞产生抗增殖作用。宁波利可增加细胞内 ROS 水平,加速细胞钙积累,从而促进内质网应激和癌细胞凋亡。此外,宁波利通过改变线粒体膜电位和凋亡蛋白的表达激活了 Caspase cascade,从而抑制了肿瘤细胞的活力。我们的数据表明,宁波利通过诱导 ROS 生成、ER 应激和线粒体功能障碍,导致 OSCC 细胞凋亡,从而抑制肿瘤生长。总之,我们的研究突出表明,宁波利内酯是一种治疗 OSCC 的潜在天然化合物。
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引用次数: 0
Increased Susceptibility of Cardiac Tissue to PM2.5-Induced Toxicity in Uremic Cardiomyopathic Rats Is Linked to Elevated Levels of Mitochondrial Dysfunction. 尿毒症心肌病大鼠心脏组织对 PM2.5 诱导毒性的易感性增加与线粒体功能障碍水平升高有关。
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-27 DOI: 10.1002/tox.24437
Bhavana Sivakumar, Gino A Kurian

Patients with chronic kidney disease (CKD) frequently develop uremic cardiomyopathy, characterized by mitochondrial dysfunction as one of its pathologically significant mediators. Given that PM2.5 specifically targets cardiac mitochondria, exacerbating toxicity, this study addresses the potential alterations in the severity of PM2.5 toxicity in the context of CKD conditions. Female Wistar rats were exposed to PM2.5 at a concentration of 250 μg/m3 daily for 3 h for 21 days after which an adenine-induced CKD model was developed. While both PM2.5 exposure and the induction of CKD in rats lead to cardiomyopathy, the CKD animals exposed to PM2.5 exhibited a notably severe extent of myocardial hypertrophy and fibrosis. ECG recordings in CKD+ PM2.5 animals revealed a depressed ST segment and prolonged QRS interval, with both PM2.5 and CKD animals displaying an elevated ST segment. Subcellular level analysis confirmed a significantly low mitochondrial copy number and a severe decline in mitochondrial bioenergetic function in the CKD+ PM2.5 group. The prominent decline in PGC1-α further affirmed the severe mitochondrial functional deterioration in CKD+ PM2.5 animals compared to other experimental groups. Additionally, myocardial calcification was enhanced in CKD+ PM2.5 animals, heightening the susceptibility of CKD animals to PM2.5 toxicity. In summary, our findings suggest that the increased vulnerability of CKD myocardium to PM2.5-induced toxicity may be attributed to severe mitochondrial damage and increased calcification in the myocardium.

慢性肾脏病(CKD)患者经常会发生尿毒症性心肌病,其特点是线粒体功能障碍是其重要的病理介质之一。鉴于 PM2.5 特别针对心脏线粒体,会加剧毒性,本研究探讨了在 CKD 条件下 PM2.5 毒性严重程度的潜在变化。雌性 Wistar 大鼠每天暴露于浓度为 250 μg/m3 的 PM2.5 中 3 小时,持续 21 天,之后建立了腺嘌呤诱导的 CKD 模型。虽然暴露于PM2.5和诱导大鼠患CKD都会导致心肌病,但暴露于PM2.5的CKD动物的心肌肥厚和纤维化程度明显更严重。CKD+PM2.5动物的心电图记录显示ST段压低和QRS间期延长,PM2.5和CKD动物均显示ST段升高。亚细胞水平分析证实,CKD+ PM2.5 组的线粒体拷贝数明显偏低,线粒体生物能功能严重下降。与其他实验组相比,PGC1-α的显著下降进一步证实了CKD+ PM2.5动物线粒体功能的严重退化。此外,CKD+PM2.5动物的心肌钙化增强,增加了CKD动物对PM2.5毒性的易感性。总之,我们的研究结果表明,CKD 心肌对 PM2.5 诱导的毒性的易感性增加可能是由于严重的线粒体损伤和心肌钙化增加所致。
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引用次数: 0
Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis. 麦伐他汀诱导心脏成纤维细胞中 HO-1 的表达:对抗心血管炎症和纤维化的策略
IF 4.5 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-21 DOI: 10.1002/tox.24429
I-Ta Lee,Chien-Chung Yang,Yan-Jyun Lin,Wen-Bin Wu,Wei-Ning Lin,Chiang-Wen Lee,Hui-Ching Tseng,Fuu-Jen Tsai,Li-Der Hsiao,Chuen-Mao Yang
Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.
众所周知,麦伐他汀(MVS)具有抗炎作用,可能是通过上调血红素加氧酶-1(HO-1)实现的,HO-1 是一种参与细胞保护以防止氧化损伤的酶。然而,MVS 刺激人心脏成纤维细胞(HCFs)中 HO-1 表达的具体过程尚未完全明了。在本研究中,我们发现 MVS 处理可提高 HCFs 中 HO-1 的 mRNA 和蛋白水平。使用 p38 MAPK、JNK1/2 和 FoxO1 的特异性抑制剂以及靶向 NOX2、p47phox、p38、JNK1、FoxO1、Keap1 和 Nrf2 的 siRNA 预处理可抑制这种诱导。MVS 还引发了 ROS 生成并激活了 JNK1/2 和 p38 MAPK,NADPH 氧化酶或 ROS 抑制剂均可减轻这两种作用。此外,MVS 还促进了 FoxO1 和 Nrf2 的磷酸化,p38 MAPK 或 JNK1/2 抑制剂抑制了这种磷酸化。此外,MVS 还能通过 HO-1/CO 通路抑制 TNF-α 诱导的 NF-κB 激活和 HCFs 中血管细胞粘附分子-1(VCAM-1)的表达。总之,MVS 在 HCFs 中诱导 HO-1 的表达是通过两个主要信号通路介导的:NADPH 氧化酶/ROS/p38 MAPK 以及 JNK1/2/FoxO1 和 Nrf2。这项研究阐明了 MVS 通过调节心脏成纤维细胞中的 HO-1 发挥抗炎作用的基本过程。
{"title":"Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis.","authors":"I-Ta Lee,Chien-Chung Yang,Yan-Jyun Lin,Wen-Bin Wu,Wei-Ning Lin,Chiang-Wen Lee,Hui-Ching Tseng,Fuu-Jen Tsai,Li-Der Hsiao,Chuen-Mao Yang","doi":"10.1002/tox.24429","DOIUrl":"https://doi.org/10.1002/tox.24429","url":null,"abstract":"Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.","PeriodicalId":11756,"journal":{"name":"Environmental Toxicology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis. 麦伐他汀诱导心脏成纤维细胞中 HO-1 的表达:对抗心血管炎症和纤维化的策略
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-21 DOI: 10.1002/tox.24429
I-Ta Lee, Chien-Chung Yang, Yan-Jyun Lin, Wen-Bin Wu, Wei-Ning Lin, Chiang-Wen Lee, Hui-Ching Tseng, Fuu-Jen Tsai, Li-Der Hsiao, Chuen-Mao Yang

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.

众所周知,麦伐他汀(MVS)具有抗炎作用,可能是通过上调血红素加氧酶-1(HO-1)实现的,HO-1 是一种参与细胞保护以防止氧化损伤的酶。然而,MVS 刺激人心脏成纤维细胞(HCFs)中 HO-1 表达的具体过程尚未完全明了。在本研究中,我们发现 MVS 处理可提高 HCFs 中 HO-1 的 mRNA 和蛋白水平。使用 p38 MAPK、JNK1/2 和 FoxO1 的特异性抑制剂以及靶向 NOX2、p47phox、p38、JNK1、FoxO1、Keap1 和 Nrf2 的 siRNA 预处理可抑制这种诱导。MVS 还引发了 ROS 生成并激活了 JNK1/2 和 p38 MAPK,NADPH 氧化酶或 ROS 抑制剂均可减轻这两种作用。此外,MVS 还促进了 FoxO1 和 Nrf2 的磷酸化,p38 MAPK 或 JNK1/2 抑制剂抑制了这种磷酸化。此外,MVS 还能通过 HO-1/CO 通路抑制 TNF-α 诱导的 NF-κB 激活和 HCFs 中血管细胞粘附分子-1(VCAM-1)的表达。总之,MVS 在 HCFs 中诱导 HO-1 的表达是通过两个主要信号通路介导的:NADPH 氧化酶/ROS/p38 MAPK 以及 JNK1/2/FoxO1 和 Nrf2。这项研究阐明了 MVS 通过调节心脏成纤维细胞中的 HO-1 发挥抗炎作用的基本过程。
{"title":"Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis.","authors":"I-Ta Lee, Chien-Chung Yang, Yan-Jyun Lin, Wen-Bin Wu, Wei-Ning Lin, Chiang-Wen Lee, Hui-Ching Tseng, Fuu-Jen Tsai, Li-Der Hsiao, Chuen-Mao Yang","doi":"10.1002/tox.24429","DOIUrl":"https://doi.org/10.1002/tox.24429","url":null,"abstract":"<p><p>Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47<sup>phox</sup>, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.</p>","PeriodicalId":11756,"journal":{"name":"Environmental Toxicology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
H3K27 Acetylation-Activated GLDC Accelerated the Advancement of Oral Squamous Cell Carcinoma by Suppressing the p53 Signaling Pathway. H3K27乙酰化激活的GLDC通过抑制p53信号通路加速口腔鳞状细胞癌的发展
IF 4.5 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-17 DOI: 10.1002/tox.24379
Chen Xu,Qingfeng Xu,Haibing Yang
Glycine decarboxylase (GLDC) has been identified to be dysregulated and plays pivotal roles in various cancers. Besides, studies have suggested that GLDC expression is elevated in oral squamous cell carcinoma (OSCC) and associated with a worse prognosis, but the precise role and molecular mechanism of GLDC in OSCC remain unexplored. The current study first confirmed the high expression of GLDC in OSCC and its correlation with worse survival in patients with OSCC. By knocking down GLDC, it was discovered that the growth and colony formation of OSCC cells, as well as the development of xenograft tumors, were effectively suppressed. In addition, GLDC deficiency inhibited the migration and invasion of OSCC cells in vitro through regulating EMT markers and attenuated lung metastasis in vivo. Mechanistically, GLDC was found to affect the activity of the p53 signaling pathway. GLDC depletion retarded the progression of OSCC by activating the p53 signaling pathway. Moreover, p300 co-functioned with TFAP2A to induce acetylation of GLDC, which resulted in the upregulation of GLDC in OSCC. To conclude, acetylation-induced GLDC upregulation facilitated the tumorigenesis and metastasis of OSCC by its inhibition of the activity of the p53 signaling pathway.
甘氨酸脱羧酶(Glycine decarboxylase,GLDC)已被发现在多种癌症中失调并发挥关键作用。此外,有研究表明,GLDC在口腔鳞状细胞癌(OSCC)中表达升高,并与预后恶化相关,但GLDC在OSCC中的确切作用和分子机制仍有待探索。本研究首次证实了GLDC在OSCC中的高表达及其与OSCC患者生存率降低的相关性。研究发现,通过敲除GLDC,OSCC细胞的生长和集落形成以及异种移植肿瘤的发生均被有效抑制。此外,GLDC的缺乏还通过调节EMT标记物抑制了体外OSCC细胞的迁移和侵袭,并减轻了体内的肺转移。从机理上讲,GLDC会影响p53信号通路的活性。通过激活p53信号通路,GLDC耗竭可延缓OSCC的进展。此外,p300与TFAP2A共同作用诱导GLDC乙酰化,从而导致GLDC在OSCC中上调。总之,乙酰化诱导的GLDC上调通过抑制p53信号通路的活性促进了OSCC的肿瘤发生和转移。
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引用次数: 0
Anticancer Potential of Ethanolic Extract of Xylopia aethiopica (Dunal) A. Rich (Annonaceae) Dried Fruits on Breast Adenocarcinoma: In Vitro and In Vivo Evidences. 木犀科干果乙醇提取物对乳腺癌的抗癌潜力:体外和体内证据
IF 4.5 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-14 DOI: 10.1002/tox.24428
Merline Ymele Nguedia,Roland Nhouma Rebe,Berlise Yengwa Bakam,Dieudonné Njamen,Joseph Marie Nkodo Mendimi,Stéphane Zingue
Breast cancer incidence and mortality rate in Cameroonian women is incredibly high, thus there is need for more effective therapy. Xylopia aethiopica dry fruits are traditionally used for both nutritional and medicinal purposes, including the management of diverse ailments such as cancer. This study evaluated the in vitro and in vivo anti-mammary cancer potential of X. aethiopica. The cytotoxic activity of the ethanolic extract of X. aethiopica dry fruits was assessed at different concentrations against MDA-MB 231 and MCF-7 cells using the MTT assay. Additionally, clone formation, apoptosis/necrosis, cell adhesion, cell migration, and chemotaxis were examined. Furthermore, the chemo-preventive potential of X. aethiopica dry fruit extract (XAE) was evaluated on breast tumors induced by DMBA in 42 female rats of age 45-55 days (~80 g). The normal (NOR) and negative (DMBA) control groups were daily treated with the vehicle, while the positive (Tamox) and test (XAE) groups were administered tamoxifen (3.3 mg/kg) and X. aethiopica extract (75, 150, and 300 mg/kg BW), respectively for 20 weeks. Parameters such as tumor volume and burden, tumor incidence, CA 15-3 serum level, inflammatory status, antioxidant and histopathology were evaluated. X. aethiopica significantly (p < 0.05) decreased ER+ (MCF-7) and ER- (MDA-MB 231) breast adenocarcinoma cell growth from 12.5 to 100 μg/mL after 72 h. At the 100 μg/mL concentration, clone formation, cell proliferation, and migration were notably decreased in MDA-MB 231 cells after 48 h, while there was an observed rise in cell adhesion to the collagen extracellular matrix. Additionally, there was a rise in apoptotic cell count (p < 0.01) and caspase-3 activity (p < 0.05) observed in MDA-MB 231 cells following exposure to XAE at 100 μg/mL. XAE, across all tested doses, demonstrated significant reductions in tumor incidence, burden, and volume, akin to tamoxifen, compared to untreated rats (DMBA). Furthermore, there was an elevation in antioxidants (SOD, CAT, and GSH) and a decrease in pro-inflammatory cytokines (INF-γ, TNF-α, IL-12, and IL-6) observed at all tested doses. Overall, X. aethiopica dry fruit displays anticancer potential through caspase-3-dependent apoptosis pathways, alongside antioxidant and anti-inflammatory activities.
喀麦隆妇女的乳腺癌发病率和死亡率高得惊人,因此需要更有效的治疗方法。Xylopia aethiopica 干果传统上用于营养和医疗目的,包括治疗癌症等多种疾病。本研究评估了 X. aethiopica 的体外和体内抗乳腺癌潜力。采用 MTT 法评估了不同浓度的 X. aethiopica 干果乙醇提取物对 MDA-MB 231 和 MCF-7 细胞的细胞毒性活性。此外,还检测了克隆形成、细胞凋亡/坏死、细胞粘附、细胞迁移和趋化性。此外,还评估了 X. aethiopica 干果提取物(XAE)对 42 只年龄在 45-55 天(约 80 克)的雌性大鼠由 DMBA 诱导的乳腺肿瘤的化学预防潜力。正常对照组(NOR)和阴性对照组(DMBA)每天用药物治疗,而阳性对照组(Tamox)和试验组(XAE)则分别服用他莫昔芬(3.3 毫克/千克)和 X. aethiopica 提取物(75、150 和 300 毫克/千克体重)20 周。对肿瘤体积和负荷、肿瘤发病率、CA 15-3 血清水平、炎症状态、抗氧化性和组织病理学等参数进行了评估。在 100 μg/mL 浓度下,MDA-MB 231 细胞的克隆形成、细胞增殖和迁移在 48 小时后明显降低,同时观察到细胞对胶原细胞外基质的粘附上升。此外,MDA-MB 231 细胞暴露于 100 μg/mL 的 XAE 后,观察到凋亡细胞计数(p < 0.01)和 caspase-3 活性(p < 0.05)上升。与未经处理的大鼠(DMBA)相比,所有测试剂量的 XAE 都能显著降低肿瘤发病率、负荷和体积,与他莫昔芬类似。此外,在所有测试剂量下都观察到抗氧化剂(SOD、CAT 和 GSH)的增加和促炎细胞因子(INF-γ、TNF-α、IL-12 和 IL-6)的减少。总之,X. aethiopica 干果通过依赖于 caspase-3 的细胞凋亡途径显示出抗癌潜力,同时还具有抗氧化和抗炎活性。
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引用次数: 0
Integrated Analysis of Serum and Tissue microRNA Transcriptome for Biomarker Discovery in Gastric Cancer 综合分析血清和组织 microRNA 转录组,发现胃癌生物标记物
IF 4.5 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-10-14 DOI: 10.1002/tox.24430
Xinfeng Wang, Zhuoran Li, Chengyan Zhang
Gastric cancer (GC) poses a significant global health challenge, demanding a detailed exploration of its molecular landscape. Studies suggest that exposure to environmental pollutants can lead to changes in microRNA (miRNA) expression patterns, which may contribute to the development and progression of GC. MiRNAs have emerged as crucial regulators implicated in GC pathogenesis. The largest GC serum miRNA dataset to date, comprising 1417 non‐cancer controls and 1417 GC samples was used. We conducted a comprehensive analysis of miRNA expression profiles. Differential expression analysis, co‐expression network construction, and machine learning models were employed to identify key serum miRNAs and their association with clinical parameters. Weighted Gene Co‐expression Network Analysis (WGCNA) and immune infiltration analysis were used to validate the importance of the key miRNA. A total of 1766 differentially expressed miRNAs were identified, with miR‐1290, miR‐1246, and miR‐451a among the top up‐regulated, and miR‐6875‐5p, miR‐6784‐5p, miR‐1228‐5p, and miR‐6765‐5p among the top down‐regulated. WGCNA revealed that modules M1 and M5 were significantly associated with GC subtypes and disease status. MiRNA‐target gene network analysis identified prognostically significant genes TP53, EMCN, CBX8, and ALDH1A3. Machine learning models LASSO, SVM, randomforest, and XGBOOST demonstrated the diagnostic potential of miRNA profiles. Tissue and serum miR‐187 emerged as an independent prognostic factor, influencing patient survival across clinical parameters. Gene expression and immune cell infiltration were different in tissues stratified by miR‐187 expression. In summary, the integration of differential gene expression, co‐expression analysis, and immune cell profiling provided insights into the molecular intricacies of GC progression.
胃癌(GC)对全球健康构成了重大挑战,需要对其分子结构进行详细研究。研究表明,暴露于环境污染物会导致微RNA(miRNA)表达模式的改变,这可能会导致胃癌的发生和发展。miRNA 已成为与 GC 发病机制有关的关键调控因子。我们使用了迄今为止最大的 GC 血清 miRNA 数据集,其中包括 1417 份非癌症对照样本和 1417 份 GC 样本。我们对 miRNA 表达谱进行了全面分析。我们采用了差异表达分析、共表达网络构建和机器学习模型来确定关键的血清 miRNA 及其与临床参数的关系。加权基因共表达网络分析(WGCNA)和免疫浸润分析被用来验证关键miRNA的重要性。共鉴定出1766个差异表达的miRNA,其中miR-1290、miR-1246和miR-451a的表达量最高,miR-6875-5p、miR-6784-5p、miR-1228-5p和miR-6765-5p的表达量最低。WGCNA显示,模块M1和M5与GC亚型和疾病状态显著相关。MiRNA 靶基因网络分析发现了对预后有重要意义的基因 TP53、EMCN、CBX8 和 ALDH1A3。机器学习模型 LASSO、SVM、randomforest 和 XGBOOST 证明了 miRNA 图谱的诊断潜力。组织和血清 miR-187 是一个独立的预后因素,影响着患者的临床生存。基因表达和免疫细胞浸润在 miR-187 表达分层的组织中有所不同。总之,通过整合差异基因表达、共表达分析和免疫细胞图谱,我们可以深入了解 GC 进展的分子奥秘。
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Environmental Toxicology
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