锌指蛋白A20对树突状细胞的免疫调控及其在炎症性肠病发病机制中的作用

泛素化修饰对蛋白质降解及多种细胞功能都具有重要的调控作用,如DNA损伤修复、细胞周期调控、细胞生长、免疫系统功能等。泛素修饰酶锌指蛋白A20被认为是调控机体免疫和炎症反应的重要门户,为NF-κB信号通路中的关键负性调控因子。树突状细胞(DC)是专职的抗原提呈细胞,可以通过多种受体识别炎性反应或病原微生物,是维持机体免疫稳态的关键调节者。近年来,有研究表明,A20在DC功能的调控中发挥着重要作用,可能参与了炎症性肠病的发生和发展。文章基于最新的研究进展,总结A20对DC的免疫调控及其在炎症性肠病发病机制中的作用。     

Pathological findings of multifocal choroiditis with panuveitis and punctate inner choroidopathy

PURPOSE: To compare the pathological findings between multifocal choroiditis with panuveitis (MCP) and punctate inner choroidopathy (PIC). METHODS: Fourteen eyes of 14 patients clinically diagnosed as having MCP or PIC who underwent surgical excision of choroidal neovascularization (CNV) were studied. Immunohistochemical findings of the excised CNV in MCP (eight eyes) and PIC (six eyes) cases were compared. Antibodies against vascular endothelial growth factor (VEGF), CD68, CD3, and CD20 were used as primary antibodies. RESULTS: Expression of VEGF and CD68 in the CNV was observed in all MCF and PIC cases. In three of eight eyes with MCP, intraocular inflammatory findings were found clinically, while immunohistochemical study demonstrated infiltration of CD20-positive B lymphocytes in the CNV. No B lymphocyte infiltration was found in the six eyes with PIC. No differences in pathological findings were found between the five MCP eyes without intraocular inflammation and the six PIC eyes, with all eyes showing no B lymphocyte infiltration. CONCLUSIONS: In MPC cases showing clinical inflammatory findings, infiltration of B lymphocytes was also observed histopathologically, suggesting that the presence of inflammatory cells in the anterior chamber or vitreous body clinically is an indicator of active inflammatory CNV. However, this study clarifies that MCP eyes without intraocular inflammation and PIC eyes are not different in histopathological findings.     

Antibody Therapies for Progressive Multiple Sclerosis and for Promoting Repair

Progressive multiple sclerosis (PMS) is clinically distinct from relapsing–remitting MS (RRMS). In PMS, clinical disability progression occurs independently of relapse activity. Furthermore, there is increasing evidence that the pathological mechanisms of PMS and RRMS are different. Current therapeutic options for the treatment of PMS remain inadequate, although ocrelizumab, a B-cell-depleting antibody, is now available as the first approved therapeutic option for primary progressive MS. Recent advances in understanding the pathophysiology of PMS provide hope for new innovative therapeutic options: these include antibody therapies with anti-inflammatory, neuroprotective, and/or remyelination-fostering effects. In this review, we summarize the relevant trial data relating to antibody therapy and consider future antibody options for treating PMS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01214-x.     

化合物Au20大鼠体内药动学及绝对生物利用度研究

目的建立HPLC法测定大鼠血浆中化合物Au20的浓度,研究其在大鼠体内的药动学及绝对生物利用度。方法双周期自身交叉设计,SD大鼠静注给药和灌胃给药化合物Au20,剂量分别为4.0和40.0 mg/kg,给药后不同时间点取血,HPLC法测定血浆中化合物Au20的浓度,用DAS 2.0软件计算其药动学参数。结果血浆中化合物Au20在7.8～1 000 ng/mL浓度范围内线性关系良好(r=0.999 9),提取回收率75.91%～89.06%,日内和日间RSD均小于5%。静脉注射给药的药-时曲线符合三室模型。经剂量校正,口服给药的绝对生物利用度为(4.08±1.85)%。结论化合物Au20口服给药的绝对生物利用度低。     

黏蛋白2和细胞角蛋白20在乳房外佩吉特病皮损中的表达

目的探讨黏蛋白2(MUC2)和细胞角蛋白20(CK20)在乳房外佩吉特病(EMPD)中的表达情况及两者之间的关系。方法应用生物素蛋白免疫组织化学法(SP法)检测24例EMPD及10名美容切除术后正常组织上MUC2与CK20的表达。结果 24例EMPD常规苏木素-伊红(HE)染色显示:11例为原位性佩吉特病:Paget细胞局限在上皮内;13例为浸润性佩吉特病:Paget细胞穿破基底膜浸润到真皮及皮下脂肪。11例原位性EMPD细胞质中CK20表达中等强度阳性1例,弱阳性5例,阴性5例;13例浸润性EMPD细胞质中CK20表达强阳性9例,阳性4例;10例正常皮肤细胞质中CK20表达4例弱阳性,6例阴性。11例原位性EMPD细胞质中MUC2表达阳性1例,弱阳性7例,阴性3例;13例浸润性EMPD中MUC2表达强阳性13例;10例正常皮肤中MUC2表达6例弱阳性,4例阴性。浸润性EMPD中MUC2的阳性细胞表达明显高于CK20(P<0.05),原位性EMPD中CK20与MUC2之间的阳性表达差异无统计学意义(P>0.05)。结论 MUC2在浸润性EMPD中的阳性细胞表达明显高于CK20的阳性表达,MUC2可能是EMPD发生发展中的重要因子,可能在EMPD的侵袭和转移中起着重要作用。在EMPD中联合检测MUC2和CK20,有助于对EMPD做出更为明确的诊断,指导临床治疗和预防。     

美罗华治疗32例弥漫型大B细胞性非何杰金氏淋巴瘤

目的 评价美罗华治疗弥漫型大B细胞性非何杰金氏淋巴瘤DLBCL的临床效果及不良反应。方法 用同期对照的前瞻性研究方法,将68例弥漫型大B细胞性NHL患者分为研究组(美罗华组)和对照组,前组32例用CHOP方案(环磷酰胺、阿霉素、长春新碱和强的松)联合美罗华治疗;后组36例单用CHOP方案。每4周循环1个疗程,3～6疗程后作评价。将两组患者按国际淋巴瘤预后因子指数(IPI)分为中低危组和高危组,分析其疗效与预后。全部患者6个疗程后停止治疗,随访观察生存情况。结果 美罗华组完全缓解率(CR)达56.3％,总有效率87.5%;对照组分别为13.9％、63.9%,两组疗效差异有统计学意义(P<0.001)。美罗华组6、12、24、36月总的生存率分别为96.9％、87.5％、71.9％和65.6％,对照组分别为91.7％、80.6％、58.3％和41.7％(P>0.05)。美罗华组中中低危组的CR及部分缓解率(PR)分别为68.4％、26.3％,高危组分别为38.5%、38.5％(P<0.01);对照组中低危组的CR及PR分别为15.8％、68,4％,高危组则分别为11.8％、29.4％(P<0.001)。结论 美罗华联合CHOP方案治疗DLBCL的疗效显著,3年生存率高,不良反应较单纯化疗少,可作为该病目前的首选方案。     

CACNA1H基因敲除对小鼠孤独症样行为及海马神经元形态学的影响

目的研究CACNA1H基因敲除(knockout, KO)对小鼠孤独症样行为及海马神经元形态学的影响。方法25只3~4周龄C57BL/6背景的CACNA1H KO小鼠作为实验组, 26只同年龄同背景的野生型(wild type, WT)小鼠作为对照组。通过三箱实验和旷场实验观察小鼠社交、焦虑和重复刻板行为后测量其脑质量与脑体积, 用尼氏染色法(Nissl staining)观察海马神经元数目。将CACNA1H杂合子小鼠与Thy1-GFP-O小鼠杂交, 构建CACNA1H^-/--Thy1⁺(KO-GFP)及CACNA1H^+/+-Thy1⁺(WT-GFP)小鼠, 观察海马神经元树突棘密度及成熟度。结果三箱实验中, 社交测试阶段, KO小鼠在陌生鼠箱中的时间比空箱更长(F_{1, 14}=95.086, P < 0.05;Post-Hoc: P < 0.05), 探索的偏好指数与对照组相比差异无统计学意义(t=1.044, P>0.05);新社交对象识别测试阶段, KO小鼠在新陌生鼠箱与陌生鼠箱中的时间差异无统计学意义(F_{1, 14}=18.062, P < 0.05;Post-Hoc: P>0.05), 探索的偏好指数低于对照组(t=2.390, P < 0.05)。旷场实验中, KO小鼠在旷场中心活动时间明显少于对照组(t=2.503, P < 0.05), 自梳理时间明显多于对照组(t=-2.299, P < 0.05)。形态学结果显示, KO小鼠脑质量/体质量和脑体积与对照组相比差异均无统计学意义(t=0.356, P>0.05;t=-0.660, P>0.05), 但其海马齿状回区神经元数目较对照组减少(t=2.323, P < 0.05), 且KO-GFP小鼠海马齿状回区树突棘密度较对照组增加(t=-2.374, P < 0.05), 而成熟度差异无统计学意义(t=-1.935, P>0.05)。结论CACNA1H KO小鼠具有孤独症样行为, 可能与海马齿状回区神经元数目减少及树突棘密度增高有关。     

siRNA靶向沉默fbxl20基因对肝癌SMMC-7721细胞生物学行为的影响

目的:通过沉默fbxl20基因,以观察基因沉默后对SMMC-7721细胞的增殖、迁移和周期分布的影响。方法:通过脂质体Lipofectamine2000介导转染SMMC-7721细胞,靶向fbxl20基因的siRNA片段阻低肝癌SMMC-7721细胞株fbxl20 mR-NA表达。结果:siRNA能有效沉默SMMC-7721细胞fbxl20 mRNA的表达,沉默效率为71.49%。MTT试验实验显示:siRNA转染SMMC-7721细胞后,细胞增殖能力显著降低。Transwell小室和划痕愈合实验表明,fbxl20基因被沉默后,SMMC-7721细胞在迁移能力明显减弱,迁移抑制率高达62.03%。流式细胞术检测细胞周期结果显示:转染48 h后,SMMC-7721实验组细胞G1/G0期比率(81.21%)显著高于阴性对照组(71.49%)和空白对照组(67.90%)。结论:本实验运用RNA干扰技术成功抑制了SMMC-7721细胞中fbxl20基因的表达,并且发现fbxl20基因可能与肝癌细胞的增值和迁移相关。