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Adverse Effects of COVID-19 Treatments: A Special Focus on Susceptible Populations. COVID-19治疗的不良影响:特别关注易感人群。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2022-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2022039271
Beyza Nur Küçük, Rahime Şimşek, Selinay Başak Erdemli Köse, Anil Yirun, Pinar Erkekoglu

On December 2019, the world faced a new pandemic caused by a novel type of coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is named as "coronavirus disease 2019 (COVID-19)." This RNA virus infected millions of people around the world causing millions of deaths. It takes approximately 8-10 years to develop a new drug and it seems hard to have a specific pharmaceutical agent against COVID-19. So far, there is only one drug that has applied for registration. The drugs used in clinics against COVID-19 were approved for malaria, human immunodeficiency syndrome (HIV), influenza A and B, and other viral diseases. All these drugs for COVID-19 treatment are being applied according to "drug repurposing (drug repositioning)" strategy. However, they could cause some severe adverse effects on susceptible populations. In some cases, patients can survive after disease. However, the adverse effects of these drugs may lead to morbidity and mortality later. In this review, drugs used against COVID-19 in clinics, their mechanisms of action and possible adverse effects on susceptible populations will be discussed.

2019年12月,世界面临一场由新型冠状病毒引起的新大流行,即严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)。这种疾病被命名为“冠状病毒病2019 (COVID-19)”。这种RNA病毒感染了全世界数百万人,导致数百万人死亡。开发新药大约需要8-10年的时间,而且似乎很难开发出针对COVID-19的特定药物。到目前为止,只有一种药物申请了注册。临床用于治疗COVID-19的药物已被批准用于治疗疟疾、人类免疫缺陷综合征(HIV)、甲型和乙型流感以及其他病毒性疾病。所有用于治疗COVID-19的药物都是根据“药物再利用(药物重新定位)”战略使用的。然而,它们可能对易感人群造成一些严重的不利影响。在某些情况下,患者可以在患病后存活下来。然而,这些药物的副作用可能导致发病和死亡。本文将对临床抗COVID-19药物、作用机制及对易感人群可能产生的不良影响进行综述。
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引用次数: 0
miR-1246 Promotes Laryngeal Squamous Cell Carcinoma Progression by Interacting with THBS1. miR-1246通过与THBS1相互作用促进喉癌进展
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2022-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2022040516
Lifeng Wu, Na Zuo, Shuo Pan, Yue Wang, Qixue Wang, Jun Ma

MicroRNAs (miRNAs) have been confirmed to be related to the occurrence and progress of multiple cancers, including laryngeal squamous cell carcinoma (LSCC). The present work focused on exploring the role of miR-1246 in LSCC and investigating the possible mechanisms. miR-1246 expression levels within clinical LSCC tissues and cell lines (TU212 and AMC-HN-8) were detected through quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. Then the overall survival (OS) rates of LSCC patients with different miR-1246 expressions were assessed by the Kaplan-Meier method. In addition, the roles of miR-1246 in the proliferation, apoptosis and migration of TU212 and AMC-HN-8 cells were measured by colony formation, flow cytometry, wound-healing, and Western blot (WB) assays, respectively. Moreover, TargetScan was carried out to predict the miR-1246 targets (thrombospondin-1, THBS1), further confirmed by a dual-luciferase reporter assay. Afterward, the negative relationship between miR-1246 and THBS1 was assessed by qRT-PCR and WB. Furthermore, the restoring effects of THBS1 on TU212 and AMC-HN-8 functional roles transfected with miR-1246 inhibitor were further investigated. miR-1246 expression levels were increased in clinical LSCC tissues and cell lines. Patients with low miR-1246 expression exhibited improved OS rates. In addition, miR-1246 down-regulation notably suppressed cell proliferation and migration and induced cell apoptosis of TU212 and AMC-HN-8 cells. Moreover, THBS1 was predicted and confirmed as a direct target of miR-1246 and negatively related to miR-1246 expression. Mechanically, THBS1 inhibition partially rescued the effects of the miR-1246 inhibitor on proliferation, apoptosis and migration of TU212 and AMC-HN-8 cells. This study provides an experimental basis suggesting the potential of miR-1246/THBS1 as the novel markers for LSCC.

MicroRNAs (miRNAs)已被证实与包括喉鳞状细胞癌(LSCC)在内的多种癌症的发生和进展有关。目前的工作重点是探索miR-1246在LSCC中的作用并研究可能的机制。通过定量逆转录聚合酶链反应(qRT-PCR)检测miR-1246在临床LSCC组织和细胞系(TU212和AMC-HN-8)中的表达水平。然后采用Kaplan-Meier法评估不同miR-1246表达的LSCC患者的总生存率(OS)。此外,通过集落形成、流式细胞术、创面愈合和Western blot (WB)检测分别检测miR-1246在TU212和AMC-HN-8细胞增殖、凋亡和迁移中的作用。此外,TargetScan用于预测miR-1246靶点(血栓反应蛋白-1,THBS1),并通过双荧光素酶报告基因试验进一步证实。随后,通过qRT-PCR和WB评估miR-1246与THBS1的负相关关系。进一步研究THBS1对转染miR-1246 inhibitor的TU212和AMC-HN-8功能角色的恢复作用。miR-1246在临床LSCC组织和细胞系中的表达水平升高。miR-1246低表达的患者OS率提高。此外,miR-1246下调可显著抑制TU212和AMC-HN-8细胞的增殖和迁移,诱导细胞凋亡。此外,预测并证实THBS1是miR-1246的直接靶点,与miR-1246的表达呈负相关。机械上,THBS1抑制部分恢复了miR-1246抑制剂对TU212和AMC-HN-8细胞增殖、凋亡和迁移的影响。本研究为miR-1246/THBS1作为LSCC新标志物的潜力提供了实验依据。
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引用次数: 1
Oncogenic Role of Heterogeneous Nuclear Ribonucleoprotein C in Multiple Cancer Types, with a Particular Focus on Lung Adenocarcinoma, Using a Pan-Cancer Analysis and Cell Line Experiments. 异质核核糖核蛋白C在多种癌症类型中的致癌作用,特别是肺腺癌,使用泛癌症分析和细胞系实验。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2022-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2022042822
Libin Zhang, Hao Peng, Lihong Jiang

Although some evidence has validated the connection between heterogeneous nuclear ribonucleoprotein C (HNRNPC) and the progression of tumors, a pan-cancer investigation is still required. Thus, we explored the oncogenic effect of HNRNPC across many tumors using The Cancer Genome Atlas datasets. Moreover, short hairpin RNAs (shRNAs) were found to repress HNRNPC in lung adenocarcinoma (LUAD) cells, and the effect on LUAD cells proliferation and metastasis was examined using a Cell Counting Kit-8, transwell, and invasion test. HNRNPC was found to be overexpressed in most cancers, and a divergent relationship was observed between the abnormal levels of HNRNPC and tumor prognosis. HNRNPC level was observed to correlate with the cancer-associated fibroblast infiltration, such as lung cancer. Furthermore, higher HNRNPC levels were found in LUAD tissues and cells. Subsequently, Kaplan-Meier analysis revealed that the increased HNRNPC level was connected with worse overall survival and disease-free survival in LUAD patients. Moreover, HNRNPC silencing reduced the progression of A549 and H1299 cells, including proliferation, migration, and invasion. This is the first pan-cancer investigation that presents a relatively systematic finding of the oncogenic effect of HNRNPC among many cancer types. Our data indicate that HNRNPC facilitates the biological processes of LUAD cells; nevertheless, further research on the mechanism underlying the role of HNRNPC in LUAD development is warranted.

尽管一些证据已经证实了异质核核糖核蛋白C (HNRNPC)与肿瘤进展之间的联系,但仍需要进行泛癌症研究。因此,我们利用癌症基因组图谱数据集探索了HNRNPC在许多肿瘤中的致癌作用。此外,在肺腺癌(LUAD)细胞中发现短发夹rna (shRNAs)抑制HNRNPC,并通过细胞计数试剂盒-8、transwell和侵袭试验检测其对LUAD细胞增殖和转移的影响。HNRNPC在大多数肿瘤中均存在过表达,但其异常水平与肿瘤预后之间存在差异关系。观察到HNRNPC水平与癌症相关的成纤维细胞浸润相关,如肺癌。此外,在LUAD组织和细胞中发现较高的HNRNPC水平。随后,Kaplan-Meier分析显示,HNRNPC水平升高与LUAD患者总生存期和无病生存期较差有关。此外,HNRNPC沉默降低了A549和H1299细胞的增殖、迁移和侵袭等进展。这是首次对HNRNPC在许多癌症类型中的致癌作用进行相对系统的泛癌症研究。我们的数据表明,HNRNPC促进LUAD细胞的生物学过程;然而,对HNRNPC在LUAD发展中的作用机制的进一步研究是必要的。
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引用次数: 0
PI3K/Akt/mTOR Pathways Inhibitors with Potential Prospects in Non-Small-Cell Lung Cancer. PI3K/Akt/mTOR通路抑制剂在非小细胞肺癌中的潜在应用前景
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2022-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2022042281
Khalid Saad Alharbi, Mohammad Arshad Javed Shaikh, Waleed Hassan Almalki, Imran Kazmi, Fahad A Al-Abbasi, Sami I Alzarea, Syed Sarim Imam, Sultan Alshehri, Mohammed M Ghoneim, Sachin Kumar Singh, Dinesh Kumar Chellappan, Brian G Oliver, Kamal Dua, Gaurav Gupta

Lung cancer is the leading cause of cancer-related mortality across the globe. The most prevalent pathological form of lung cancer is non-small-cell lung cancer (NSCLC). Elevated stimulation of the PI3K/Akt/mTOR pathway causes a slew of cancer-related symptoms, making it a promising target for new anticancer drugs. The PI3K/Akt/mTOR path is involved extensively in carcinogenesis and disease advancement in NSCLC. Several new inhibitors targeting this pathway have been discovered in preclinical investigations and clinical trials. The etiology and epidemiology of NSCLC and biology of the PI3K/Akt/mTOR cascade and its role in NSCLC pathogenesis have all been discussed in this article. In this article, we've reviewed PI3K/Akt/mTOR cascade inhibitors that have been proven in vitro and in preclinical trials to be effective in NSCLC. Drugs targeting the PI3K/Akt/mTOR path in the treatment of NSCLC were also addressed. A better knowledge of the underlying molecular biology, including epigenetic changes, is also critical to detecting relevant biomarkers and guiding combination methods. Additionally, improved clinical trial designs will increase the capacity to test novel drugs and combinations for accounting for genomic variation and eventually improve patient outcomes.

肺癌是全球癌症相关死亡的主要原因。肺癌最常见的病理形式是非小细胞肺癌(NSCLC)。PI3K/Akt/mTOR通路的刺激升高导致一系列癌症相关症状,使其成为新的抗癌药物的有希望的靶点。PI3K/Akt/mTOR通路广泛参与非小细胞肺癌的癌变和疾病进展。在临床前研究和临床试验中发现了几种新的靶向该途径的抑制剂。本文就非小细胞肺癌的病因、流行病学、PI3K/Akt/mTOR级联的生物学机制及其在非小细胞肺癌发病中的作用进行了综述。在本文中,我们回顾了PI3K/Akt/mTOR级联抑制剂,这些抑制剂已在体外和临床前试验中被证明对非小细胞肺癌有效。针对PI3K/Akt/mTOR通路治疗NSCLC的药物也得到了讨论。更好地了解潜在的分子生物学,包括表观遗传变化,对于检测相关的生物标志物和指导组合方法也至关重要。此外,改进的临床试验设计将增加测试新药物和组合的能力,以解释基因组变异,并最终改善患者的结果。
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引用次数: 9
Mangiferin Inhibits Inflammation and Cell Proliferation, and Activates Proapoptotic Events via NF-κB Inhibition in DMBA-Induced Mammary Carcinogenesis in Rats. 在 DMBA 诱导的大鼠乳腺癌发生过程中,芒果苷通过抑制 NF-κB 抑制炎症和细胞增殖,并激活促凋亡事件。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2021036057
Xin Wang, Tong Yuwen, Tian Yanqin

The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.

本研究旨在探讨芒果苷(MGN)抗7,12-二甲基苯并(a)蒽(DMBA)诱导的乳腺癌的抗炎、抗增殖和促凋亡分子机制。在大鼠乳腺中单次皮下注射 0.5 毫升 DMBA(80 毫克/千克芝麻油)诱发乳腺癌。我们观察到肿瘤发病率和体积增大以及其他致瘤特性。此外,我们还观察到这些大鼠的抗氧化酶活性降低,血浆和组织中硫代巴比妥酸活性物质(TBARS)水平升高。DMBA 诱导的大鼠显示出炎症标志物 NF-κBp65、COX-2 和 iNOS 的表达增强,PCNA 和 Cyclin D1 的增殖以及抗凋亡标志物 Bcl-2 的过度表达。芒果苷(100 毫克/千克体重)每天口服一次,可显著提高(p < 0.05)抗氧化水平并降低 TBARS 水平。此外,芒果苷还能抑制 NF-κBp65 核转录激活,从而抑制炎症和细胞增殖,并增加促凋亡蛋白。细胞凋亡由 TUNEL 试验证实。总之,MGN 通过提高抗氧化水平、抑制 NF-κB 和正向调节凋亡信号,抑制了 DMBA 诱导的乳腺癌。
{"title":"Mangiferin Inhibits Inflammation and Cell Proliferation, and Activates Proapoptotic Events via NF-κB Inhibition in DMBA-Induced Mammary Carcinogenesis in Rats.","authors":"Xin Wang, Tong Yuwen, Tian Yanqin","doi":"10.1615/JEnvironPatholToxicolOncol.2021036057","DOIUrl":"10.1615/JEnvironPatholToxicolOncol.2021036057","url":null,"abstract":"<p><p>The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.</p>","PeriodicalId":50201,"journal":{"name":"Journal of Environmental Pathology Toxicology and Oncology","volume":"40 2","pages":"1-9"},"PeriodicalIF":2.4,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25564151","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
SHP1 Decreases Level of P-STAT3 (Ser727) and Inhibits Proliferation and Migration of Pancreatic Cancer Cells. SHP1 降低 P-STAT3 (Ser727) 的水平并抑制胰腺癌细胞的增殖和迁移
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2020035980
Mingming Zhang, Xiaoru Hu, Ye Kang, Zhe Wang, Wenyang Zhou, Chang Liu, Xianghong Yang

Purpose: To identify the direct effects and functional mechanisms of SHP1, plus its relationship with STAT3 in pancreatic cancer.

Methods: Immunohistochemistry and Western blot assays were used to test SHP1 expression in pancreatic cancer. The functions of SHP1 in pancreatic cancer cells were analyzed by cell viability, colony formation, flow cytometric analysis of apoptosis, migration and invasion assays. Co-immunoprecipitation, combined with shotgun mass spectrometry, verified the direct or indirect interactions with JAK1 and p-STAT3(Ser727). Non-labeling and quantitative proteomics analysis evaluated the effect of SHP1 on protein expression levels. PRM phosphorylation modification of quantitative proteomics analysis confirmed p-STAT3(Ser727) levels.

Results: SHP1 was missing or weakly expressed in human pancreatic ductal adenocarcinoma tissues and cells: PANC-1, AsPC-1, BxPC-3, and SW1990. SHP1 inhibited cell proliferation and migration. SHP1 had a slight effect on the protein expression level of PANC-1 cells. The level of p-STAT3(Ser727) was decreased by SHP1 at 0.53 multiple. Co-IP analysis revealed no direct or indirect interactions between SHP1and p-STAT3(Ser727) in protein complex patterns.

Conclusion: These results suggest that SHP1 negatively regulate pancreatic cancer cells progression. It inhibits STAT3 activation by decreasing STAT3 phosphorylation at serine 727.

目的:明确SHP1在胰腺癌中的直接作用和功能机制,以及它与STAT3的关系:方法:采用免疫组化和 Western 印迹检测 SHP1 在胰腺癌中的表达。通过细胞活力、集落形成、流式细胞仪分析凋亡、迁移和侵袭实验分析了 SHP1 在胰腺癌细胞中的功能。共免疫沉淀结合枪式质谱法验证了SHP1与JAK1和p-STAT3(Ser727)的直接或间接相互作用。非标记和定量蛋白质组学分析评估了 SHP1 对蛋白质表达水平的影响。定量蛋白质组学分析的PRM磷酸化修饰证实了p-STAT3(Ser727)的水平:结果:SHP1在人胰腺导管腺癌组织和细胞中缺失或弱表达:结果:SHP1在人胰腺导管腺癌组织和细胞(PANC-1、AsPC-1、BxPC-3和SW1990)中缺失或弱表达。SHP1 可抑制细胞增殖和迁移。SHP1 对 PANC-1 细胞的蛋白表达水平有轻微影响。SHP1使p-STAT3(Ser727)的水平下降了0.53倍。Co-IP分析表明,SHP1与p-STAT3(Ser727)在蛋白复合物模式中没有直接或间接的相互作用:这些结果表明,SHP1 对胰腺癌细胞的进展具有负调控作用。结论:这些结果表明,SHP1 对胰腺癌细胞的进展有负向调节作用,它通过降低 STAT3 在丝氨酸 727 处的磷酸化来抑制 STAT3 的活化。
{"title":"SHP1 Decreases Level of P-STAT3 (Ser727) and Inhibits Proliferation and Migration of Pancreatic Cancer Cells.","authors":"Mingming Zhang, Xiaoru Hu, Ye Kang, Zhe Wang, Wenyang Zhou, Chang Liu, Xianghong Yang","doi":"10.1615/JEnvironPatholToxicolOncol.2020035980","DOIUrl":"10.1615/JEnvironPatholToxicolOncol.2020035980","url":null,"abstract":"<p><strong>Purpose: </strong>To identify the direct effects and functional mechanisms of SHP1, plus its relationship with STAT3 in pancreatic cancer.</p><p><strong>Methods: </strong>Immunohistochemistry and Western blot assays were used to test SHP1 expression in pancreatic cancer. The functions of SHP1 in pancreatic cancer cells were analyzed by cell viability, colony formation, flow cytometric analysis of apoptosis, migration and invasion assays. Co-immunoprecipitation, combined with shotgun mass spectrometry, verified the direct or indirect interactions with JAK1 and p-STAT3(Ser727). Non-labeling and quantitative proteomics analysis evaluated the effect of SHP1 on protein expression levels. PRM phosphorylation modification of quantitative proteomics analysis confirmed p-STAT3(Ser727) levels.</p><p><strong>Results: </strong>SHP1 was missing or weakly expressed in human pancreatic ductal adenocarcinoma tissues and cells: PANC-1, AsPC-1, BxPC-3, and SW1990. SHP1 inhibited cell proliferation and migration. SHP1 had a slight effect on the protein expression level of PANC-1 cells. The level of p-STAT3(Ser727) was decreased by SHP1 at 0.53 multiple. Co-IP analysis revealed no direct or indirect interactions between SHP1and p-STAT3(Ser727) in protein complex patterns.</p><p><strong>Conclusion: </strong>These results suggest that SHP1 negatively regulate pancreatic cancer cells progression. It inhibits STAT3 activation by decreasing STAT3 phosphorylation at serine 727.</p>","PeriodicalId":50201,"journal":{"name":"Journal of Environmental Pathology Toxicology and Oncology","volume":"40 1","pages":"17-27"},"PeriodicalIF":2.4,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25409778","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: 1
Troxerutin Abrogates Ischemic/Reperfusion-Induced Brain Injury through Ameliorating Oxidative Stress and Neuronal Inflammation by Inhibiting the Expression of NLRP3 in Sprague Dawley Rats. Troxerutin通过抑制NLRP3的表达,改善Sprague Dawley大鼠氧化应激和神经元炎症,从而消除缺血/再灌注诱导的脑损伤。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2021038860
Chao Gao, Yunfei Song, Taotao Dou, Shuai Jiang, Haoze Wu, Vidya Devanathadesikan Seshadri, Vishnu Priya Veeraraghavan, Pengfei Hou

Cerebral ischemic reperfusion (I/R) infarction is mostly associated with serious brain injury, cognitive damage, and neurological deficits. The oxidative stress mechanisms in the neurological region lead to higher reactive oxygen species production followed by oxidative stress, inflammation of neurons, and death of brain cells. The current work aims to evaluate the effect of troxerutin (TXN) on cerebral injury stimulated by I/R-induced ischemic stroke and examines the mechanistic effect of TXN on neuroinflammation in the Sprague Dawley model. The experimental rats were randomized in to four groups: (i) sham control, (ii) I/R + vehicle, (iii) I/R + 10 mg/kg bw TXN, and (iv) I/R + 20 mg/kg bw TXN. In the TXN administration and control, groups were injected intraperitoneally 15 min before reperfusion and every day for 7 days, except the sham group. Orally administered TXN (10 and 20 mg/kg/bw) modulated the water content, lowered the infarct volume, and abrogated score defects of neuron and changes in the brain tissue sample. In our study, the TXN-stimulated cerebral injury exhibited leakage of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) of the neuronal sample of tissues and showed higher antioxidant enzymes superoxide dismutase, catalase, the oxidized form of glutathione peroxidase, and the reduced form of glutathione levels. This biochemical result was additionally proved by histopathological assessment. Changes were made in antioxidant and inflammatory markers expressions interleukin-6 (IL-6), IL-4, IL-10, vascular endothelial growth factor, and cerebral induced rats. The overall findings showed that TXN protected the brain tissues from neuroinflammatory oxidative stress by reducing cerebral injury in Sprague Dawley rats. Further, the messenger RNA expression of cerebral I/R-induced animal tissues down-regulated NLRP3, caspase-1, tumor necrosis factor-α, ASC, IL-1β, and Toll-like receptor 3 (TLR3). Therefore, the TXN action on TLR3 induced brain stroke is an excellent therapeutic approach for brain damage.

脑缺血再灌注(I/R)梗死多与严重脑损伤、认知损伤和神经功能缺损相关。神经区域的氧化应激机制导致更高的活性氧产生,随后是氧化应激、神经元炎症和脑细胞死亡。本研究旨在通过Sprague - Dawley模型评价曲克鲁汀(troxerutin, TXN)对I/ r缺血性脑卒中脑损伤的影响,并探讨TXN对神经炎症的作用机制。实验大鼠随机分为4组:(i)假对照,(ii) i /R +对照,(iii) i /R + 10 mg/kg bw TXN, (iv) i /R + 20 mg/kg bw TXN。在给药组和对照组中,除假手术组外,其余各组在再灌注前15 min、每天腹腔注射TXN,连续7 d。口服TXN(10和20 mg/kg/bw)可调节脑组织含水量,降低梗死面积,消除脑组织样本神经元的评分缺陷和改变。在我们的研究中,txn刺激的脑损伤表现出组织神经元样本中硫巴比妥酸反应物质(TBARS)、脂质氢过氧化物(LOOH)的渗漏,并表现出较高的抗氧化酶超氧化物歧化酶、过氧化氢酶、氧化型谷胱甘肽过氧化物酶和谷胱甘肽还原型水平。这一生化结果也被组织病理学评价所证实。白细胞介素-6 (IL-6)、IL-4、IL-10、血管内皮生长因子和脑诱导大鼠抗氧化和炎症标志物表达发生变化。总体结果表明,TXN通过减少Sprague Dawley大鼠的脑损伤,保护脑组织免受神经炎性氧化应激。此外,脑I/ r诱导动物组织的信使RNA表达下调NLRP3、caspase-1、肿瘤坏死因子-α、ASC、IL-1β和toll样受体3 (TLR3)。因此,TXN对TLR3诱导的脑卒中的作用是一种很好的脑损伤治疗方法。
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引用次数: 2
Potential of Curcumin and Quercetin in Modulation of Premature Mitochondrial Senescence and Related Changes during Lung Carcinogenesis. 姜黄素和槲皮素在肺癌发生过程中调节线粒体过早衰老和相关变化的潜力。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2021039371
Wenfu Wang, Ying Xie, Anshoo Malhotra

Ferroptosis is a classification of programmed cell death, which activates oxidative cell death in an iron and lipid peroxides-dependent manner. Targeting ferroptosis is a novel therapeutic approach for cancer therapy. Lung cancer is the leading cause of cancer related deaths all over the world. Circular RNAs (circRNAs), as a form of noncoding RNAs with a specific closed circular sequence are emerging as a new field in cancer research. However, the regulatory mechanisms of circRNAs in ferroptosis during lung cancer development are still elusive. In this work, we elucidate the potential prognostic value and the crucial role of circular RNA circFOXP1 in ferroptosis of lung cancer. We found that the expression of circFOXP1 was remarkably up-regulated in clinical lung sample tissues compared with adjacent tissues. The up-regulation of circFOXP1 was closely correlated with the poor overall survival of lung cancer patients. The knockdown of circFOXP1 suppressed the cell viability of lung cancer cells. The colony formation counts of lung cancer cells were repressed by the depletion of circFOXP1 as well. The Edu-positive lung cancer cells were attenuated by the silencing of circFOXP1. The migration and invasion of lung cancer cells were suppressed by circFOXP1 short hairpin RNA (shRNA). The expression of E-cadherin was enhanced, and vimentin expression was reduced by the knockdown of circFOXP1. Moreover, the treatment of ferroptosis activator erastin or RSL3 repressed the cell viability of lung cancer cells and the overexpression of circFOXP1 rescued the phenotype. The levels of malondialdehyde (MDA), iron, and lipid reactive oxygen species (ROS) were enhanced by the silencing of circFOXP1 in both erastin and RSL3-stimulated lung cancer cells. Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells. Importantly, circFOXP1 contributed to tumor growth of lung cancer cells by enhancing SLC7A11 in vivo. Collectively, we concluded that circular RNA circFOXP1 is a potential diagnostic biomarker and contributes to malignant progression by repressing ferroptosis of lung cancer. Targeting circFOXP1 may be served as a promising therapeutic approach for lung cancer.

铁死亡是一种程序性细胞死亡,它以铁和脂质过氧化物依赖的方式激活氧化性细胞死亡。靶向铁下垂是一种新的肿瘤治疗方法。肺癌是全世界癌症相关死亡的主要原因。环状rna (Circular rna, circRNAs)作为一种具有特定闭合环状序列的非编码rna,正在成为癌症研究的一个新领域。然而,在肺癌发展过程中,环状rna在铁下垂中的调控机制仍然是未知的。在这项工作中,我们阐明了环状RNA circFOXP1在肺癌铁下垂中的潜在预后价值和关键作用。我们发现circFOXP1在临床肺样本组织中的表达与邻近组织相比显著上调。circFOXP1基因的上调与肺癌患者总生存率较差密切相关。敲低circFOXP1抑制肺癌细胞的细胞活力。肺癌细胞的集落形成计数也被circFOXP1的缺失所抑制。通过沉默circFOXP1可使edu阳性肺癌细胞减弱。circFOXP1短发夹RNA (shRNA)可抑制肺癌细胞的迁移和侵袭。通过敲低circFOXP1, E-cadherin的表达增强,vimentin的表达降低。此外,铁下垂激活子erastin或RSL3的处理抑制了肺癌细胞的细胞活力,circFOXP1的过表达挽救了表型。在erastin和rsl3刺激的肺癌细胞中,通过沉默circFOXP1,丙二醛(MDA)、铁和脂质活性氧(ROS)水平增强。机械上,circFOXP1通过在肺癌细胞中直接海绵化miR-520a-5p来增加SLC7A11的表达。miR-520a-5p抑制剂或SLC7A11过表达可逆转circFOXP1 shrna诱导的肺癌细胞铁下垂表型。重要的是,circFOXP1在体内通过增强SLC7A11促进肺癌细胞的肿瘤生长。总之,我们得出结论,环状RNA circFOXP1是一种潜在的诊断性生物标志物,并通过抑制肺癌铁下垂来促进恶性进展。靶向circFOXP1可能是一种有希望的肺癌治疗方法。
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引用次数: 6
Dialogue between Neuroinflammation and Neurodegenerative Diseases in COVID-19. COVID-19中神经炎症与神经退行性疾病的对话。
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2021038365
Bisruta Chowdhury, Apoorva Sharma, Sairaj Satarker, Jayesh Mudgal, Madhavan Nampoothiri

It has now been almost a year since the emergence of the deadly SARS-CoV-2 with millions of people losing their lives due to resultant COVID-19. Apart from the well-known consequences of respiratory illnesses, it has even effortlessly mapped itself into the nervous system through routes like blood, CSF, neurons, and olfactory cells. Interestingly, the interaction of SARS-CoV-2 with the nervous system cells like neurons, microglia, and astrocytes has been a factor to worsen COVID-19 through its neuroinflammatory actions. The release of cytokines due to astrocyte and microglial activation could progress towards the most anticipated cytokine storm proving to be detrimental in the management of COVID-19. Such hyper-inflammatory conditions could make the BBB vulnerable, encouraging excessive viral particles into the CNS, leading to further neurodegenerative pathologies like Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Multiple Sclerosis. Excessive neuroinflammation and neurodegeneration being the anticipated root causes of these multiple conditions, it is also essential to look into other factors that synergistically enhance the worsening of these diseases in COVID-19 patients for which additional studies are essential.

自致命的SARS-CoV-2出现以来已经快一年了,数百万人因由此产生的COVID-19而丧生。除了众所周知的呼吸系统疾病的后果,它甚至毫不费力地通过血液、脑脊液、神经元和嗅觉细胞等途径进入神经系统。有趣的是,SARS-CoV-2与神经元、小胶质细胞和星形胶质细胞等神经系统细胞的相互作用是通过其神经炎症作用使COVID-19恶化的一个因素。星形胶质细胞和小胶质细胞激活导致的细胞因子释放可能朝着最令人期待的细胞因子风暴发展,这被证明对COVID-19的管理是有害的。这种高度炎症会使血脑屏障变得脆弱,鼓励过多的病毒颗粒进入中枢神经系统,导致进一步的神经退行性病变,如阿尔茨海默病、帕金森病、克雅氏病和多发性硬化症。过度的神经炎症和神经退行性变是这些多重疾病的预期根本原因,因此还必须研究协同加剧COVID-19患者这些疾病恶化的其他因素,这需要进一步的研究。
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引用次数: 4
Toxicity Assessment of Transfluthrin, Benzyl Butyl Phthalate, and 17β-Estradiol on the Primary Fibroblast of the Striped Field Mouse, Apodemus agrarius. 氟氯菊酯、邻苯二甲酸苄丁酯和17β-雌二醇对黑线姬鼠原代成纤维细胞的毒性评价
IF 2.4 4区 医学 Q3 TOXICOLOGY Pub Date : 2021-01-01 DOI: 10.1615/JEnvironPatholToxicolOncol.2021036845
Ji Min Lee, Ukjin Kim, Byoung-Hee Lee, Seo-Na Chang, Juha Song, Bokyeong Ryu, Jae-Hak Park

Environmental pollution (EP) is a well-known threat to wild animals, but its toxicological impact is poorly understood. In vitro toxicity evaluation using cells of lower predators could be a promising way to assess and monitor the effects of EPs on whole wildlife populations that are related in the food web. Here, we describe EPs' toxic effect and mechanism in the primary fibroblast derived from the embryo of the striped field mouse, Apodemus agrarius. Characterization of the primary fibroblast was via morphology, genetics, immunocytochemistry, and stable culture conditions for optimal toxicity screening. Cell viability assays-MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH)-were performed to observe cytotoxicity, and quantitative PCR was conducted to confirm gene alteration by EP exposure. MTT and LDH assays confirmed the cytotoxicity of transfluthrin (TF), benzyl butyl phthalate (BBP), and 17β-estradiol (E2) with IC50 values of 10.56 μM, 10.82 μM, and 24.08 μM, respectively, following 48-h exposures. mRNA expression of androgen-binding protein, growth hormone receptor, cytochrome C oxidase, and cytochrome P450-1A1 was induced after exposure to TF, BBP, and E2. We unveiled new EP mechanisms at the mammalian cellular level and discovered potential biomarker genes for monitoring of EPs. Based on our findings, we propose the primary fibroblast of A. agrarius as a valuable model to assess the toxicological effects of EP on wildlife.

环境污染对野生动物的威胁是众所周知的,但其毒理学影响却知之甚少。利用低等捕食者的细胞进行体外毒性评估可能是评估和监测EPs对整个食物网中相关野生动物种群影响的一种有希望的方法。在这里,我们描述了EPs对条纹田鼠(黑线姬鼠)胚胎的原代成纤维细胞的毒性作用和机制。原代成纤维细胞的特征是通过形态学、遗传学、免疫细胞化学和稳定的培养条件进行最佳毒性筛选。采用mtt(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑)和乳酸脱氢酶(LDH)检测细胞毒性,并采用定量PCR方法证实EP暴露导致的基因改变。MTT和LDH实验证实了氟氯菊酯(TF)、邻苯二甲酸苄丁酯(BBP)和17β-雌二醇(E2)在48 h后的细胞毒性,IC50值分别为10.56 μM、10.82 μM和24.08 μM。暴露于TF、BBP和E2后,雄激素结合蛋白、生长激素受体、细胞色素C氧化酶和细胞色素P450-1A1的mRNA表达被诱导。我们在哺乳动物细胞水平上揭示了新的EP机制,并发现了监测EP的潜在生物标记基因。在此基础上,我们建议黑线姬鼠原代成纤维细胞作为评估EP对野生动物毒理学影响的一个有价值的模型。
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引用次数: 0
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Journal of Environmental Pathology Toxicology and Oncology
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