低氧刺激鼻息肉黏膜上皮细胞炎性因子变化的初探

目的研究低氧刺激慢性鼻窦炎伴鼻息肉(CRSwNP)与正常鼻黏膜上皮细胞炎性因子的变化与异同,探讨其在CRSwNP发病机制中的作用。方法选择2015年6月至2018年1月在吉林大学中日联谊医院就诊的68例CRSwNP患者,其中男性36例,女性32例,年龄(45.2±12.5)岁(xˉ±s,下同),患者的鼻息肉黏膜纳入慢性鼻窦炎鼻息肉组(CRS-NP组),下鼻甲黏膜纳入慢性鼻窦炎下鼻甲组(CRS-IT组),并根据组织病理学结果进一步分成嗜酸粒细胞浸润及非浸润两种类型,即嗜酸粒细胞浸润性鼻息肉组(Eos-NP组,n=34)、非嗜酸粒细胞浸润性鼻息肉组(Non-Eos-NP组,n=34)、嗜酸粒细胞浸润性鼻息肉患者的下鼻甲组(Eos-IT组,n=20)和非嗜酸粒细胞浸润性鼻息肉患者的下鼻甲组(Non-Eos-IT组,n=20);同期25例鼻窦囊肿或鼻中隔偏曲患者的下鼻甲黏膜作为对照组(n=25),其中男性14例,女性11例,年龄(42.8±10.2)岁。免疫组织化学染色分析各组黏膜上皮组织中白细胞介素(IL)17A、干扰素γ(IFN-γ)、肿瘤坏死因子α(TNF-α)与乏氧诱导因子(hypoxia-inducible factor 1α,HIF-1α)的表达情况。酶联免疫吸附试验检测低氧刺激0、24和48 h后各组原代鼻黏膜上皮细胞分泌IL-17A、IFN-γ和TNF-α的差异;免疫荧光、固态光源高内涵与免疫印记实验检测原代鼻黏膜上皮细胞HIF-1α的表达情况。应用SPSS 17.0软件对数据进行统计学分析,采用双向方差分析作为主要统计学方法。结果免疫组织化学染色结果显示,IL-17A和TNF-α在对照组中表达最高(光密度值分别为0.37±0.03、0.53±0.02),IFN-γ和HIF-1α在Eos-IT组中表达最高(光密度值分别为0.47±0.03、0.39±0.02)。未接受低氧刺激时,IL-17A与TNF-α在对照组中水平较低;低氧刺激48 h后,对照组的IL-17A与TNF-α分泌量明显高于其他各组。未接受低氧刺激时,Eos-NP组分泌的IFN-γ明显高于对照组[(13.7±1.3)pg/ml比(11.1±1.6)pg/ml,P<0.05];低氧刺激48 h后,IFN-γ在对照组和Eos-NP组中的分泌量没有显著区别。对照组与CRS-IT组表达的HIF-1α随低氧时间延长而增加,Eos-NP组与Non-Eos-NP组表达的HIF-1α随低氧时间延长而减少。对照组与CRS-IT组HIF-1α主要表达于鼻黏膜上皮细胞的细胞质内,CRS-NP组HIF-1α主要表达于鼻黏膜上皮细胞的细胞核内。结论低氧刺激下,CRSwNP患者的鼻息肉、下鼻甲与正常鼻黏膜上皮细胞中IL-17A、TNF-α、IFN-γ的分泌以及HIF-1α的表达水平存在差异,且呈现不同的亚细胞定位,提示其可能参与了CRSwNP发病相关基因的转录与调控。     

Chronic acidosis rewires cancer cell metabolism through PPARα signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH_e) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH_e, but not at acidic pH_e. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.     

益气养阴解毒方联合环磷腺苷葡胺注射液治疗病毒性心肌炎35例

目的:探讨益气养阴解毒方联合环磷腺苷葡胺注射液对病毒性心肌炎患者心功能及外周血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、转化生长因子-β1(transforming growth factor-β1,TGF-β1)和干扰素-γ(interferon-γ,IFN-γ)水平的影响。方法:将70例病毒性心肌炎患者按照随机数字法分为对照组和观察组,每组各35例。两组患者均给予常规治疗,对照组在常规治疗的基础上给予环磷腺苷葡胺注射液静脉滴注,观察组在对照组的基础上联合益气养阴解毒方治疗。比较两组患者的临床疗效及治疗前后左室短轴缩短分数(left ventricular shortening fraction,LVFS)、左心室射血分数(left ventricular ejection fraction,LVEF)、心脏指数(cardiac index,CI)、TNF-α、TGF-β1和IFN-γ水平。结果:观察组有效率为88.57%,对照组有效率为68.57%,两组患者有效率比较,差异有统计学意义(P<0.05)。两组患者治疗后LVEF、LVFS高于本组治疗前,且观察组高于对照组,差异具有统计学意义(P<0.05)。两组患者治疗后TGF-β1、TNF-α水平低于治疗前比较,IFN-γ高于治疗前,且观察组TGF-β1、TNF-α低于对照组,IFN-γ高于对照组,差异均有统计学意义(P<0.05)。两组患者不良反应发生率比较,差异无统计学意义(P>0.05)。结论:益气养阴解毒方联合环磷腺苷葡胺注射液治疗病毒性心肌炎疗效更显著,可减轻机体的炎症反应,恢复患者心功能。     

维生素D联合糠酸莫米松乳膏治疗婴幼儿中重度湿疹的临床分析

目的:分析维生素D联合糠酸莫米松乳膏治疗婴幼儿中重度湿疹的临床疗效并探究维生素D对患儿免疫功能的影响。方法:104例中重度湿疹婴幼儿随机分为对照组和治疗组各52例,对照组用0.1%糠酸莫米松乳膏治疗,治疗组在对照组基础上予维生素D制剂阿法骨化醇滴剂治疗。分析治疗后2组患儿治疗总有效率,同时检测患儿治疗前及治疗4周后血清25-(OH)D3、干扰素-γ(IFN-γ)、白细胞介素(IL-2)、IL-4、IL-13水平。结果:治疗组总有效率为92.31%,优于对照组(76.92%),差异有统计学意义(P<0.05)。治疗组治疗后血清IFN-γ、IL-2水平较治疗前上升,并明显高于对照组,血清IL-4、IL-13水平较治疗前下降,并明显低于对照组(P<0.05)。结论:维生素D能调节中重度湿疹婴幼儿免疫功能,因此维生素D联合糠酸莫米松乳膏能提高中重度湿疹婴幼儿治疗疗效,值得在临床上应用。     

Predictions of genotoxic potential,mode of action,molecular targets,and potency via a tiered multiflow® assay data analysis strategy

The in vitro MultiFlow® DNA Damage Assay multiplexes γH2AX, p53, phospho-histone H3, and polyploidization biomarkers into a single flow cytometric analysis. The current report describes a tiered sequential data analysis strategy based on data generated from exposure of human TK6 cells to a previously described 85 chemical training set and a new pharmaceutical-centric test set (n = 40). In each case, exposure was continuous over a range of closely spaced concentrations, and cell aliquots were removed for analysis following 4 and 24 hr of treatment. The first data analysis step focused on chemicals' genotoxic potential, and for this purpose, we evaluated the performance of a machine learning (ML) ensemble, a rubric that considered fold increases in biomarkers against global evaluation factors (GEFs), and a hybrid strategy that considered ML and GEFs. This first tier further used ML output and/or GEFs to classify genotoxic activity as clastogenic and/or aneugenic. Test set results demonstrated the generalizability of the first tier, with particularly good performance from the ML ensemble: 35/40 (88%) concordance with a priori genotoxicity expectations and 21/24 (88%) agreement with expected mode of action (MoA). A second tier applied unsupervised hierarchical clustering to the biomarker response data, and these analyses were found to group certain chemicals, especially aneugens, according to their molecular targets. Finally, a third tier utilized benchmark dose analyses and MultiFlow biomarker responses to rank genotoxic potency. The relevance of these rankings is supported by the strong agreement found between benchmark dose values derived from MultiFlow biomarkers compared to those generated from parallel in vitro micronucleus analyses. Collectively, the results suggest that a tiered MultiFlow data analysis pipeline is capable of rapidly and effectively identifying genotoxic hazards while providing additional information that is useful for modern risk assessments—MoA, molecular targets, and potency. Environ. Mol. Mutagen. 60:513–533, 2019. © 2019 Wiley Periodicals, Inc.     

Unmasking antibiotic-associated neurological disorders: The underminer in Intensive Care Unit

Psychosis is a common and intractable disorder of hospitalization, especially in patients hospitalized in Intensive Care Unit (ICU). Along with the widely use of multiple antibiotics in community-acquired infection and hospital-acquired infection, the occurrence of antibiotic-associated neurological disorders has become more frequently. However, antibiotic neurotoxicity is often overlooked or misinterpreted. In this review, we summarized the neurological disorders caused by antibacterial agent usage and firstly systematically formulated the pathogenesis of antibiotic-associated neurotoxic reactions. Precautions of the complications are critical in preventing serious clinical outcome as the inducement is curable. Regular neurological physical examination, electroencephalogram (EEG) examination, lumbar puncture and therapeutic drug monitoring closely are essential for early diagnosis and differential diagnosis.     

Circulating CCL20: A potential biomarker for active vitiligo together with the number of Th1/17 cells

Background

Vitiligo is an autoimmune disease with varying pathological features. Activation of the CCL20-CCR6 axis plays an important role in chronic inflammatory diseases. However, whether CCL20-CCR6 and Th1/17 cells are indicative of active vitiligo is unclear.

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

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Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.     

Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer

Because the peroxisome proliferator-activated receptor (PPAR) signaling pathway is involved in development and progression of pancreatic cancer, we investigated associations between genetic variants of the PPAR pathway genes and pancreatic cancer risk by using three published genome-wide association study datasets including 8477 cases and 6946 controls of European ancestry. Expression quantitative trait loci (eQTL) analysis was also performed for correlations between genotypes of the identified genetic variants and messenger RNA (mRNA) expression levels of their genes by using available databases of the 1000 Genomes, TCGA, and GTEx projects. In the single-locus logistic regression analysis, we identified 1141 out of 17 532 significant single-nucleotide polymorphisms (SNPs) in 112 PPAR pathway genes. Further multivariate logistic regression analysis identified three independent, potentially functional loci (rs12947620 in MED1, rs11079651 in PRKCA, and rs34367566 in PRKCB) for pancreatic cancer risk (odds ratio [OR] = 1.11, 95% confidence interval [CI], [1.06-1.17], P = 5.46 × 10⁻⁵; OR = 1.10, 95% CI, [1.04-1.15], P = 1.99 × 10⁻⁴; and OR = 1.09, 95% CI, [1.04-1.14], P = 3.16 × 10⁻⁴, respectively) among 65 SNPs that passed multiple comparison correction by false discovery rate (< 0.2). When risk genotypes of these three SNPs were combined, carriers with 2 to 3 unfavorable genotypes (NUGs) had a higher risk of pancreatic cancer than those with 0 to 1 NUGs. The eQTL analysis showed that rs34367566 A>AG was associated with decreased expression levels of PRKCB mRNA in 373 lymphoblastoid cell lines. Our findings indicate that genetic variants of the PPAR pathway genes, particularly MED1, PRKCA, and PRKCB, may contribute to susceptibility to pancreatic cancer.