长效干扰素联合利巴韦林治疗慢性丙型肝炎患者疗效及其对静息能量消耗和营养状态的影响*

目的 探讨应用长效α-干扰素联合利巴韦林治疗慢性丙型肝炎(CHC)患者疗效及静息能量消耗和营养状态的变化。方法 2017年4月～2019年4月我院收治的CHC患者48例,采用随机数字表法分为观察组24例和对照组24例,分别给予聚乙二醇干扰素α-2a(peg-IFNα-2a)和利巴韦林治疗或干扰素α-2a(IFNα-2a)联合利巴韦林治疗48 w。测量静息能量消耗(REE)和预测静息能量消耗(pREE),常规检测血清前白蛋白(PA)和白蛋白(ALB)水平,计算体质指数(BMI)。结果 在治疗48 w结束和随访6 m时,观察组完全应答率分别为62.5%和54.2%,显著高于对照组的37.5%和29.2%,差异有统计学意义(P＜0.05);在观察组,用药前REE和pREE分别为(1504.6±481.5)kcal/d和(1432.3±229.3)kcal/d,在治疗结束时显著增加至(1822.1±546.7)kcal/d和(1241.8±208.6)kcal/d,对照组用药前REE和pREE分别为(1505.2±482.1)kcal/d和(1433.5±231.2)kcal/d,在治疗结束时,显著增加至(1824.4±547.6)kcal/d和(1243.1±208.8)kcal/d, 但两组之间REE和pREE变化无显著性差异(P>0.05);治疗前,观察组BMI及血清PA和ALB水平分别为(19.2±2.0)kg/m²、(161.5±45.2)mg/L和(38.4±4.2)g/L,在治疗结束时分别降为(17.1±1.5)kg/m²、(135.8±40.2)mg/L和(34.2±3.2)g/L,治疗前对照组BMI及血清PA和ALB水平分别为(19.3±2.1)kg/m²、(161.3±45.0)mg/L和(38.5±4.4)g/L,在治疗结束时分别降为(17.2±1.5)kg/m²、(136.3±40.2)mg/L和(34.2±3.1)g/L,但两组之间这些指标的变化无显著性差异(P>0.05)。结论 相对于IFNα-2a与利巴韦林联合,应用peg-IFNα-2a与利巴韦林联合治疗CHC患者能够获得更好的治疗效果,但无论何种治疗方案,均增加了能量消耗,降低了体质量和血清白蛋白水平,提示标准方案抗病毒治疗的不良反应还是值得重视的。     

HIF-1α和miR210与子痫前期的相关性研究

目的:研究HIF-1α和miR210与子痫前期的相关性。方法:回顾性分析本院2017年9月至2018年9月收治的子痫前期患者40例作为研究组,并选择本院同期健康妊娠妇女40例作为对照组,观察两组入选者HIF-1α、miR210表达水平;观察研究组中合并胎儿生长受限(FGR)的患者的HIF-1、miR210表达水平与无FGR组患者的对比情况。结果:研究组HIF-1α、miR210表达水平均高于对照组,合并FGR子痫前期患者HIF-1α、miR210表达水平高于无FGR子痫前期,差异有统计学意义,子痫前期发生率与HIF-1α、miR210呈正相关,P<0.05。结论:对于子痫前期诊断可配合HIF-1α和miR210表达水平检测,能够预测患者是否出现子痫前期,有利于对疾病的判断,改善预后,值得在临床上应用。     

Ochratoxin A induced differentiation nephrotoxicity in renal tubule and glomeruli via autophagy differential regulation

Ochratoxin A (OTA) is a mycotoxin that mainly causes nephrotoxicity. The single nephrotoxicity of OTA exposure on glomeruli or renal tubule had been well documented, however, the comparison toxicity between it is still unclear. Here, C57BL/6 mice and two types of nephrocyte were treated with concentration-gradient OTA to explore its differentiation nephrotoxicity. Results showed that OTA induced nephrotoxicity in vivo and in vitro, manifested as the deteriorative kidney function in mice and the cut-down cell viability in nephrocyte. Besides, results of murine kidney pathological section and IC₅₀ of two types nephrocyte indicated that OTA-induced toxicity in renal tubule was higher than its in glomeruli. In addition, OTA exposure induced autophagy signaling differentiation expression. It revealed that autophagy was implicated in OTA-induced differential nephrotoxicity in glomeruli and renal tubule. Altogether, we proved that OTA induces a differentiation nephrotoxicity in glomeruli and renal tubule, and it is related to autophagy differential regulation.     

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。     

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.     

血清鸢尾素、血小板因子4及低氧诱导因子-1α水平在膀胱癌中的作用

目的 探讨血清鸢尾素、血小板因子4（PF4）及低氧诱导因子-1α（HIF-1α）水平在膀胱癌中的诊断及预后作用。方法 选择2018年10月至2020年6月于本院确诊并行膀胱癌根治术治疗的膀胱癌患者75例（疾病组），并随机选择同时期健康体检者72例（健康组）。收集受试者的一般资料、手术相关情况及血清鸢尾素、PF4、HIF-1α水平，对血清鸢尾素、PF4及HIF-1α水平与膀胱癌发生及预后的相关性进行分析。结果 疾病组患者的血清鸢尾素、PF4及HIF-1α水平均高于健康组（均P<0.05）。血清鸢尾素、PF4及HIF-1α在膀胱癌诊断方面具有较高的灵敏度（63.25%、78.30%、84.96%）和特异度（88.52%、87.45%、91.02%）（均P<0.05）。75例膀胱癌患者中39例患者预后良好、36例患者预后不良。单因素结果显示，两组年龄、肿瘤直径、病理分级、临床分期、肿瘤转移、血清鸢尾素、PF4、HIF-1α水平比较，差异具有统计学意义（P<0.05）；肿瘤转移、血清鸢尾素、PF4、HIF-1α水平是膀胱癌预后的独立影响因素（P<0.05）；多元线性逐步回归分析结果显示，血清鸢尾素、HIF-1α水平是影响膀胱癌患者预后的影响因子（P<0.05）。血清鸢尾素、PF4及HIF-1α在膀胱癌预后评估中具有较高灵敏度（70.12%、89.11%、86.52%）和特异度（78.96%、82.23%、91.07%）（均P<0.05）。结论 血清鸢尾素、HIF-1α、PF4水平在膀胱癌患者中上调，高水平的血清鸢尾素、HIF-1α及PF4与膀胱癌术后的预后不良相关，可作为患者预后的预测因子。     

The effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus

Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory, however the cellular mechanism of these actions remains elusive. With help from newly developed biosensors and optogenetic tools, recent studies provide new insights on signaling mechanisms involved in the activation of nAChRs. Here we will review α7 nAChR’s action in the tri-synaptic pathway in the hippocampus. The effects of α7 nAChR activation via either exogenous compounds or endogenous cholinergic innervation are detailed for spontaneous and evoked glutamatergic synaptic transmission and synaptic plasticity, as well as the underlying signaling mechanisms. In summary, α7 nAChRs trigger intracellular calcium rise and calcium-dependent signaling pathways to enhance glutamate release and induce glutamatergic synaptic plasticity.