Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep

Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial‐ and muscular‐dependent pathways. This was associated with an enhanced nitric oxide‐dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.     

生物型与骨水泥型假体全髋关节置换术治疗老年移位型股骨颈骨折的疗效分析

目的 比较生物型与骨水泥型假体全髋关节置换术(THA)治疗老年移位型股骨颈骨折(DFNF)的临床疗效.方法 前瞻性纳入2015年7月—2018年6月佳木斯大学附属第一医院骨科收治的老年DFNF患者128例,男性71例,女性57例;年龄61～84岁,平均72.7岁.骨折原因:跌伤75例,撞伤32例,高处坠落伤21例.依据随机数字表法分为生物型假体THA组(BPTHA组,n=64)与骨水泥型假体THA组(CPTHA组,n=64).BPTHA组行生物型假体髋关节置换,CPTHA组行骨水泥型假体髋关节置换.观察两组术中出血量、手术时间、术后引流量等围术期指标及住院时间.比较术前及术后6、12个月髋关节功能(Harris),血清前列腺素缓激肽(BK)、5-羟色胺(5-HT)等疼痛因子水平及视觉模拟评分(VAS),血清淀粉样蛋白A(SAA)、C反应蛋白(CRP)、红细胞沉降率(ESR)等炎性反应指标水平;分析术后并发症发生情况.结果 两组术中出血量、手术时间、术后引流量差异均无统计学意义(P>0.05);BPTHA组住院时间长于CPTHA组[(19.76±2.24)d vs.(15.37±1.71)d,P<0.05].术后6个月,BPTHA组Harris评分低于CPTHA组[(81.72±8.37)分vs.(86.68±8.85)分,P<0.05];术后12个月,BPTHA组Harris评分高于CPTHA组[(95.54±9.67)分vs.(90.72±9.12)分,P<0.05].术后6个月,BPTHA组血清BK、5-HT、SAA、CRP、ESR水平及VAS均高于CPTHA组(P<0.05);术后12个月,BPTHA组血清BK、5-HT、SAA、CRP、ESR水平及VAS均低于CPTHA组(P<0.05).BPTHA组并发症发生率为3.13％,CPTHA组并发症发生率为4.69％,两组比较差异无统计学意义(P>0.05).结论 BPTHA、CPTHA均可应用于老年DFNF的临床治疗,但CPTHA近期疗效优于BPTHA,而BPTHA远期疗效优于CPTHA.     

miR-26b通过调节Notch1信号通路参与原发性肝细胞肝癌侵袭的机制研究

目的:探讨miR-26b参与原发性肝细胞肝癌（HCC）侵袭的机制。方法:在细胞培养液中培养人肝细胞系HL-7702和HCC细胞各系Hepb-3、HuH-7、MHCC97-L、MHCC97-H。实时荧光定量PCR法（qRT-PCR）检测miR-26b的表达水平；用miR-26b mimics、miR-26b inhibitors和Notch1-siRNA分别转染HCC细胞；MTT实验检测转染后HCC细胞的活力；采用Western blot检测Notch1受体蛋白表达水平的变化；Transwell小室测定不同处理后的HCC细胞的侵袭能力。结果:人正常肝细胞系HL-7702和HCC细胞系Hepb-3、HuH-7、MHCC97-L、MHCC97-H中的miR-26b相对表达含量随其侵袭和迁移能力的升高而依次下降；抑制miR-26b的表达，Notch1受体蛋白表达明显增高，而此时HCC细胞的侵袭性显著增强；相反，上调miR-26b的表达，Notch1受体蛋白表达明显降低，而HCC细胞侵袭性显著下降；miR-26b可能通过调控Notch1信号通路调节HCC细胞侵袭性。结论:miR-26b通过负调控Notch1信号通路抑制HCC细胞侵袭能力，为HCC侵袭的机制奠定了理论基础，miR-26b可能成为HCC治疗的新靶点。     

Spontaneous generation of functional osteoclasts from synovial fluid mononuclear cells as a model of inflammatory osteoclastogenesis

In osteoimmunology, osteoclastogenesis is understood in the context of the immune system. Today, the in vitro model for osteoclastogenesis necessitates the addition of recombinant human receptor activator of nuclear factor kappa‐B ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). The peripheral joints of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are characterized by an immune‐mediated inflammation that can lead to bone destruction. Here, we evaluate spontaneous in vitro osteoclastogenesis in cultures of synovial fluid mononuclear cells (SFMCs) activated only in vivo. SFMCs were isolated and cultured for 21 days at 0.5–1.0 × 10⁶ cells/mL in culture medium. SFMCs and healthy control peripheral blood monocytes were cultured with RANKL and M‐CSF as controls. Tartrate‐resistant acid phosphatase (TRAP) positive multinucleated cells were found in the SFMC cultures after 21 days. These cells expressed the osteoclast genes calcitonin receptor, cathepsin K, and integrin β3, formed lacunae on dentin plates and secreted matrix metalloproteinase 9 (MMP9) and TRAP. Adding RANKL and M‐CSF potentiated this secretion. In conclusion, we show that SFMCs from inflamed peripheral joints can spontaneously develop into functionally active osteoclasts ex vivo. Our study provides a simple in vitro model for studying inflammatory osteoclastogenesis.