let-7在小鼠哮喘模型气道炎性反应中的作用及机制

目的 观察let-7家族微RNA抑制剂(anti-let-7)对支气管哮喘(简称哮喘)小鼠气道炎性反应的影响,并探讨let-7参与哮喘形成的机制.方法 32只小鼠按随机数字法分为4组(n=8),即正常对照组(A组)、哮喘组(B组)、干预对照组(C组)和干预组(D组).其中B、C和D组用鸡卵蛋白(OVA)免疫,建立哮喘模型,A组以生理盐水替代OVA处理.D组小鼠激发前注射anti-let-7以抑制内源性let-7表达,C组小鼠注射乱序siRNA对照.比较各组小鼠支气管肺泡灌洗液(BALF)的细胞计数,肺组织中let-7e以及BALF中白细胞介素-10(IL-10)含量；体外用anti-let-7转染肺癌细胞A549,并检测细胞中let-7e表达和细胞培养上清中IL-10的含量；荧光素酶报告法检测let-7e是否直接靶向IL-10.结果 与A组相比,B组和C组小鼠BALF中细胞总数和嗜酸粒细胞数显著增加[(20.32±5.33)×109/L和(24.74±6.69)×109/L比(7.12± 1.88)×109/L,(6.45±2.5)×109/L和(7.12±2.66)×109/L比(0.04±0.01)×109/L,均P＜0.01]；肺组织中let-7e水平明显升高(分别为3.83倍和3.27倍,均P＜0.01).与C组比较,D组BALF中细胞总数和嗜酸粒细胞数明显减少[(13.85±3.74)× 109/L比(24.74±6.69)×109/L,(2.15±1.13)×109/L比(7.12±2.66)×109/L,均P＜0.05]；肺组织中let-7e显著降低[(0.45±0.22)比(3.28±0.45),P＜0.01],同时BALF中IL-10水平明显升高[(4.68±0.85)比(1.70±0.29),P＜0.01].此外,在肺癌细胞A549 中转染anti-let-7,let-7e表达显著下降[(0.22±0.03)比(1.00±0.11),P＜0.01],同时培养上清中IL-10明显上升[(2.58±0.35)比(1.00±0.15),P＜0.01].体外let-7e过表达显著降低IL-10报告载体的荧光素酶活性[(0.59±0.06)比(1.00±0.03),P＜0.01],而对突变的IL-10报告载体没有抑制作用.结论 anti-let-7对哮喘小鼠气道炎性反应具有明显的抑制作用,其作用机制可能与let-7直接靶向并抑制IL-10有关.     

狭鳕鱼皮胶原多肽对去势大鼠骨微结构影响的研究

目的通过观察狭鳕鱼皮胶原多肽对去势大鼠骨质疏松模型骨微结构的影响，探讨其防治骨质疏松的可行性。方法成年 Wistar 雌性大鼠 60 只，体质量（250±10）g，随机分为 5 组（n=12），分别为正常对照组（A 组）、骨质疏松模型组（B 组）、骨质疏松模型+狭鳕鱼皮胶原多肽预防组（C 组）、骨质疏松模型+狭鳕鱼皮胶原多肽低剂量治疗组（D 组）、骨质疏松模型+狭鳕鱼皮胶原多肽高剂量治疗组（E 组），每组 12 只。B、C、D、E 组采用摘除双侧卵巢法制备大鼠骨质疏松模型。C 组从术前 4 周开始、D、E 组从术后 6 周开始，每天按照 1.0、0.5、1.0 g/kg 行狭鳕鱼皮胶原多肽灌胃，连续 6 周；A、B 组于术后同时间点给予等体积生理盐水灌胃。末次给药 24 h 后，A、B 组大鼠摄股骨 X 线片并测定灰度值；然后颈椎脱臼法处死各组大鼠，取左侧胫骨近端骨组织行 HE 染色，观察骨组织病理学改变，测量骨小梁数量（trabecular number，TN）、平均骨小梁厚度（mean trabecular plate thickness，MTPT）、平均骨小梁间距（mean trabecular plate spacing，MTPS）、骨小梁体积百分比（trabecular bone volume，TBV）、平均骨皮质厚度（mean bone cortical thickness，MBCT）；免疫组织化学染色观测降钙素受体（caltitonin receptor，CTR）及 IL-1 表达水平。 结果B 组大鼠股骨灰度值显著低于 A 组（t=45.130，P=0.000），表明去势大鼠骨质疏松模型制备成功。组织学观察示，A、C、E 组 TN、MTPS、TBV、MBCT 与 B 组比较，差异有统计学意义（P<0.05）；C 组各骨组织形态计量学参数与 D、E 组比较，差异均有统计学意义（P<0.05）；D 组 TN、MTPS、TBV、MBCT 与 A 组比较差异有统计学意义（P<0.05）；E 组仅 MTPS 与 A 组比较差异有统计学意义（P<0.05）；E 组 MTPS、TBV、MBCT 与 D 组比较，差异有统计学意义（P<0.05）。免疫组织化学染色观察示，A、C、D、E 组 CTR、IL-1 表达水平较 B 组降低，C、E 组低于 D 组，差异有统计学意义（P<0.05）；其余组间比较差异均无统计学意义（P>0.05）。 结论狭鳕鱼皮胶原多肽能够改善骨质疏松大鼠的骨微结构，其机制可能与抑制骨组织中 CTR、IL-1 表达有关，但尚未发现其对骨质疏松症有预防作用。     

5-hydroxytryptamine subtype 6 receptor modulators: a patent survey

Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT₆ receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.

Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.

What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.

Take home message: Several of 5-HT₆-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease.     

Antidepressant Drugs in the Elderly — Rôle of the Cytochrome P450 2D6

Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacological treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses.

Comedications induce drug interactions that depend on the patient's metabolic capacity, linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphisms on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized.

The author approaches successively the notions of the cytochrome P450 (2D6), its role in drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping, and phenotyping are also explained. The author's experience on the relationship between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly.     

子宫颈鳞癌术后组织中CEACAM6和MMP-7的表达及意义

目的观察子宫颈鳞癌中癌胚抗原相关细胞黏附分子6(CEACAM6)和基质金属蛋白酶-7(MMP-7)的表达,探讨二者在子宫颈鳞癌发生、发展及转移中的作用。方法收集83例子宫颈鳞癌标本作为观察组及50例慢性宫颈炎的上皮组织作为对照组,应用免疫组化技术检测两组中CEACAM6和MMP-7蛋白的表达,比较其在不同临床特征中的表达差别。结果观察组中CEACAM6和MMP-7表达的阳性率明显高于对照组,观察组中CEACAM6和MMP-7在不同分化、不同宫颈管内浸润深度、不同淋巴结转移和不同Ki67阳性率中表达的差别有统计学意义。经相关性分析显示观察组中CEACAM6和MMP-7的表达呈正相关性。结论子宫颈鳞状细胞癌中CEACAM6和MMP-7异常表达,两者可能具有协同作用。CEACAM6对细胞外基质的降解作用可能是其促进肿瘤进展的重要因素。     

235361例新生儿疾病筛查情况分析

目的调查黄冈市2016年1月1日—2019年6月30日新生儿遗传代谢性疾病的筛查结果。方法采用实时数据分析调查的方法,对黄冈市2016年1月1日—2019年6月30日出生并在黄冈市妇幼保健院进行遗传代谢病5项[先天性甲状腺功能减低症(CH)、苯丙酮尿症(PKU)、葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症、先天性肾上腺皮质增生症(CAH)和地中海贫血]检测的235361例活产新生儿的结果及确诊数据进行分析和统计。结果2016年1月1日—2019年6月30日期间共筛查235361例新生儿,确诊CH患儿61例,发病率约为1:3858;确诊PKU患儿14例,发病率约为1:16812;确诊G6PD缺乏症(蚕豆病)患儿179例,发病率约为1:1315;确诊CAH患儿9例,发病率约为1:26151;确诊地中海贫血患儿446例,发病率约为1:528。结论黄冈市CH、PKU、G6PD缺乏症、CAH及地中海贫血发病率均低于全国平均发病率。加强健康教育和普及,通过分析质量控制指标加强质量管理,规范筛查流程,减少漏筛,提高召回确诊病例,不断提高服务质量。     

Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMα expression in T cells

1. Download : Download high-res image (170KB)
2. Download : Download full-size image

     

Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease

AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease.METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease(MELD) and Pediatric End Stage Liver Disease(PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition(Z-score -1.00) and malnutrition(Z-score -2.00). Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median(25th-75 th centile) age of the study population was 60(17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease(72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values were increased in patients at nutritional risk(34.9%) compared with those who were well-nourished [7.12(0.58-34.23) pg/m L vs 1.63(0.53-3.43) pg/m L; P = 0.02], correlating inversely with triceps skinfold-for-age z-score(rs =-0.61; P 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score(P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.