Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Background

Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

Methods

The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.

Results

We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

Conclusions

Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

     

根据孕妇参数预测胎儿体重的神经网络方法

本文采用反向传播神经网络算法,根据孕妇身高、体重、宫高及腹围预测胎儿体重。建立了一个预测胎儿体重的网络模型,讨论了确定网络拓扑结构的方法。采用该方法预测了１４０例胎儿体重,预测符合率高达８５％,相对误≤１０％者占预测总数的９４．２８％。采用神经网络分析输入对于输出的贡献的结果表明孕妇宫高对于胎儿体重影响最大。     

435例子宫内膜癌综合治疗疗效分析

目的探讨子宫内膜癌患者综合治疗后的生存情况。方法回顾性分析1992年1月至2009年12月收治的有完整随访资料的435例子宫内膜癌患者的临床病理资料,分析不同治疗方案对患者预后的影响。结果 435例患者的中位随访时间为55.5个月,其中59例(13.6%)患者复发,58例(13.3%)患者死亡,5年总生存率为92.2%,5年无瘤生存率为88.3%。术后单纯辅助孕激素治疗≥12个月者5年无瘤生存率[(95.1±2.7)%]显著高于术后无辅助治疗组[(93.1±2.7)%,P<0.05];术后孕激素+放疗组患者5年总生存率[(94.3±6.5)%]、5年无瘤生存率[(86.1±10.8)%]均显著高于术后单纯放疗组[均为(69.4±14.4)%,P<0.05)];术后单纯化疗组5年总生存率[(84.2±6.3)%]、5年无瘤生存率[(81.9±6.8)%]略低于术后无辅助治疗组,但两组比较,差异无统计学意义(P>0.05);术后放疗+化疗组5年总生存率[(87.9±6.0)%]、5年无瘤生存率[(78.3±8.7)%]与术后化疗组、放疗组和无辅助治疗组比较,差异均无统计学意义(P>0.05)。结论术后辅助孕激素治疗≥12个月、化疗、放疗+化疗可以在一定程度上改善高危子宫内膜癌患者的预后。     

Apigenin inhibits fibrous scar formation after acute spinal cord injury through TGFβ/SMADs signaling pathway

AimTo investigate the effect of apigenin on fibrous scar formation after mouse spinal cord injury (SCI).MethodsThe pneumatic impactor strike method was used to establish an SCI model. Mice were intraperitoneally injected with 5 mg/kg or 20 mg/kg apigenin daily for 28 days after SCI. The Basso Mouse Scale (BMS) score, hematoxylin–eosin staining, and immunohistochemical staining were used to assess the effect of apigenin on scar formation and motor function recovery. Western blotting and qRT‐PCR were used to detect the expression of fibrosis‐related parameters in spinal cord tissue homogenates. NIH‐3 T3 cells and mouse primary spinal cord fibroblasts, α‐Smooth muscle actin (α‐SMA), collagen 1, and fibronectin were used to evaluate apigenin''s effect in vitro. Western blotting and immunofluorescence techniques were used to study the effect of apigenin on TGFβ/SMADs signaling.ResultsApigenin inhibited fibrous scar formation in the mouse spinal cord and promoted the recovery of motor function. It reduced the expression of fibroblast‐related parameters and increased the content of nerve growth factor in vivo, decreasing myofibroblast activation and collagen fiber formation by inhibiting TGFβ‐induced SMAD2/3 phosphorylation and nuclear translocation in vitro.ConclusionApigenin inhibits fibrous scar formation after SCI by decreasing fibrosis‐related factor expression through TGFβ/SMADs signaling.     

Distribution characteristics and ecological risk assessment of toxic heavy metals and metalloid in surface water of lakes in Daqing Heilongjiang Province,China

It is necessary to estimate heavy metal concentrations and risk in surface water for understanding the heavy metal contaminations and for sustainable protection of ecosystems and human health. To investigate the anthropogenic contribution of heavy metal accumulation surrounding an industrial city in China, the concentrations of six heavy metals, including mercury (Hg), arsenic (As), chromium (Cr), lead (Pb), copper (Cu), and cadmium (Cd) were examined; from four different regions of Daqing in autumn 2011 and winter 2012. The results showed heavy metals distributed in the industrial area at concentrations relatively higher than those in other three areas, while concentrations in the farming area and the protected area were lower. The heavy metal concentrations of water bodies in all areas, except those for Hg and As, Cu, Pb and Cr were lower than the cutoff values for the Class I water quality that was set as the highest standard to protect the national nature reserves. While Hg and As of lakes in industry region had a higher level than those in the agriculture and landscape water, the lowest allowed. The concentrations of all the heavy metals in winter were higher than in the autumn. Cu had a higher ecological risks level to freshwater organisms. The discharge of urban sewage and industrial wastewater might be a major pollutant source, thus these sources should identified before remediation efforts. Efforts are needed to protect the lakes from pollution and also to reduce environmental health risks. This study and the valuable data will pave the way for future research on these Lakes in Daqing.     

更年灵胶囊主要药效学研究

更年灵胶囊2．0和1．Og/kg明显抑制正常和老年小鼠的自主活动，缩短戊巴比妥钠催眠潜伏期，延长睡眠时间，对抗由苯丙胺和尼可刹来诱导的小鼠中枢兴奋或惊厥，抑制麻黄所致的小鼠汗腺过度分泌，刺激老年小鼠肾上腺组织增生，对阴虚和阳虚模型小鼠细胞免疫功能具有明显的改善作用，提示更年灵胶囊对更年期综合症相关症状可能有明显的保护作用。     

"肺炎1号"治疗新型冠状病毒肺炎451例多中心临床研究

目的:观察“肺炎1号”治疗新型冠状病毒肺炎的临床疗效。方法:选取2020年2月17日至2020年3月15日湖北省中医院、监利县中医院、蕲春县人民医院、潜江市中医院、洪湖市中医医院、阳新县中医医院、浠水县中医院、大冶市中医医院、汉川市人民医院、武昌方舱医院收治的新型冠状病毒肺炎患者451例,采用“肺炎1号”联合西医常规治疗,观察“肺炎1号”对新型冠状病毒肺炎患者的临床症状、舌象、实验室检查结果及肺部CT情况。结果:共纳入451例患者,其中轻型21例,普通型378例,重型46例,危重型6例。疑似病例6例(1.33%),临床诊断病例168例(37.25%),确诊病例277例(61.42%)。治疗后与治疗前比较,患者发热、咳嗽、乏力主要症状发生率显著降低(P<0.05);恶寒、鼻塞、流涕、打喷嚏、咽部痒、咽痛、呼吸困难、胸闷、肌肉酸痛或关节疼痛、头晕头痛、纳差、恶心呕吐、腹胀、大便稀溏症状发生率显著改善(P<0.05);白细胞计数、中性粒细胞绝对值变化差异无统计学意义(P>0.05);淋巴细胞绝对值明显升高,差异有统计学意义(P<0.05);C反应蛋白、降钙素原明显降低,差异有统计学意义(P<0.05)。退热时间3(1～3.25)d。229例患者舌质由红或绛逐渐转为淡红,好转率为75.58%;177例患者白腻苔、厚腻苔、黄腻苔明显变薄,好转率为65.31%。新型冠状病毒核酸转阴时间为8(5,11)d。415例(92.02%)肺部CT明显好转,主要表现在病灶面积减小,变薄变淡。达到出院标准430例,临床治愈率95.34%;好转15例;无效3例;死亡3例(0.67%)。治疗过程中,未见明显不良反应,临床应用安全。结论:“肺炎1号”结合西医常规治疗对新型冠状病毒肺炎有较好的治疗作用,能够快速稳定病情,阻断轻型、普通型向重型、危重型转化;明显改善患者临床症状;较好促进肺部炎性反应吸收;使用安全可靠。     

新冠肺炎临床评价核心指标集比较分析＊

目的 对已公开发表的新冠肺炎核心指标集及其研究方法进行比较分析，为临床试验和证据转化研究提供参考信息。方法 计算机检索COMET数据库，并补充检索CNKI、WanFang、PubMed、Web of Science、The Cochrane Library等数据库，收集发表的新型冠状病毒肺炎（Coronavirus Disease 2019，COVID-19）核心指标集（Core Outcome Set，COS）研究，检索时间截至为2021年3月31日。按照纳入排除标准筛选文献，并提取研究基本信息、研究方法及指标数据，对其进行描述性分析。结果 共纳入5项COVID-19核心指标集相关研究（4项为COVID-19-COS研究，1项为COVID-19核心指标测量工具研究）。相同的结局指标包括死亡率、病毒核酸检测、临床进展、恢复期、临床症状评分及临床分型等。指标来源主要来自临床试验注册平台和问卷调查；达成共识的方法主要采用共识会议；利益相关群体中临床专家、方法学专家和医疗管理人员涉及较多。结论 不同的新冠肺炎核心指标集研究有一定的共性，但由于应用场景不同，也存在一定差异。随着对疾病认识的深化，相关COVID-19核心指标需要加强测量方法和疗程推荐。     

第2轮"经行乳房胀痛中医诊疗指南"问卷分析

制订中医经行乳房胀痛诊疗指南.问卷调查采用德尔菲(Delphi)法进行,在第1轮专家问卷的基础上,编制第2轮专家问卷,向全国40位中医、中西医结合妇科、妇产科专家发送问卷调查,对收回的35份有效答卷利用SPSS11.5软件进行统计分析.且分布在16个省、及直辖市的专家积极性与专业水平均较高,分布地区广,具有代表性.经第2轮专家问卷调查,<经行乳房胀痛中医诊疗指南>框架涉及的条目基本得到专家的认可.在两轮专家问卷调查的基础上中医"经行乳房胀痛中医诊疗指南"初稿基本形成.