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The mechanism of radiotherapy for lung adenocarcinoma in promoting protein SIRT6-mediated deacetylation of RBBP8 to enhance the sensitivity of targeted therapy. 肺腺癌放疗促进sirt6介导的RBBP8去乙酰化以提高靶向治疗敏感性的机制
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221130727
Jiying Wang, Zhaoying Sheng, Zhiyi Dong, Qiongya Wu, Yong Cai

Background: Lung cancer has the fastest increase in morbidity and mortality, and is one of the most threatening malignant tumors to human health and life. Both radiotherapy and targeted therapy are typical treatments after lung cancer surgery. Radiotherapy is a means of locally killing cancer lesions, and it plays an important role in the entire management of lung cancer. Gefitinib is one of the most commonly used targeted therapy drugs in the treatment of lung cancer. The purpose of this project is to explore the mechanism by which deacetylation of RBBP8 mediated by radiotherapy-promoting protein SIRT6 in lung adenocarcinoma enhances the sensitivity of targeted therapy.

Methods: In both the cell experiments and the animal experiments, the samples were divided into five groups: Model group, RT group, CT group, RT+CT group, and RT+CT+inhibitor group. The CCK8 method was used to detect the viability of each group of cells. The flow cytometry experiment was used to analyze the apoptotic characteristics of each group of cells. The scratch test was used to detect the migration ability of each group of cells. Transwell invasion test was used to determine the invasion ability of each group of cells. The lung tumor tissues of each group of mice were collected to analyze the tumor size, volume, and metastasis characteristics. The TUNEL experiment was used to detect the apoptosis characteristics of the cells in the lung cancer tissues of each group mice. Immunohistochemistry experiments were used to analyze the distribution and relative expression characteristics of protein SIRT6 in mouse lung cancer tissues. The colorimetric experiments were used to detect the activity of Caspase 3 and Caspase 8 in each group. Western blot method was used to detect the expression of SIRT6, RBBP8, and MYC in each group.

Results: In each experiment, the results of the experiment have mutually proven consistency, and there is no contradiction. In addition to the Model group, the other 4 groups used different treatment methods. The better the curative effect, the lower the cell viability of cancer cells and the higher the apoptotic ratio. This is reflected in the CCK8 test, flow cytometry analysis, cell scratch test, Transwell cell migration test, and TUNEL detection. At the same time, colorimetric detection and Western blot analysis also analyzed the levels of SIRT6, RBBP8 and other cancer-related proteins in each group at the molecular level, implying the importance of SIRT6 protein in the treatment process.

Conclusion: Our project has proved that radiotherapy can promote the protein SIRT6 to deacetylate RBBP8 proteins, and ultimately enhance targeted therapy drug sensitivity.

背景:肺癌是发病率和死亡率增长最快的恶性肿瘤之一,是对人类健康和生命威胁最大的恶性肿瘤之一。放疗和靶向治疗是肺癌手术后的典型治疗方法。放疗是局部杀伤癌灶的一种手段,在肺癌的整个治疗中起着重要的作用。吉非替尼是治疗肺癌最常用的靶向治疗药物之一。本课题旨在探讨肺腺癌中放疗促进蛋白SIRT6介导的RBBP8去乙酰化提高靶向治疗敏感性的机制。方法:在细胞实验和动物实验中,将样品分为5组:模型组、RT组、CT组、RT+CT组、RT+CT+抑制剂组。CCK8法检测各组细胞活力。流式细胞术实验分析各组细胞的凋亡特征。采用划痕法检测各组细胞的迁移能力。采用Transwell侵袭试验测定各组细胞的侵袭能力。采集各组小鼠肺肿瘤组织,分析肿瘤大小、体积及转移特征。采用TUNEL实验检测各组小鼠肺癌组织中细胞的凋亡特征。采用免疫组化实验分析SIRT6蛋白在小鼠肺癌组织中的分布及相对表达特征。采用比色法检测各组Caspase 3和Caspase 8的活性。Western blot法检测各组SIRT6、RBBP8、MYC的表达。结果:在每次实验中,实验结果相互证明了一致性,不存在矛盾。除模型组外,其余4组均采用不同的治疗方法。疗效越好,肿瘤细胞活力越低,细胞凋亡率越高。这体现在CCK8试验、流式细胞术分析、细胞划痕试验、Transwell细胞迁移试验和TUNEL检测中。同时,比色检测和Western blot分析还在分子水平上分析了各组中SIRT6、RBBP8等肿瘤相关蛋白的表达水平,提示SIRT6蛋白在治疗过程中的重要性。结论:我们的项目证明了放疗可以促进SIRT6蛋白去乙酰化RBBP8蛋白,最终增强靶向治疗药物敏感性。
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引用次数: 3
Immune system and atherosclerosis: Hostile or friendly relationship 免疫系统与动脉粥样硬化:敌对或友好关系
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221092188
Iman Razeghian-Jahromi, Ali Karimi Akhormeh, M. Razmkhah, M. Zibaeenezhad
Coronary artery disease has remained a major health challenge despite enormous progress in prevention, diagnosis, and treatment strategies. Formation of atherosclerotic plaque is a chronic process that is developmentally influenced by intrinsic and extrinsic determinants. Inflammation triggers atherosclerosis, and the fundamental element of inflammation is the immune system. The immune system involves in the atherosclerosis process by a variety of immune cells and a cocktail of mediators. It is believed that almost all main components of this system possess a profound contribution to the atherosclerosis. However, they play contradictory roles, either protective or progressive, in different stages of atherosclerosis progression. It is evident that monocytes are the first immune cells appeared in the atherosclerotic lesion. With the plaque growth, other types of the immune cells such as mast cells, and T lymphocytes are gradually involved. Each cell releases several cytokines which cause the recruitment of other immune cells to the lesion site. This is followed by affecting the expression of other cytokines as well as altering certain signaling pathways. All in all, a mix of intertwined interactions determine the final outcome in terms of mild or severe manifestations, either clinical or subclinical. Therefore, it is of utmost importance to precisely understand the kind and degree of contribution which is made by each immune component in order to stop the growing burden of cardiovascular morbidity and mortality. In this review, we present a comprehensive appraisal on the role of immune cells in the atherosclerosis initiation and development.
尽管在预防、诊断和治疗策略方面取得了巨大进展,冠状动脉疾病仍然是一个主要的健康挑战。动脉粥样硬化斑块的形成是一个受内在和外在决定因素影响的慢性过程。炎症引发动脉粥样硬化,而炎症的基本要素是免疫系统。免疫系统通过多种免疫细胞和多种介质参与动脉粥样硬化过程。人们认为,该系统的几乎所有主要成分都对动脉粥样硬化起着深远的作用。然而,它们在动脉粥样硬化进展的不同阶段发挥着相互矛盾的作用,要么是保护性的,要么是进行性的。可见单核细胞是动脉粥样硬化病变中首先出现的免疫细胞。随着斑块的生长,其他类型的免疫细胞如肥大细胞和T淋巴细胞逐渐参与其中。每个细胞释放几种细胞因子,引起其他免疫细胞聚集到病变部位。随后影响其他细胞因子的表达以及改变某些信号通路。总而言之,相互交织的相互作用决定了最终的结果,无论是轻微还是严重的表现,无论是临床还是亚临床。因此,准确了解每种免疫成分所起作用的种类和程度,以阻止心血管发病率和死亡率日益增加的负担,是至关重要的。在这篇综述中,我们对免疫细胞在动脉粥样硬化的发生和发展中的作用进行了全面的评价。
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引用次数: 6
Association between cytokine concentration kinetics and prolonged fever in febrile neutropenic children with bacteremia 中性粒细胞减少伴菌血症发热儿童的细胞因子浓度动力学与长期发热的关系
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221095015
Seongkoo Kim, S. Han, J. Kang
Introduction: Although prolonged fever in patients with neutropenic fever (NF) during empirical antibiotic therapy could be caused by dysregulated immune responses, its association with cytokine concentrations has rarely been investigated. This study determined the kinetics of cytokine concentrations in pediatric patients with NF and bacteremia and evaluated the impact of cytokine concentration kinetics on prolonged fever. Methods: Concentrations of 13 cytokines were measured on the initial day of NF (Day 1) and 3 days (Day 4) and 7 days (Day 8) later in 10 patients with NF with bacteremia, and their kinetics was determined. The results for each cytokine concentration on each sampling day were compared for patients with fever that lasted ⩾3 days and those with fever that lasted <3 days. Results: Interleukin (IL)-6 (p < .001) and IL-10 (p = .001) concentrations were significantly higher on Day 1 than on Days 4 and 8. However, the increased IL-6 (p = 1.000) and IL-10 (p = 1.000) concentrations on Day 1 were not associated with prolonged fever (⩾3 days). For other cytokines, the concentrations measured on Days 1, 4, and 8 were similar regardless of fever duration. Conclusion: Prolonged fever in patients with NF and bacteremia was not associated with a prolonged increase in a specific cytokine concentration.
导论:虽然中性粒细胞减少热(NF)患者在经经性抗生素治疗期间持续发热可能是由免疫反应失调引起的,但其与细胞因子浓度的关系很少被研究。本研究确定了小儿NF和菌血症患者的细胞因子浓度动力学,并评估了细胞因子浓度动力学对延长发烧的影响。方法:对10例伴有菌血症的NF患者,分别在NF发病第1天、第3天(第4天)和第7天(第8天)检测13种细胞因子浓度,并测定其动力学。对持续大于或小于3天的发热患者和持续小于3天的发热患者在每个采样日的每个细胞因子浓度的结果进行比较。结果:白细胞介素(IL)-6 (p < 0.001)和IL-10 (p = 0.001)浓度在第1天显著高于第4、8天。然而,在第1天增加的IL-6 (p = 1.000)和IL-10 (p = 1.000)浓度与延长发烧(大于或等于3天)无关。对于其他细胞因子,无论发烧持续时间如何,在第1、4和8天测量的浓度相似。结论:NF合并菌血症患者的持续发热与特定细胞因子浓度的持续升高无关。
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引用次数: 0
Virtual screening of phytochemicals by targeting multiple proteins of severe acute respiratory syndrome coronavirus 2: Molecular docking and molecular dynamics simulation studies. 针对严重急性呼吸系统综合征冠状病毒 2 的多种蛋白虚拟筛选植物化学物质:分子对接和分子动力学模拟研究。
IF 3 3区 医学 Q3 IMMUNOLOGY Pub Date : 2022-01-01 DOI: 10.1177/03946320221142793
Muhammad Azeem, Ghulam Mustafa, Hafiza S Mahrosh

Objective: Medicinal herbs are being investigated for medicationhg development against SARS-CoV-2 as a rich source of bioactive chemicals. One of the finest approaches for finding therapeutically effective drug molecules in real time is virtual screening scheme such as molecular docking in conjunction with molecular dynamics (MD) simulation. These virtual techniques provide an ample opportunity for the screening of plausible inhibitors of SARS-CoV-2 different target proteins from a comprehensive and extensive phytochemical library. The study was designed to identify potential phytochemicals by virtual screening against different receptor proteins.

Methods: In the current study, a library of plant secondary metabolites was created by manually curating 120 phytochemicals known to have antimicrobial as well as antiviral properties. In the current study, different potential phytochemicals were identified by virtual screening against various selected receptor proteins (i.e., viral main proteases, RNA-dependent RNA polymerase (RdRp), ADP ribose phosphatase, nonstructural proteins NSP7, NSP8, and NSP9) which are key proteins responsible for transcription, replication and maturation of SARS-CoV-2 in the host. Top three phytochemicals were selected against each viral receptor protein based on their best S-scores, RMSD values, molecular interactions, binding patterns and drug-likeness properties.

Results: The results of molecular docking study revealed that phytochemicals (i.e., baicalin, betaxanthin, epigallocatechin, fomecin A, gallic acid, hortensin, ichangin, kaempferol, limonoic acid, myricetin hexaacetat, pedalitin, quercetin, quercitrin, and silvestrol) have strong antiviral potential against SARS-CoV-2. Additionally, the reported preeminent reliable phytochemicals also revealed toxicity by no means during the evaluation through ADMET profiling. Moreover, the MD simulation study also exhibited thermal stability and stable binding affinity of the pedalitin with SARS-CoV-2 RdRp and SARS-CoV-2 main protease which suggests appreciable efficacy of the lead optimization.

Conclusion: The biological activity and pharmacologically distinguishing characteristics of these lead compounds also satisfied as repurposing antiviral drug contenders and are worth substantial evaluation in the biological laboratory for the recommendation of being plausible antiviral drug candidates against SARS-CoV-2.

目的:药用植物是生物活性化学物质的丰富来源,目前正在研究开发抗 SARS-CoV-2 的药物。实时寻找有效治疗药物分子的最佳方法之一是虚拟筛选方案,如分子对接和分子动力学(MD)模拟。这些虚拟技术为从全面而广泛的植物化学物质库中筛选 SARS-CoV-2 不同靶蛋白的合理抑制剂提供了充分的机会。本研究旨在通过虚拟筛选不同受体蛋白来确定潜在的植物化学物质:方法:在本研究中,通过人工整理 120 种已知具有抗菌和抗病毒特性的植物化学物质,建立了植物次生代谢产物库。在目前的研究中,通过对各种选定的受体蛋白(即病毒主要蛋白酶、RNA 依赖性 RNA 聚合酶 (RdRp)、ADP 核糖磷酸酶、非结构蛋白 NSP7、NSP8 和 NSP9)进行虚拟筛选,确定了不同的潜在植物化学物质,这些受体蛋白是 SARS-CoV-2 在宿主体内负责转录、复制和成熟的关键蛋白。根据每种病毒受体蛋白的最佳 S 值、RMSD 值、分子相互作用、结合模式和药物亲和性,选出了针对每种病毒受体蛋白的前三种植物化学物质:分子对接研究结果表明,植物化学物质(即黄芩苷、白桦脂素、表没食子儿茶素、福美胂 A、没食子酸、拳参苷、山柰酚、柠檬酸、杨梅素六乙酸酯、踏板苷、槲皮素、槲皮苷和硅vestrol)对 SARS-CoV-2 具有很强的抗病毒潜力。此外,在通过 ADMET 分析进行评估期间,所报告的卓越可靠的植物化学物质也没有显示出任何毒性。此外,MD 模拟研究还显示了 pedalitin 与 SARS-CoV-2 RdRp 和 SARS-CoV-2 主要蛋白酶的热稳定性和稳定的结合亲和力,这表明先导优化物具有显著的功效:这些先导化合物的生物活性和药理特征也符合抗病毒药物再利用的要求,值得在生物实验室进行大量评估,以推荐其作为抗 SARS-CoV-2 的候选抗病毒药物。
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引用次数: 0
Comparative study of six SARS-CoV-2 serology assays: Diagnostic performance and antibody dynamics in a cohort of hospitalized patients for moderate to critical COVID-19. 6项SARS-CoV-2血清学检测在中重度肺炎住院患者中的诊断性能和抗体动态的比较研究
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/20587384211073232
Sameh Chamkhi, Tarak Dhaouadi, Imen Sfar, Salma Mokni, Alia Jebri, Dhouha Mansouri, Salma Ghedira, Emna Ben Jemia, Samia Ben Boujemaa, Mohamed Houissa, Hichem Aouina, Taïeb Ben Abdallah, Yousr Gorgi

Background: To overcome the COVID-19 pandemic, serology assays are needed to identify past and ongoing infections. In this context, we evaluated the diagnostic performance of 6 immunoassays on samples from hospitalized patients for moderate to critical COVID-19.

Methods: 701 serum samples obtained from 443 COVID-19 patients (G1: 356 positive RT-PCR patients and G2: 87 negative RT-PCR cases) and 108 pre-pandemic sera from blood donors were tested with 6 commercial immunoassays: (1) Elecsys Anti-SARS-CoV-2, Roche (Nucleocapsid, N), (2) Elecsys Anti-SARS-CoV-2 S, Roche (Spike, S), (3) Vidas SARS-COV-2 IgM/IgG, BioMérieux (S), (4) SARS-CoV-2 IgG, Abbott (N), (5) Access SARS-CoV-2 IgG, Beckman Coulter (Receptor Binding Domain), and (6) Standard F COVID-19 IgM/IgG Combo FIA, SD Biosensor (N).

Results: Global sensitivities of the evaluated assays were as follows: (1) Roche anti-N = 74.5% [69.6-79.3], (2) Roche anti-S = 92.7% [84.7-100], (3) Vidas IgM = 74.9% [68.6-81.2], (4) Vidas IgG = 73.9% [67.6-80.1], (5) Abbott = 78.6% [63.4-93.8], (6) Beckman Coulter = 74.5% [62-86.9], (7) SD Biosensor IgM = 73.1% [61-85.1], and (8) SD Biosensor IgG = 76.9% [65.4-88.4]. Sensitivities increased gradually from week 1 to week 3 as follow: (1) Roche anti-N: 63.3%, 81% and 82.1%; (2) Vidas IgM: 68.2%, 83.2% and 85.9%; and (3) Vidas IgG: 66.7%, 79.1% and 86.6%. All immunoassays showed a specificity of 100%. Seropositivity was significantly associated with a higher frequency of critical COVID-19 (50.8% vs. 38.2%), p = 0.018, OR [95% CI] = 1.668 [1.09-2.553]. Inversely, death occurred more frequently in seronegative patients (28.7% vs. 13.6%), p=3.02 E-4, OR [95% CI] = 0.392 [0.233-0.658].

Conclusion: Evaluated serology assays exhibited good sensitivities and excellent specificities. Sensitivities increased gradually after symptoms onset. Even if seropositivity is more frequent in patients with critical COVID-19, it may predict a recovery outcome.

背景:为了克服COVID-19大流行,需要进行血清学检测以确定过去和正在发生的感染。在此背景下,我们评估了对住院患者中至重症COVID-19样本的6种免疫测定的诊断性能。方法:对443例COVID-19患者(G1: 356例RT-PCR阳性,G2: 87例RT-PCR阴性)的701份血清和108份大流行前献血者的血清进行6种商业免疫测定:(1) Elecsys Anti-SARS-CoV-2, Roche (Nucleocapsid, N), (2) Elecsys Anti-SARS-CoV-2 S, Roche (Spike, S), (3) Vidas SARS-COV-2 IgM/IgG, biomacrieux (S), (4) SARS-COV-2 IgG, Abbott (N), (5) Access SARS-COV-2 IgG, Beckman Coulter(受体结合域),(6)Standard F COVID-19 IgM/IgG Combo FIA, SD Biosensor (N)。结果:评价方法的整体敏感性如下:(1) Roche anti-N = 74.5% [69.6-79.3], (2) Roche anti-S = 92.7% [84.7-100], (3) Vidas IgM = 74.9% [68.6-81.2], (4) Vidas IgG = 73.9% [67.6-80.1], (5) Abbott = 78.6% [63.4-93.8], (6) Beckman Coulter = 74.5% [62-86.9], (7) SD Biosensor IgM = 73.1% [61-85.1], (8) SD Biosensor IgG = 76.9%[65.4-88.4]。从第1周到第3周,敏感性逐渐升高:(1)Roche anti-N分别为63.3%、81%和82.1%;(2) Vidas IgM分别为68.2%、83.2%和85.9%;(3) Vidas IgG分别为66.7%、79.1%和86.6%。所有免疫分析均显示特异性为100%。血清阳性与危重型COVID-19的发生频率显著相关(50.8%比38.2%),p = 0.018, OR [95% CI] = 1.668[1.09-2.553]。相反,血清阴性患者的死亡发生率更高(28.7%比13.6%),p=3.02 E-4, OR [95% CI] = 0.392[0.233-0.658]。结论:评价的血清学方法具有良好的敏感性和良好的特异性。症状出现后,敏感性逐渐升高。即使血清阳性在COVID-19危重患者中更为常见,它也可以预测康复结果。
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引用次数: 7
Garcinia kola treatment exhibits immunomodulatory properties while not affecting type 1 diabetes development in an experimental mouse model 在实验小鼠模型中,藤黄治疗显示出免疫调节特性,同时不影响1型糖尿病的发展
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/20587384211069831
M. Cetkovic-Cvrlje, S. Rogan, Emily Barbaro
Objective T cells orchestrate an inflammatory response that destroys pancreatic insulin-producing β cells during the development of autoimmune type 1 diabetes (T1D). Garcinia kola Heckel (GK) is a plant widely exploited in West African traditional medicine. Some of the therapeutic effects of GK nut’s extract (GKE) have been suggested to be due to its anti-inflammatory potential. Since GKE has never been investigated in a T1D experimental model, nor in the T cells’ context, we aimed to determine whether GKE exhibits antidiabetic properties and affects T cells by its anticipated anti-inflammatory action. Methods The effect of aqueous GKE (aGKE) ingestion, 100 mg/kg daily by drinking water over the period of 6 weeks, has been tested in a low-dose streptozotocin-induced (LDSTZ) mouse model of autoimmune T1D. T cells were studied in vitro and in vivo in mice treated by aGKE. Results The results showed that aGKE treatment, which started a week before induction of disease, neither delayed the development of T1D, nor reduced glycemia severity. Interestingly, aGKE treatment did affect T cells and their function, significantly decreasing the frequency of helper (TH) and cytotoxic (TC) T cells, while elevating the levels of pro-inflammatory cytokines, TNF-α, IL-6, and IFN-γ, and suppressing IL-2. Conclusion In conclusion, our results did not confirm the antidiabetic property of GKE, while suggesting its therapeutic exploration in TH2-dependent pathologies that benefit from an aggravated TH1 response, such as allergies.
目的在自身免疫性1型糖尿病(T1D)的发展过程中,T细胞协调破坏胰腺胰岛素产生β细胞的炎症反应。藤黄(GK)是西非传统医药中广泛使用的一种植物。GK坚果提取物(GKE)的一些治疗作用被认为是由于其抗炎潜力。由于GKE从未在T1D实验模型中进行过研究,也从未在T细胞中进行过调查,我们旨在确定GKE是否具有抗糖尿病特性,并通过其预期的抗炎作用影响T细胞。方法在低剂量链脲佐菌素诱导(LDSTZ)的自身免疫性T1D小鼠模型中,通过饮水每天摄入100mg/kg的GKE(aGKE),持续6周。在用aGKE处理的小鼠中对T细胞进行了体外和体内研究。结果aGKE治疗在疾病诱导前一周开始,既没有延缓T1D的发展,也没有降低血糖的严重程度。有趣的是,aGKE治疗确实影响了T细胞及其功能,显著降低了辅助性(TH)和细胞毒性(TC)T细胞的频率,同时提高了促炎细胞因子、TNF-α、IL-6和IFN-γ的水平,并抑制了IL-2。结论总之,我们的研究结果并没有证实GKE的抗糖尿病特性,同时表明它在TH2依赖性疾病中的治疗探索,这些疾病受益于TH1反应加重,如过敏。
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引用次数: 1
Mucin 5AC expression is common but unrelated to tumor progression in pancreatic adenocarcinoma. 粘蛋白 5AC 的表达在胰腺腺癌中很常见,但与肿瘤进展无关。
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221106504
Sebastian Dwertmann Rico, Franziska Büscheck, David Dum, Andreas M Luebke, Martina Kluth, Claudia Hube-Magg, Andrea Hinsch, Doris Höflmayer, Daniel Perez, Jakob R Izbicki, Michael Neipp, Hamid Mofid, Thies Daniels, Christoph Isbert, Christoph Fraune, Katharina Möller, Anne Menz, Christian Bernreuther, Patrick Lebok, Till Clauditz, Guido Sauter, Ria Uhlig, Waldemar Wilczak, Ronald Simon, Stefan Steurer, Eike Burandt, Andreas Marx, Till Krech

Introduction: Mucin 5AC (MUC5AC) belongs to the family of secreted gel-forming mucins. It is physiologically expressed in some normal mucin producing epithelial cells but also in pancreatic, ovarian, and colon cancer cells. The role of MUC5AC expression in cancer is not fully understood. This study was designed to explore the role of MUC5AC for pancreatic cancer progression, its association to microsatellite instability, and its diagnostic utility. Methods: Mucin 5AC expression was studied immunohistochemically in a tissue microarray (TMA) from 532 pancreatic cancers, 61 cancers of the ampulla Vateri, six acinar cell carcinomas and 12 large sections of pancreatitis. Results: Mucin 5AC staining was interpretable in 476 of 599 (79%) arrayed cancers. Staining was completely absent in normal pancreas and pancreatitis, but frequent in pancreatic cancer. Membranous and cytoplasmic MUC5AC expression was most common in pancreatic adenocarcinomas (71% of 423), followed by carcinomas of the ampulla Vateri (43% of 47), and absent in six acinar cell carcinomas. Mucin 5AC expression was unrelated to tumor phenotype (tumor stage, tumor grade, lymph node, and distant metastasis), and microsatellite instability in ductal adenocarcinomas and carcinomas of the ampulla Vateri. Conclusion: Our study indicates that MUC5AC is an excellent biomarker for pancreatic cancer diagnosis, especially to support the sometimes-difficult diagnosis on small biopsies. Mucin 5AC expression is unrelated to pancreatic cancer aggressiveness.

简介粘蛋白 5AC(MUC5AC)属于分泌型凝胶粘蛋白家族。它在一些产生粘蛋白的正常上皮细胞以及胰腺癌、卵巢癌和结肠癌细胞中均有生理表达。MUC5AC 的表达在癌症中的作用尚不完全清楚。本研究旨在探讨 MUC5AC 在胰腺癌进展中的作用、与微卫星不稳定性的关联及其诊断作用。研究方法对 532 例胰腺癌、61 例瓦氏鞍癌、6 例尖锐细胞癌和 12 例胰腺炎大切片的组织芯片(TMA)中粘蛋白 5AC 的表达进行免疫组化研究。结果显示在 599 例阵列癌症中,有 476 例(79%)的粘蛋白 5AC 染色是可解释的。正常胰腺和胰腺炎中完全没有染色,但在胰腺癌中却很常见。膜和胞浆 MUC5AC 表达在胰腺腺癌中最常见(423 例中占 71%),其次是瓦特氏瓿癌(47 例中占 43%),6 例尖锐细胞癌中无表达。粘蛋白 5AC 的表达与肿瘤表型(肿瘤分期、肿瘤分级、淋巴结和远处转移)以及导管腺癌和膀胱癌的微卫星不稳定性无关。结论我们的研究表明,MUC5AC 是诊断胰腺癌的绝佳生物标记物,尤其是对有时难以诊断的小活检组织提供支持。粘蛋白 5AC 的表达与胰腺癌的侵袭性无关。
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引用次数: 1
Niloticin binds to MD-2 to promote anti-inflammatory pathway activation in macrophage cells. Niloticin结合MD-2促进巨噬细胞抗炎途径的激活。
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221133017
Guirong Chen, Chang Liu, Mingbo Zhang, Xiaobo Wang, Yubin Xu

Objectives: Niloticin is an active compound isolated from Cortex phellodendri with uncharacterized anti-inflammatory activity. We assessed the drug potential of niloticin and examined its ability to target myeloid differentiation protein 2 (MD-2) to ascertain the mechanism for its anti-inflammatory activity.

Methods: The Traditional Chinese Medicine Systems Pharmacology Database was used to evaluate niloticin. Bio-layer interferometry and molecular docking technologies were used to explore how niloticin targets MD-2, which mediates a series of toll-like receptor 4 (TLR4)-dependent inflammatory responses. The cytokines involved in the lipopolysaccharide (LPS)-TLR4/MD-2-NF-κB pathway were evaluated using ELISA, RT-qPCR, and western blotting.

Results: Niloticin could bind to MD-2 and had no evident effects on cell viability. Niloticin treatment significantly decreased the levels of NO, IL-6, TNF-α, and IL-1β induced by LPS (p < 0.01). IL-1β, IL-6, iNOS, TNF-α, and COX-2 mRNA expression levels were decreased by niloticin (all p < 0.01). Compared with that in the control group, the increase in TLR4, p65, MyD88, p-p65, and iNOS expression levels induced by LPS were suppressed by niloticin (all p < 0.01).

Conclusion: Our results suggest that niloticin has therapeutic potential and binds to MD-2. Niloticin binding to MD-2 antagonized the effects of LPS binding to the TLR4/MD-2 complex, resulting in the inhibition of the LPS-TLR4/MD-2-NF-κB signaling pathway.

目的:Niloticin是一种从黄柏中分离得到的具有抗炎活性的活性化合物。我们评估了niloticin的药物潜力,并检测了其靶向髓样分化蛋白2 (MD-2)的能力,以确定其抗炎活性的机制。方法:采用中药系统药理学数据库对尼罗提辛进行评价。利用生物层干涉法和分子对接技术探索niloticin如何靶向MD-2, MD-2介导一系列toll样受体4 (TLR4)依赖性炎症反应。采用ELISA、RT-qPCR和western blotting检测脂多糖(LPS)-TLR4/MD-2-NF-κB通路中参与的细胞因子。结果:尼洛替辛能与MD-2结合,对细胞活力无明显影响。尼罗替辛显著降低LPS诱导的NO、IL-6、TNF-α、IL-1β水平(p < 0.01)。niloticin降低IL-1β、IL-6、iNOS、TNF-α、COX-2 mRNA表达水平(p < 0.01)。与对照组相比,niloticin抑制LPS诱导的TLR4、p65、MyD88、p-p65、iNOS表达水平升高(均p < 0.01)。结论:我们的研究结果表明,尼罗替辛具有治疗潜力,并与MD-2结合。Niloticin结合MD-2可拮抗LPS结合TLR4/MD-2复合物的作用,从而抑制LPS-TLR4/MD-2- nf -κB信号通路。
{"title":"Niloticin binds to MD-2 to promote anti-inflammatory pathway activation in macrophage cells.","authors":"Guirong Chen,&nbsp;Chang Liu,&nbsp;Mingbo Zhang,&nbsp;Xiaobo Wang,&nbsp;Yubin Xu","doi":"10.1177/03946320221133017","DOIUrl":"https://doi.org/10.1177/03946320221133017","url":null,"abstract":"<p><strong>Objectives: </strong>Niloticin is an active compound isolated from <i>Cortex phellodendri</i> with uncharacterized anti-inflammatory activity. We assessed the drug potential of niloticin and examined its ability to target myeloid differentiation protein 2 (MD-2) to ascertain the mechanism for its anti-inflammatory activity.</p><p><strong>Methods: </strong>The Traditional Chinese Medicine Systems Pharmacology Database was used to evaluate niloticin. Bio-layer interferometry and molecular docking technologies were used to explore how niloticin targets MD-2, which mediates a series of toll-like receptor 4 (TLR4)-dependent inflammatory responses. The cytokines involved in the lipopolysaccharide (LPS)-TLR4/MD-2-NF-κB pathway were evaluated using ELISA, RT-qPCR, and western blotting.</p><p><strong>Results: </strong>Niloticin could bind to MD-2 and had no evident effects on cell viability. Niloticin treatment significantly decreased the levels of NO, IL-6, TNF-α, and IL-1β induced by LPS (<i>p</i> < 0.01). IL-1β, IL-6, iNOS, TNF-α, and COX-2 mRNA expression levels were decreased by niloticin (all <i>p</i> < 0.01). Compared with that in the control group, the increase in TLR4, p65, MyD88, p-p65, and iNOS expression levels induced by LPS were suppressed by niloticin (all <i>p</i> < 0.01).</p><p><strong>Conclusion: </strong>Our results suggest that niloticin has therapeutic potential and binds to MD-2. Niloticin binding to MD-2 antagonized the effects of LPS binding to the TLR4/MD-2 complex, resulting in the inhibition of the LPS-TLR4/MD-2-NF-κB signaling pathway.</p>","PeriodicalId":14046,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/48/dc/10.1177_03946320221133017.PMC9629566.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40439119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ETS variant transcription factor 6 enhances oxidized low-density lipoprotein-induced inflammatory response in atherosclerotic macrophages via activating NF-κB signaling. ETS变异体转录因子6通过激活NF-κB信号增强氧化低密度脂蛋白诱导的动脉粥样硬化巨噬细胞炎症反应
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/20587384221076472
Xiaofang Xiong, Zheng Yan, Wei Jiang, Xuejun Jiang

Objectives: Macrophages play a critical role in atherosclerosis by contributing to plaque development, local inflammation, and thrombosis. Elucidation of the molecular cascades in atherosclerotic macrophages is important for preventing and treating atherosclerosis. This study aims to deepen the understanding of the mechanisms that regulate the function of aorta macrophage in atherosclerosis. Methods: In the current study, the expression and function of ETS variant transcription factor 6 (ETV6) in aorta macrophages in a mouse atherosclerosis model. Aorta macrophages were enriched by flow cytometry. ETV6 expression was analyzed by quantitative RT-PCR. The role of ETV6 in macrophage-mediated pro-inflammatory response was evaluated both in vitro and in vivo after ETV6 silencing. Results: A remarkable elevation of ETV6 in aorta macrophages of atherosclerotic mice was observed. In addition, in vitro analysis indicated that oxidized low-density lipoprotein (oxLDL) up-regulated ETV6 in macrophages via the NF-κB pathway. ETV6 silencing suppressed oxLDL-induced expression of IL-1β, IL-6, and TNF-α in macrophages in vitro. However, ETV6 silencing did not impact the uptake of either oxLDL or cholesterol by macrophages. Furthermore, ETV6 silencing suppressed oxLDL-induced activation of the NF-κB pathway in macrophages, as evidenced by less phosphorylation of IKKβ and NF-κB p65, more cytoplasmic IκBα, and lower nuclear NF-κB p65. Moreover, ETV6 silencing inhibited the production of IL-1β and TNF-α in aorta macrophages in vivo. Conclusion: ETV6 supports macrophage-mediated inflammation in atherosclerotic aortas. This is a novel mechanism regulating the pro-inflammatory activity of atherosclerotic macrophages.

目的:巨噬细胞通过促进斑块形成、局部炎症和血栓形成,在动脉粥样硬化中发挥着关键作用。阐明动脉粥样硬化巨噬细胞中的分子级联对于预防和治疗动脉粥样硬化是重要的。本研究旨在加深对动脉粥样硬化中调节主动脉巨噬细胞功能的机制的理解。方法:在本研究中,在小鼠动脉粥样硬化模型中,观察ETS变异体转录因子6(ETV6)在主动脉巨噬细胞中的表达和功能。流式细胞术富集主动脉巨噬细胞。通过定量RT-PCR分析ETV6的表达。在ETV6沉默后,在体外和体内评估了ETV6在巨噬细胞介导的促炎反应中的作用。结果:动脉粥样硬化小鼠主动脉巨噬细胞ETV6明显升高。此外,体外分析表明,氧化低密度脂蛋白(oxLDL)通过NF-κB途径上调巨噬细胞中的ETV6。ETV6沉默抑制oxLDL诱导的巨噬细胞IL-1β、IL-6和TNF-α的表达。然而,ETV6沉默不影响巨噬细胞对oxLDL或胆固醇的摄取。此外,ETV6沉默抑制了oxLDL诱导的巨噬细胞NF-κB通路的激活,如IKKβ和NF-κBp65的磷酸化减少、细胞质IκBα增加和细胞核NF-κB-p65降低所证明。此外,ETV6沉默抑制了体内主动脉巨噬细胞中IL-1β和TNF-α的产生。结论:ETV6支持巨噬细胞介导的动脉粥样硬化性主动脉炎症。这是一种调节动脉粥样硬化巨噬细胞促炎活性的新机制。
{"title":"ETS variant transcription factor 6 enhances oxidized low-density lipoprotein-induced inflammatory response in atherosclerotic macrophages via activating NF-κB signaling.","authors":"Xiaofang Xiong, Zheng Yan, Wei Jiang, Xuejun Jiang","doi":"10.1177/20587384221076472","DOIUrl":"10.1177/20587384221076472","url":null,"abstract":"<p><p><b>Objectives</b>: Macrophages play a critical role in atherosclerosis by contributing to plaque development, local inflammation, and thrombosis. Elucidation of the molecular cascades in atherosclerotic macrophages is important for preventing and treating atherosclerosis. This study aims to deepen the understanding of the mechanisms that regulate the function of aorta macrophage in atherosclerosis. <b>Methods</b>: In the current study, the expression and function of ETS variant transcription factor 6 (ETV6) in aorta macrophages in a mouse atherosclerosis model. Aorta macrophages were enriched by flow cytometry. ETV6 expression was analyzed by quantitative RT-PCR. The role of ETV6 in macrophage-mediated pro-inflammatory response was evaluated both <i>in vitro</i> and <i>in vivo</i> after ETV6 silencing. <b>Results:</b> A remarkable elevation of ETV6 in aorta macrophages of atherosclerotic mice was observed. In addition, <i>in vitro</i> analysis indicated that oxidized low-density lipoprotein (oxLDL) up-regulated ETV6 in macrophages via the NF-κB pathway. ETV6 silencing suppressed oxLDL-induced expression of IL-1β, IL-6, and TNF-α in macrophages <i>in vitro</i>. However, ETV6 silencing did not impact the uptake of either oxLDL or cholesterol by macrophages. Furthermore, ETV6 silencing suppressed oxLDL-induced activation of the NF-κB pathway in macrophages, as evidenced by less phosphorylation of IKKβ and NF-κB p65, more cytoplasmic IκBα, and lower nuclear NF-κB p65. Moreover, ETV6 silencing inhibited the production of IL-1β and TNF-α in aorta macrophages <i>in vivo</i>. <b>Conclusion:</b> ETV6 supports macrophage-mediated inflammation in atherosclerotic aortas. This is a novel mechanism regulating the pro-inflammatory activity of atherosclerotic macrophages.</p>","PeriodicalId":14046,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48656444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Preventative effects of antioxidants on changes in sebocytes, outer root sheath cells, and Cutibacterium acnes-pretreated mice by particulate matter: No significant difference among antioxidants. 抗氧化剂对微粒物质引起的皮脂细胞、外根鞘细胞和痤疮杆菌预处理小鼠变化的预防作用:不同抗氧化剂之间无明显差异。
IF 3.5 3区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-01-01 DOI: 10.1177/03946320221112433
Mi Hee Kwack, Dae-Lyong Ha, Weon Ju Lee

Objectives: Particulate matter (PM) is an air pollutant that can damage human skin; antioxidants have shown some efficacy in alleviating PM-induced skin inflammation. We investigated the antioxidant effects of punicalagin, epigallocatechin-3-gallate (EGCG), and resveratrol on PM-induced changes in cultured human sebocytes, outer root sheath (ORS) cells, and Cutibacterium acnes-pretreated mice.

Methods: Sebocytes and ORS cells were cultured with 100 μg/mL PM10 and 5 μM punicalagin, 1 μM EGCG, or 1 μM resveratrol for 24 h. In C. acnes-pretreated mice, inflammatory nodules were treated with 100 μg/mL PM10 and 5 μM punicalagin, 1 μM EGCG, or 1 μM resveratrol. Cell viability was measured using an MTT assay. Antioxidant effects were analyzed according to RNA expression, using real-time PCR, as well as reactive oxygen species (ROS) and sebum measurements.

Results: Antioxidants inhibited the upregulation of inflammatory cytokines, matrix metalloproteinase, aryl hydrocarbon receptor, and NF-kB as well as the production of ROS induced by PM10 in cultured sebocytes and ORS cells. The preventative effects of punicalagin and EGCG on biomarker expression in cultured sebocytes and ORS cells were slightly greater than those of resveratrol, though the difference was not significant. In C. acnes-pretreated mice, the antioxidants inhibited inflammatory cytokine and matrix metalloproteinase expression as well as sebum production.

Conclusions: Antioxidants effectively reduced the expression of inflammatory biomarkers and sebum production in cultured sebocytes, ORS cells, and C. acnes-pretreated mice.

目的:颗粒物(PM)是一种可损害人体皮肤的空气污染物;抗氧化剂在缓解颗粒物诱发的皮肤炎症方面显示出一定的功效。我们研究了Punicalagin、表儿茶素-3-棓酸盐(EGCG)和白藜芦醇对PM诱导的培养人皮脂细胞、外根鞘(ORS)细胞和痤疮丙酸杆菌小鼠变化的抗氧化作用:用 100 μg/mL PM10 和 5 μM punicalagin、1 μM EGCG 或 1 μM 白藜芦醇培养皮脂腺细胞和外根鞘细胞 24 小时;用 100 μg/mL PM10 和 5 μM punicalagin、1 μM EGCG 或 1 μM 白藜芦醇处理痤疮丙酸杆菌预处理小鼠的炎性结节。细胞活力用 MTT 法测定。根据实时 PCR 的 RNA 表达以及活性氧(ROS)和皮脂测量结果分析了抗氧化剂的作用:结果:抗氧化剂抑制了PM10诱导的炎症细胞因子、基质金属蛋白酶、芳基烃受体和NF-kB的上调以及ROS的产生。潘立卡金和 EGCG 对培养的皮脂细胞和 ORS 细胞中生物标志物表达的预防作用略大于白藜芦醇,但差异不显著。在痤疮丙酸杆菌预处理的小鼠中,抗氧化剂抑制了炎性细胞因子和基质金属蛋白酶的表达以及皮脂的生成:结论:抗氧化剂能有效降低培养皮脂细胞、ORS 细胞和痤疮丙酸杆菌处理小鼠的炎症生物标志物表达和皮脂分泌。
{"title":"Preventative effects of antioxidants on changes in sebocytes, outer root sheath cells, and <i>Cutibacterium acnes</i>-pretreated mice by particulate matter: No significant difference among antioxidants.","authors":"Mi Hee Kwack, Dae-Lyong Ha, Weon Ju Lee","doi":"10.1177/03946320221112433","DOIUrl":"10.1177/03946320221112433","url":null,"abstract":"<p><strong>Objectives: </strong>Particulate matter (PM) is an air pollutant that can damage human skin; antioxidants have shown some efficacy in alleviating PM-induced skin inflammation. We investigated the antioxidant effects of punicalagin, epigallocatechin-3-gallate (EGCG), and resveratrol on PM-induced changes in cultured human sebocytes, outer root sheath (ORS) cells, and <i>Cutibacterium acnes</i>-pretreated mice.</p><p><strong>Methods: </strong>Sebocytes and ORS cells were cultured with 100 μg/mL PM10 and 5 μM punicalagin, 1 μM EGCG, or 1 μM resveratrol for 24 h. In <i>C</i>. <i>acnes</i>-pretreated mice, inflammatory nodules were treated with 100 μg/mL PM10 and 5 μM punicalagin, 1 μM EGCG, or 1 μM resveratrol. Cell viability was measured using an MTT assay. Antioxidant effects were analyzed according to RNA expression, using real-time PCR, as well as reactive oxygen species (ROS) and sebum measurements.</p><p><strong>Results: </strong>Antioxidants inhibited the upregulation of inflammatory cytokines, matrix metalloproteinase, aryl hydrocarbon receptor, and NF-kB as well as the production of ROS induced by PM10 in cultured sebocytes and ORS cells. The preventative effects of punicalagin and EGCG on biomarker expression in cultured sebocytes and ORS cells were slightly greater than those of resveratrol, though the difference was not significant. In <i>C</i>. <i>acnes</i>-pretreated mice, the antioxidants inhibited inflammatory cytokine and matrix metalloproteinase expression as well as sebum production.</p><p><strong>Conclusions: </strong>Antioxidants effectively reduced the expression of inflammatory biomarkers and sebum production in cultured sebocytes, ORS cells, and <i>C</i>. <i>acnes</i>-pretreated mice.</p>","PeriodicalId":14046,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ad/bc/10.1177_03946320221112433.PMC9252012.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40577143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
International Journal of Immunopathology and Pharmacology
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