药学学报

MASM通过Wnt5a/FZD5途径调控星形胶质细胞活化抗多发性硬化症的机制研究

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陈腾翔 , 罗润永 , 李世国 , 黄益兴 , 傅思凡 , 李鑫炜 , 林小婷 , 胡若莹 , 南丽红 ^* , 陈亚萍 ^*

药学学报 | 研究论文 2026,61(2): 515-522

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药学学报 |研究论文 2026 , 61 (2) : 515 -522

MASM通过Wnt5a/FZD5途径调控星形胶质细胞活化抗多发性硬化症的机制研究

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陈腾翔, 罗润永, 李世国, 黄益兴, 傅思凡, 李鑫炜, 林小婷, 胡若莹, 南丽红^*, 陈亚萍^*

作者信息

福建中医药大学药学院, 福建福州 350122

通讯作者:

南丽红, E-mail: nlhong1152@163.com

陈亚萍, E-mail: zlchenyaping@126.com

作者简介:

作者贡献:

陈腾翔、罗润永负责实验和文章初稿撰写; 李世国、黄益兴、傅思凡、李鑫炜参与部分动物实验; 林小婷、胡若莹负责数据分析; 陈亚萍、南丽红负责课题设计、实验指导和文章修订。

The mechanism of MASM in treating multiple sclerosis by regulating astrocyte activation through Wnt5a/FZD5 pathway

Teng-xiang CHEN, Run-yong LUO, Shi-guo LI, Yi-xing HUANG, Si-fan FU, Xin-wei LI, Xiao-ting LIN, Ruo-ying HU, Li-hong NAN^*, Ya-ping CHEN^*

Affiliations

College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China

出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-1123

文章导航

摘要

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通过采用髓鞘少突胶质细胞糖蛋白MOG_35-55多肽联合百日咳毒素建立实验性自身免疫性脑脊髓炎(EAE) 小鼠模型, 研究13-甲氨基-18-硫代苦参碱(MASM) 对EAE小鼠的治疗作用及可能机制。采用Kono's 5分法进行神经功能评分, 将评分为0.5~3.5分的小鼠随机分为EAE组、MASM低、中、高剂量(1.5、3、6 mg·kg^-1) 及阳性对照组(芬戈莫德组, 1.0 mg·kg^-1), 另设一组正常对照组, 分组当天开始给药, 1次/天, 连续21天; HE染色观察小鼠脊髓组织的病理变化; 电镜法观察脊髓髓鞘超微结构的完整性; ELISA法检测血清中转化生长因子-β1 (TGF-β1) 和单核细胞趋化蛋白-1 (MCP-1) 的含量; qRT-PCR检测脊髓中抗原呈递相关基因H2T23的mRNA表达水平; 采用AutoDock软件对MASM和人卷曲同源物5 (FZD5) 蛋白进行分子对接; Western blot法检测脊髓中胶质纤维酸性蛋白(GFAP)、补体C3、糖蛋白无翅型小鼠乳房肿瘤病毒整合位点家族成员5a (Wnt5a)、FZD5、蛋白激酶Cα (PKCα) 蛋白表达情况及糖原合成酶激酶3β (GSK3β) 磷酸化水平。结果显示, MASM能明显改善EAE小鼠神经功能损伤及炎症细胞浸润、脊髓脱髓鞘等病理变化; 还可明显下调EAE小鼠脊髓中星形胶质细胞活化及A1表型标志物GFAP和C3蛋白、H2T23 mRNA的表达水平(P < 0.05, P < 0.01)。MASM与FZD5具有较强的结合能力, 并可明显下调EAE小鼠脊髓中Wnt5a、FZD5、PKCα蛋白的表达量及GSK3β的磷酸化水平(P < 0.05, P < 0.01)。提示MASM可通过抑制AST活化及向A1型极化, 改善脊髓炎症反应和髓鞘脱失, 其作用与调控Wnt5a/FZD5途径的激活有关。动物实验经福建中医药大学动物伦理委员会批准(FJTCMIACUC 2023319)。

关键词

多发性硬化症 / 实验性自身免疫性脑脊髓炎 / 13-甲氨基-18-硫代苦参碱 / 星形胶质细胞 / Wnt5a/FZD途径

Abstract

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This study systematically investigated the therapeutic mechanism of matrine derivative, (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), in experimental autoimmune encephalomyelitis (EAE) through multi-dimensional analysis. The myelin oligodendrocyte glycoprotein MOG_35-55/pertussis toxin-induced EAE mouse model was established, and neurological impairment was confirmed using Kono's 5-point scoring system, mice with scores between 0.5 and 3.5 were considered successful models. These mice were randomly divided into six groups: EAE control, MASM groups (1.5, 3 and 6 mg·kg^-1), a positive control group (fingolimod, 1.0 mg·kg^-1), and a normal control group. Drug administration was initiated on the day of grouping, once daily for 21 consecutive days. The Kono's score was used to evaluate the neurological function; HE staining and electron microscopy was used to observe the pathological changes of spinal cord; transforming growth factor-β1 and monocyte chemoattractant protein-1 content was detected by ELISA. The gene expression of H2T23 was detected by qRT-PCR, the binding interactions between MASM and human frizzled homolog (FZD5) was evaluated by molecular docking, and protein expression levels of glial fibrillary acidic protein (GFAP), complement 3 (C3), wingless type mouse mammary tumor virus integration site family member 5a (Wnt5a), FZD5, protein kinase Cα (PKCα), and the phosphorylation level of glycogen synthase kinase 3 (GSK3β) were detected by Western blot. MASM significantly improved neurological function, reduced spinal cord inflammation and demyelination, and downregulated astrocyte activation markers (GFAP, C3, H2T23) (P < 0.05, P < 0.01) and Wnt5a/FZD5 pathway components (Wnt5a, FZD5, PKCα, p-GSK3β) (P < 0.05, P < 0.01). MASM demonstrates strong binding capacity to FZD. These findings suggest that MASM alleviates EAE by inhibiting astrocyte polarization via the Wnt5a/FZD5 pathway. The animal study was approved by the Animal Ethics Committee of Fujian University of Traditional Chinese Medicine (approval number: FJTCMIACUC 2023319).

Key words

multiple sclerosis / experimental autoimmune encephalomyelitis / (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione / astrocyte / Wnt5a/FZD5 pathway

引用本文

陈腾翔, 罗润永, 李世国, 黄益兴, 傅思凡, 李鑫炜, 林小婷, 胡若莹, 南丽红, 陈亚萍. MASM通过Wnt5a/FZD5途径调控星形胶质细胞活化抗多发性硬化症的机制研究. 药学学报, 2026 , 61 (2) : 515 -522 . DOI: 10.16438/j.0513-4870.2025-1123

Teng-xiang CHEN, Run-yong LUO, Shi-guo LI, Yi-xing HUANG, Si-fan FU, Xin-wei LI, Xiao-ting LIN, Ruo-ying HU, Li-hong NAN, Ya-ping CHEN. The mechanism of MASM in treating multiple sclerosis by regulating astrocyte activation through Wnt5a/FZD5 pathway[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 515 -522 . DOI: 10.16438/j.0513-4870.2025-1123

正文

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多发性硬化症(multiple sclerosis, MS) 是一种慢性自身免疫性疾病, 其主要特征为中枢神经系统白质炎性脱髓鞘并伴有轴突损伤^[1]。研究发现星形胶质细胞(astrocyte, AST) 在MS疾病进展中起着重要作用, 当AST被“激活”, 转变为“反应性AST”时, 通过分泌神经毒性物质, 导致炎症反应、突触结构损伤, 并抑制髓鞘再生进程^{[2, 3]}。因此, 调控AST的过度活化, 抑制炎症反应, 改善髓鞘再生微环境, 成为MS治疗的有效途径。有研究发现, 糖蛋白无翅型小鼠乳房肿瘤病毒整合位点家族成员5a (wingless type mouse mammary tumor virus integration site family member 5a, Wnt5a) 在AST活化的过程中发挥重要作用^{[4, 5]}。Wnt5a/人卷曲同源物(human frizzled homolog, FZD) 信号通路是Wnt非经典通路的重要组成部分, 在炎症反应及AST成熟中发挥调控作用^{[6, 7]}。

苦参碱是清热解毒中药苦参的主要活性成分。据报道苦参碱对实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE) 模型小鼠具有较好的治疗作用^[8]。但是苦参碱半衰期短、治疗效率低^[9], 为此, 课题组以苦参碱为先导化合物, 用硫原子取代羰基氧原子, 并在酮位上引入甲基胺基, 设计合成了硫代苦参碱衍生物(专利号ZL 200910199252.0)。进一步研究发现, 衍生物中的13-甲氨基-18-硫代苦参碱[(6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione, MASM] 药理活性最强, 且口服生物利用度明显提高, 半衰期明显延长^{[10, 11]}。课题组前期研究^[12]发现, MASM可明显改善EAE小鼠症状, 减少白质炎症和脱髓鞘现象。但其是否通过Wnt5a/FZD5途径调控AST的活化发挥治疗作用, 尚未见相关报道。故本研究通过建立EAE小鼠模型, 观察MASM对髓鞘保护作用, 并进一步探讨其可能的作用机制, 为MASM在MS中的进一步深入开发提供科学依据。

材料与方法

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药物与试剂 MASM (海军军医大学特药研究中心, 批号: M192306); 芬戈莫德(fingolimod, FTY) (大连美仑生物科技有限公司, 货号: MB1552); MOG_35-55/CFA emulsion PTX试剂盒(Hooke Laboratories公司, 货号: EK-2110); 转化生长因子-β1 (transforming growth factor-β1, TGF-β1) 和单核细胞趋化蛋白-1 (monocyte chemoattractant protein-1, MCP-1) ELISA试剂盒(上海茁彩生物科技有限公司, 货号: ZC-39043、ZC-38075); 胶质纤维酸性蛋白(glial fibrillary acidic protein, GFAP) 抗体(杭州华安生物技术有限公司, 货号: EM140707); 糖原合成酶激酶3β (glycogen synthase kinase 3, GSK3β)、p-GSK3β、FZD5和β-actin抗体(苏州康何欣生物科技有限公司, 货号: CQA8398、CQA8055、CPA2255和CPA9100); 补体C3 (complement 3, C3) 抗体(武汉三鹰生物技术有限公司, 货号: 66157-1-lg); Wnt5a抗体(武汉爱博泰克生物科技有限公司, 货号: A2133); 蛋白激酶Cα (protein kinase Cα, PKCα) 抗体(美国ImmunoWay Biotechnology公司, 货号: YT3754)。RevertAid First Strand cDNA Synthesis试剂盒(美国Thermo Fisher科技公司, 货号: K1622); SYBR Green qPCR Mix (山东思科捷生物技术有限公司, 货号: AH0402)。

仪器多功能酶标仪(瑞士TECAN公司, 型号Infinite 200 PRO); 光学显微镜(德国Leica公司, 型号DM4000B LED); 化学发光成像系统(美国Bio-Rad公司, 型号ChemiDoc XRS+); 实时荧光定量PCR仪(美国Applied Biosystem公司, 型号ABI7900); 透射电子显微镜(日本Hitachi公司, 型号: HT7800)。

实验动物 SPF级健康雌性C57 BL/6小鼠, 6~8周, 体质量(20 ± 2) g, 购自广东维通利华实验动物技术有限公司, 生产许可证号: SCXK (粤) 2022-0063。于福建中医药大学实验动物管理中心实施实验饲养, 许可证号: SYXK (闽) 2019-0007。本研究获福建中医药大学动物伦理委员会审核批准, 伦理审查编号: FJTCMIACUC 2023319。动物实验操作严格遵循动物福利相关规定。

EAE模型的建立 严格按照MOG_35-55/CFA emulsion PTX试剂盒说明书, 小鼠皮毛消毒后在小鼠背部正中上下2点各皮下注射100 µL髓鞘少突胶质细胞糖蛋白(myelin oligodendrocyte glycoprotein, MOG)_35-55乳剂。注射当天2及24 h后, 腹腔注射百日咳毒素(pertussis toxin, PTX) 100 µL。造模第10天依据Kono's 5分法及说明书中的评分细则进行神经功能评分, 评分为0.5~3.5者视为造模成功, 纳入实验分组。评分细则如下, 0分: 与未免疫的小鼠相比, 运动功能无明显变化; 0.5分: 尾尖无力下垂; 1分: 尾巴无力, 从根部拿起时通常垂下; 1.5分: 尾巴和后腿无力, 行走时微晃; 2分: 尾巴和后腿无力, 歪头或行走时一条腿拖地; 2.5分: 尾巴无力, 后肢瘫痪, 行走时后肢拖地; 3分: 全尾瘫痪, 后肢双侧脚掌外翻, 腹部触地; 3.5分: 尾巴无力, 后肢瘫痪, 前肢单侧无力, 爬行时转圈; 4分: 尾巴无力, 四肢全部瘫痪, 少移动但比较警觉, 通常在持续4.0两天后进行安乐死, 该小鼠在剩余时间评分为5.0; 4.5分: 尾巴无力, 四肢全部瘫痪, 比较少进行活动, 通常推荐安乐死, 该小鼠在剩余时间评分为5.0; 5分: 因瘫痪而死亡或被安乐死。

药物的配置 精密称取1.8 mg MASM粉末, 加入6 mL生理盐水中, 超声溶解, 配成0.3 mg·mL^-1 MASM溶液。

分组和给药 将造模成功的小鼠随机为5组, 分别为模型组(EAE组)、MASM组(1.5、3.0、6.0 mg·kg^-1) 及阳性对照FTY组(1.0 mg·kg^-1), 每组10只; 另取10只作为正常对照组(control组)。各组小鼠均在分组后按0.2 mL每10 g体质量灌胃给予相应的药物, 正常对照组和EAE组均给予生理盐水, 每天1次, 连续21天(图1)。

ELISA法检测EAE小鼠血清中TGF-β1、MCP-1含量 末次给药1 h后, 摘眼球取血, 室温静置2 h后, 4 ℃, 3 000 r·min^-1, 离心15 min, 吸取上清。严格按照ELISA试剂盒说明书, 检测血清中TGF-β1和MCP-1含量。

HE染色脊髓组织石蜡切片脱蜡复水, 苏木素浸染, 分化液分化, 伊红浸染, 中性树胶封片, 于显微镜下观察脊髓病理变化。

透射电镜 取脊髓组织切成大约1 mm³的小块后在电镜固定液中进行固定, 然后用戊二醛后固定2 h, 乙醇室温梯度脱水后, 依次用丙酮和812包埋剂1∶1混合液及纯812包埋剂渗透过夜, 再放于60 ℃烤箱聚合48 h, 用半薄切片机将树脂块切为1.5 µm的半薄片, 甲苯胺蓝染色后于光镜下定位, 切片(60~80 nm), 捞片。2%醋酸铀饱和乙醇溶液染色8 min (避光), 依次用70%乙醇和超纯水清洗; 2.6%枸橼酸铅溶液染色8 min (避CO₂), 干燥过夜, 透射电子显微镜下观察。轴突直径与髓鞘厚度之间的关系用G-ratio值来表示, 其计算方法为: G-ratio =内轴突直径/轴突和髓鞘总直径。

qRT-PCR法检测脊髓中抗原呈递相关基因H2T23的mRNA表达水平 TRIzol法提取脊髓组织的总RNA, 使用RevertAid First Strand cDNA Synthesis试剂盒逆转录得到cDNA, 再采用SYBR Green qPCR Mix试剂盒检测H2T23的mRNA表达水平。引物由浙江尚亚生物技术有限公司合成并验证, H2T23序列为F (5'→3'): AGCTGTGATCATCCTTGGAGC, R (5'→3'): CCAGTCAGAGGTCTGGAAGC; β-actin序列为F (5'→3'): TGTCCACCTTCCAGCAGATGT, R (5'→3'): AGCTCAGTAACAGTCCGCCTAG。本实验以β-actin为内参进行校正, 计算H2T23的相对表达量。

MASM与靶蛋白FZD5的分子对接 从UniProtKB数据库(https://www.uniprot.org) 检索FZD5蛋白序列, 将该序列导入SWISS-MODLE网站, 获取蛋白质最优结构, 并保存为PDB格式; 通过PYMOL软件优化蛋白质结构, 去除多余配体和水分子。利用DiscoverStudio软件对化合物MASM进行能量最小化处理。采用Autodock vina1.5.6软件进行分子对接, 通过Pymol3.1和Discovery Studio 2019软件进行可视化分析。关注氢键、疏水作用和范德华力等分子间作用力并分析MASM与靶蛋白FZD5之间的分子相互作用模式。

Western blot法检测GFAP、C3蛋白及Wnt5a/FZD5途径相关蛋白的表达 严格按照试剂盒说明书, 提取脊髓组织总蛋白, BCA法测定蛋白浓度。30 μg上样, 电泳分离, 转膜至NC膜上, 用快速封闭液封闭25 min, 冰上孵育一抗(稀释比β-actin为1∶20 000, GFAP为1∶5 000, C3为1∶10 000, Wnt5a为1∶1 000, FZD5为1∶1 000, PKCα为1∶1 000, GSK3β为1∶1 000, p-GSK3β为1∶1 000) 过夜; 二抗(稀释比为1∶3 000) 室温孵育70 min后, ECL发光后显影。Image J图像软件分析灰度值, 以β-actin为内参计算目的蛋白的相对表达量。

统计学分析 利用SPSS 27.0统计分析应用软件实现资料处理数据分析, 用GraphPad Pism 9.5绘图软件绘图。统计数据用平均值±标准差(x ± s) 表示, 符合正态分布的数据各组间统计选择单因素方差(one-way ANOVA) 分析方法, 若方差齐, 事后比较选择LSD法, 方差不齐, 则选择Games-Howel法; 不符合正态分布的数据用非参数检验。以P < 0.05为有显著性差异。

结果

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1　MASM对EAE小鼠神经功能的影响

EAE组小鼠出现精神萎靡、尾巴无力、后肢外翻、全肢瘫痪爬行转圈等严重情况, 随着时间的延长, Kono's评分逐渐升高, 与正常对照组相比具有显著性差异(P < 0.01); MASM给药干预第9天, 6.0 mg·kg^-1 MASM组评分明显低于EAE组小鼠(P < 0.01), 给药干预第18、21天, 3.0和6.0 mg·kg^-1 MASM组评分均明显低于EAE组(P < 0.05, P < 0.01)。结果提示, MASM能够减轻EAE小鼠的神经损伤症状(图2)。

2　MASM对EAE小鼠脊髓病理变化的影响

如图3所示, 正常对照组小鼠脊髓组织结构清晰完整, 轴突外髓鞘结构完整, 厚度均匀, 清晰致密, 边缘规整, 具有轨道样致密板层结构。轴突直径与髓鞘厚度之间的关系用G-ratio值来表示, 该值被广泛用于评价髓鞘的结构和功能, 数值越小, 髓鞘越厚, 表明有更多的髓鞘包绕在轴突外部。实验结果显示, EAE组小鼠脊髓白质区域出现大量炎性细胞浸润, 并伴有明显的组织空泡, 且G-ratio值明显高于正常组(P < 0.01), 提示模型小鼠出现明显的脱髓鞘现象; MASM干预后, 小鼠脊髓病理改变有一定程度的改善, 且G-ratio值显著降低(P < 0.05, P < 0.01), 提示MASM可有效促进髓鞘的再生。

3　MASM对EAE小鼠脊髓内AST活化及表型的影响

GFAP是AST活化的标志物, 而C3和H2T23被认为是A1型AST特征性标志物。AST活化为A1表型, 通过释放炎症因子(TGF-β1、MCP-1等), 形成神经抑制性微环境, 阻碍髓鞘再生进程。如图4所示, 与正常对照组相比, EAE模型组小鼠脊髓组织中的GFAP、C3蛋白, H2T23 mRNA表达及血清中TGF-β1、MCP-1含量均明显升高增加(P < 0.01); 经MASM干预后, 脊髓组织中GFAP、C3蛋白, H2T23 mRNA表达及血清中TGF-β1、MCP-1含量均明显少于EAE组(P < 0.05, P < 0.01)。

4　MASM与靶蛋白FZD5的分子对接结果

采用Autodock平台进行分子对接, 并对MASM与靶蛋白FZD5的结合亲和力进行量化评估, 结果显示(图5), MASM与FZD5蛋白的结合能较低(-6.2 kcal·mol^-1), 表明MASM与靶蛋白可发生热力学上自发的强结合效应(结合能低于-5.0 kcal·mol^-1)。从分子互作机制来看, 配体与受体间主要通过疏水作用(如alkyl作用) 和范德华力形成稳定的相互作用模式。上述结果表明, FZD5可作为MASM的直接作用靶点。

5　MASM对Wnt5a/FZD5途径相关蛋白表达水平的影响

如图6所示, 与正常对照组相比, EAE组小鼠脊髓中Wnt5a、FZD5、PKCα蛋白表达量及GSK3β磷酸化水平显著升高(P < 0.01), 而经MASM干预后Wnt5a、FZD5、PKCα蛋白表达量及GSK3β磷酸化水平明显低于EAE组(P < 0.05, P < 0.01)。

讨论

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MS是一种以髓鞘破坏为主要特征, 伴有炎症反应、神经病变的中枢神经系统的渐进性退化症。MOG是免疫球蛋白超家族的成员, 仅在髓鞘和少突胶质细胞突起的表面表达, 而MOG_35-55是髓鞘少突胶质细胞糖蛋白的35~55位氨基酸片段, 作为自身抗原诱导T细胞活化, 识别和攻击髓鞘蛋白, 造成髓鞘脱失、中枢神经系统轴突传导受损, 导致小鼠进行性的后肢瘫痪。同时联合PTX使血管通透性增加, T细胞更易通过屏障作用于神经髓鞘, 故MOG_35-55多肽联合PTX建立的EAE模型表现与MS的临床病理表现相似, 是目前公认的经典模型^{[13, 14]}。实验结果显示, 造模后小鼠出现精神萎靡、尾巴无力、后肢外翻、全肢瘫痪爬行转圈等严重情况, 随着时间的延长, Kono's评分逐渐升高; 脊髓白质出现明显的炎性细胞浸润, 伴有大量组织空泡, 并出现明显的脱髓鞘现象, 以上提示EAE模型制备成功。MASM干预后, Kono's评分明显降低, 脊髓病理改变均有不同程度的改善, 且脱髓鞘现象明显减少(P < 0.05, P < 0.01), 提示MASM对EAE小鼠具有较好的治疗作用, 并呈一定的剂量依赖性。

AST是哺乳动物脑内分布最广的一类细胞, 在MS疾病进展中起着重要作用。当MS发生后, 处于静息状态的AST被激活, 形成反应性AST, 其基因表达、形态和功能发生明显变化, 活化后的AST可分化为A1表型, 通过释放炎症因子及趋化因子, 如MCP-1、TGF-β1等, 导致炎症和组织损伤, 并形成神经抑制性微环境, 阻碍髓鞘再生进程^[15]。GFAP是一种Ⅲ型中间丝状蛋白, 是AST内的主要骨架蛋白, 常作为AST活化的生物标志物, 而C3和H2T23被认为是A1型AST特征性标志物^[16]。故本研究通过检测脊髓中GFAP和C3的表达水平以评价AST的活化程度及表型转化。实验结果显示, EAE组脊髓中GFAP、C3蛋白表达量及H2T23 mRNA水平显著增加(P < 0.01), 提示造模后脊髓中AST被激活并转化为A1表型。MASM治疗后, 可明显抑制AST的活化。

Wnt5a/FZD信号通路是Wnt非经典通路的重要组成部分。当MS发生后, Wnt5a表达增加, 通过非经典途径与G蛋白偶联受体FZD结合调控蛋白激酶PKCα的重新定位与激活^[17]。活化的PKCα可磷酸化糖原合酶激酶GSK-3β, 使其失活^[18]。而GSK-3β可与二聚体转录因子AP-1中的c-Jun结合, 使其泛素化降解失活^[19]。Wnt5a信号使GSK-3β磷酸化失活后, 导致c-Jun增多, 大量易位到细胞核, 促进H2T23、C3的表达使得AS转化为A1表型^[20], 增加相关炎症因子的释放, 抑制髓鞘修复, 加重髓鞘损伤。分子对接结果显示, MASM与靶蛋白FZD5有较强的结合能力, 动物实验结果显示, EAE小鼠脊髓组织中Wnt5a、FZD5、PKCα蛋白的表达量及GSK3β磷酸化水平显著增加(P < 0.01), 经MASM治疗后Wnt5a、FZD、PKCα蛋白的表达量及GSK3β磷酸化水平显著减少(P < 0.05, P < 0.01)。

本研究表明, MASM可改善EAE小鼠的病理状态, 具有促进EAE小鼠神经功能修复的作用, 其与调控Wnt5a/FZD途径的激活、抑制AST活化及向A1型转化, 以及抑制髓鞘脱失有关。

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2026年第61卷第2期

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doi: 10.16438/j.0513-4870.2025-1123

接收时间：2025-09-19
首发时间：2026-09-21
出版时间：2026-02-12

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收稿日期：2025-09-19
修回日期：2025-12-03

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福建中医药大学药学院, 福建福州 350122

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南丽红, E-mail: nlhong1152@163.com

陈亚萍, E-mail: zlchenyaping@126.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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