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Co-Administration of a Plantain-Based Diet and Quercetin Modulates Atrazine-Induced Testicular Dysfunction in Rats via Testicular Steroidogenesis and Redox-Inflammatory Processes. 通过睾丸类固醇生成和氧化还原-炎症过程同时服用车前草和槲皮素可调节阿特拉津诱导的大鼠睾丸功能障碍
IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-11-20 DOI: 10.1002/tox.24431
Damilare Emmanuel Rotimi, Olusola Olalekan Elekofehinti, Olarewaju Michael Oluba, Oluyomi Stephen Adeyemi

Plantain has been reported to enhance testicular function indices, however, the mechanism remains unknown. The present study investigated the action mechanisms of a plantain-based diet in the treatment of rat testicular dysfunction caused by exposure to atrazine (ATZ). The rats were grouped into 10 groups (5 rats each); control group, 50% plantain-based diet (50% PBD), 25% PBD, 12.5% PBD, quercetin (QUE), ATZ only, 50% PBD + ATZ, 25% PBD + ATZ, 12.5% PBD + ATZ, and QUE + ATZ for 21 days. Results revealed that ATZ treatments in rats lowered gonadal hormone levels and the semen quality (sperm concentration, motility, count, and viability), damaged testicular morphology and functions, and impaired redox-inflammatory balance as well as cholinergic and purinergic activities. However, treatment with PBD and QUE ameliorated the testicular toxicity induced by ATZ, although the treatment did not improve the rat semen quality. In addition, the ATZ + QUE and QUE groups showed mild to moderate atrophic degenerative changes, with reduced spermatogenic activity. Together, the results are evidence that 21 days of exposure to ATZ impaired testicular function. However, co-administration of atrazine and PBD improves rat gonadal hormones, redox state, inflammatory indices, cholinergic, and purinergic activities, as well as histoarchitecture of the testes.

据报道,车前草可提高睾丸功能指数,但其机制仍不清楚。本研究探讨了车前草膳食治疗因暴露于阿特拉津(ATZ)而导致的大鼠睾丸功能障碍的作用机制。大鼠被分为 10 组(每组 5 只):对照组、50% 车前草膳食组(50% PBD)、25% PBD 组、12.5% PBD 组、槲皮素组(QUE)、仅 ATZ 组、50% PBD + ATZ 组、25% PBD + ATZ 组、12.5% PBD + ATZ 组和 QUE + ATZ 组,连续 21 天。结果显示,ATZ 会降低大鼠的性腺激素水平和精液质量(精子浓度、活力、数量和存活率),破坏睾丸的形态和功能,损害氧化还原-炎症平衡以及胆碱能和嘌呤能活性。然而,PBD 和 QUE 可改善 ATZ 引起的睾丸毒性,尽管治疗并未改善大鼠的精液质量。此外,ATZ + QUE 组和 QUE 组表现出轻度至中度萎缩性退行性变化,生精活性降低。总之,这些结果证明,接触 ATZ 21 天会损害睾丸功能。然而,同时施用阿特拉津和 PBD 可改善大鼠性腺激素、氧化还原状态、炎症指数、胆碱能和嘌呤能活性以及睾丸的组织结构。
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引用次数: 0
The Chinese Herbal Medicine Li Qi Huo Xue Di Wan Ameliorates Ischemia or Hypoxia‐Induced Cardiac Injury and Remodeling in the Heart Through a Mechanism Involving Reduction of Necroptosis 中药六味地黄丸通过减少坏死机制改善缺血缺氧诱导的心脏损伤和重塑
IF 4.5 3区 医学 Q2 ENVIRONMENTAL SCIENCES Pub Date : 2024-11-12 DOI: 10.1002/tox.24435
Yi‐Yue Zhang, Can Tang, Ya‐Qi Dou, Xiu‐Ju Luo, Jian Pu, Jun Peng
Li Qi Huo Xue Di Wan (LQHXDW), a Chinese herbal medicine, is commonly used to treat symptoms such as palpitations, chest tightness, chest pain, and shortness of breath. However, its potential to reduce ischemia or hypoxia‐induced cardiac injury and remodeling, along with the precise mechanisms involved, remains unclear. This study aims to investigate the effects of LQHXDW on cardiac injury and remodeling induced by ischemia or hypoxia, both in vivo and in vitro, and to elucidate the underlying mechanisms. The mouse heart was subjected to ischemia for 14 days, showing evident myocardial injury and notable cardiac remodeling, accompanied by a reduction in cardiac function; these phenomena were reversed in the presence of LQHXDW. In the cultured cardiomyocyte exposed to hypoxia, incubation with LQHXDW increased the cell viability and reduced lactate dehydrogenase release. Mechanistically, LQHXDW exerted inhibitory effect on the phosphorylation levels of RIPK1, RIPK3, and MLKL as well as oxidative stress in the mice hearts suffered ischemia and the cultured cardiomyocytes exposed to hypoxia. Using the methods of ultra‐high performance liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry, network pharmacology, and cellular thermal shift assay, phenethyl caffeate and isoliquiritigenin were identified as the potential active compounds in LQHXDW that counteract necroptosis. Based on these observations, we conclude that LQHXDW protects the heart against ischemia or hypoxia‐induced cardiac injury and remodeling through suppression of the RIPK1/RIPK3/MLKL pathway‐dependent necroptosis and oxidative stress.
六味地黄丸(LQHXDW)是一种中药,常用于治疗心悸、胸闷、胸痛和气短等症状。然而,它在减轻缺血或缺氧引起的心脏损伤和重塑方面的潜力及其确切机制仍不清楚。本研究旨在探讨 LQHXDW 在体内和体外对缺血或缺氧诱导的心脏损伤和重构的影响,并阐明其潜在机制。小鼠心脏缺血 14 天后出现明显的心肌损伤和心脏重塑,并伴有心功能减退;LQHXDW 的存在可逆转这些现象。在缺氧条件下培养的心肌细胞中,与 LQHXDW 一起孵育可提高细胞活力并减少乳酸脱氢酶的释放。从机理上讲,LQHXDW对缺血小鼠心脏和缺氧培养心肌细胞中RIPK1、RIPK3和MLKL的磷酸化水平以及氧化应激均有抑制作用。通过超高效液相色谱-四极杆飞行时间质谱法、网络药理学和细胞热转移分析等方法,我们发现咖啡酸苯乙酯和异桔梗素是 LQHXDW 中潜在的能对抗坏死的活性化合物。基于这些观察结果,我们得出结论:LQHXDW 通过抑制依赖于 RIPK1/RIPK3/MLKL 通路的坏死和氧化应激,保护心脏免受缺血或缺氧引起的心脏损伤和重塑。
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引用次数: 0
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
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
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
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。
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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 4.4 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。
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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
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Environmental Toxicology
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