Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model

BackgroundIschemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat.MethodsRat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed.ResultsPre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators.ConclusionOur result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.     

28例原发性卵黄囊瘤患者的CT表现分析

目的分析28例原发性卵黄囊瘤(YST)患者的CT表现。方法选择2015年2月至2019年12月收治的28例YST患者的临床资料进行回顾性分析,8例YST患者入院后均予以CT检查,然后对患者的CT影像学特征和临床资料数据进行分析比较。结果本研究中28例YST患者肿瘤位于性腺的有17例(60.71%),其中位于睾丸、卵巢处的分别有7例、10例,占比分别为60.71%、41.18%,均为单侧发病;9例(39.29%)位于性腺外,其中位于骶尾部、前纵隔、阴道的分别有6例、2例、1例,占比分别为66.67%、22.22%、11.11%。CT检测可见肿瘤"浅分叶",且呈"椭网形",18例(64.29%)肿瘤边界较为清晰,9例(32.14%)呈"深分叶状"形态不规则;8例(28.57%)边界模糊,肿瘤大小分析可见,肿瘤位于前纵隔、卵巢的相对较大,位于阴道、睾丸、骶尾部的相对较小。28例YST患者中,单纯型21例YST(75.00%),混合型7例(25.00%)。结论原发性卵黄囊瘤进行CT检测尤为重要,其CT表现具有一定特征性,可为临床治疗提供一定的依据。     

Role of site-directed mutagenesis and adjuvants in the stability and potency of anthrax protective antigen

Anthrax is a zoonotic infection caused by the gram-positive, aerobic, spore-forming bacterium Bacillus anthracis. Depending on the origin of the infection, serious health problems or mortality is possible. The virulence of B. anthracis is reliant on three pathogenic factors, which are secreted upon infection: protective antigen (PA), lethal factor (LF), and edema factor (EF). Systemic illness results from LF and EF entering cells through the formation of a complex with the heptameric form of PA, bound to the membrane of infected cells through its receptor. The currently available anthrax vaccines have multiple drawbacks, and recombinant PA is considered a promising second-generation vaccine candidate. However, the inherent chemical instability of PA through Asn deamidation at multiple sites prevents its use after long-term storage owing to loss of potency. Moreover, there is a distinct possibility of B. anthracis being used as a bioweapon; thus, the developed vaccine should remain efficacious and stable over the long-term. Second-generation anthrax vaccines with appropriate adjuvant formulations for enhanced immunogenicity and safety are desired. In this article, using protein engineering approaches, we have reviewed the stabilization of anthrax vaccine candidates that are currently licensed or under preclinical and clinical trials. We have also proposed a formulation to enhance recombinant PA vaccine potency via adjuvant formulation.     

Immunotherapy: A new standard in the treatment of metastatic clear cell renal cell carcinoma

Renal cell cancer (RCC) represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney (90%). In the mid-nineties of the last century, the standard of treatment for patients with metastatic RCC was cytokines. Sunititib and pazopanib were registered in 2007 and 2009, respectively, and have since been the standard first-line treatment for metastatic clear cell RCC (mccRCC). Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells, including CD8+ T lymphocytes, dendritic cells, natural killer cells (NK) and macrophages. This observation led to the design of new clinical trials in which patients were treated with immunotherapy. With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system, the idea of combining angiogenic drugs with immunotherapy has emerged, and new clinical trials have been designed. In the last few years, several therapeutic options have been approved [immunotherapy and immunotherapy/tyrosine kinase inhibitors (TKI)] for the first-line treatment of mccRCC. Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses. Several checkpoint inhibitors (pembrolizumab, nivolumab, avelumab) in combination with TKI (axitinib, lenvatinib, cabozantinib) are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression. There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.     

超声引导下关节腔内注射重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(益赛普)治疗血友病性关节病

目的 观察超声引导下关节腔内注射重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（益赛普）治疗血友病性关节病（HA）的价值。方法 回顾性分析32例接受超声引导下穿刺关节腔注射益赛普的HA患者，对比观察治疗前及治疗后1个月血友病关节健康评分（HJHS）、视觉模拟评分（VAS），以及超声所示目标关节增生滑膜厚度、血流信号、Melchiorre及中国早期血友病性关节病超声检测（HEAD-US-C）评分，评估其治疗价值。结果 对32例均成功完成超声引导下穿刺关节腔及腔内注射益赛普，共对18例膝关节、7例肘关节及7例踝关节进行治疗。术后未出现感染、出血等并发症。治疗后1个月，目标关节HJHS、VAS、Melchiorre评分、HEAD-US-C评分及增生滑膜最大厚度、平均厚度、血流信号均低于治疗前（P均<0.01）。结论 超声引导下关节腔内注射益赛普治疗HA安全、有效。     

核因子κB受体活化因子配体和肿瘤坏死因子α经炎性牙周膜干细胞外泌体促进破骨细胞分化

目的　慢性牙周炎表现的病理性骨吸收非常常见，牙周膜干细胞（PDLSCs）的外泌体（Exo）对骨吸收的作用和影响尚不明确，本研究分析了该Exo蛋白组分对破骨细胞分化的影响。方法　分别从正畸前拔牙患者和慢性牙周炎患者的牙周膜组织中提取PDLSCs，通过流式细胞术检测表面标记物；通过差速离心分别提取2种细胞的Exo，即Exo-WT和Exo-CP，并通过Western blot、透射电子显微镜（TEM）、蛋白浓度检测、纳米粒径追踪检测Exo特征；通过蛋白质谱检测2种Exo的蛋白组分；通过酶联免疫吸附（ELISA）验证了差异表达蛋白肿瘤坏死因子α（TNF-α）、核因子κB受体活化因子配体（RANKL）、白细胞介素（IL）-1α、转化生长因子β（TGF-β）、骨形态发生蛋白2（BMP-2）表达水平；将10、100、1 000 μg·mL^-1的Exo-CP或Exo-WT加入RAW264.7培养基中并于5 d时通过实时荧光定量聚合酶链反应（RT-qPCR）、Western blot、抗酒石酸酸性磷酸酶（TRAP）染色检测破骨分化相关指标表达情况；采用SPSS 24.0软件对实验数据进行统计学分析。结果　Exo-CP富集的差异表达蛋白主要与破骨细胞分化的TNF信号通路、核转录因子κB（NF-κB）信号通路相关；ELISA实验证实了Exo-CP中高表达TNF-α、RANKL、IL-1α，低表达TGF-β1、BMP-2（P<0.05）；Exo-CP作用于RAW264.7，显著提高了细胞的破骨分化相关基因及蛋白的表达水平，TRAP染色可见分化的破骨细胞，且呈现浓度依赖性，100、1 000 μg·mL^-1浓度Exo-CP对破骨细胞分化的促进作用显著高于10 μg·mL^-1浓度组（P<0.05）。结论　慢性牙周炎的病理性骨吸收可能由炎性PDLSCs所分泌的Exo通过促进破骨细胞分化引起，Exo中主要的作用蛋白可能为RANKL和TNF-α，本研究为慢性牙周炎骨吸收的发病机制提供了新视角。     

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.