切换至 "中华医学电子期刊资源库"
高级检索
中华妇幼临床医学杂志(电子版)

中华妇幼临床医学杂志(电子版) ›› 2020, Vol. 16 ›› Issue (02) : 171 -180. doi: 10.3877/cma.j.issn.1673-5250.2020.02.008

所属专题： 文献；

论著

儿童特发性肾病综合征低IgG血症机制：哺乳动物雷帕霉素靶蛋白过表达对滤泡辅助性T细胞数量的可能影响
刘光磊1, 杨军2, 李成荣2,†()   
  1. 1. 深圳市儿童医院肾脏免疫科，广东　518026[现在遵义医科大学第五附属(珠海)医院儿科，广东　519000]
    2. 深圳市儿童医院肾脏免疫科，广东　518026
  • 收稿日期:2019-05-07 修回日期:2020-02-21 出版日期:2020-04-01
  • 通信作者: 李成荣

Mechanism of hypo-IgG in children with idiopathic nephrotic syndrome: the possible influence of mammalian target of rapamycin over expression on follicular helper T cells

Guanglei Liu1, Jun Yang2, Chengrong Li2,†()   

  1. 1. Department of Nephrology and Immunology, Shenzhen Children′s Hospital, Shenzhen 518026, Guangdong Province, China (is working in the Department of Pediatrics, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, Zhuhai 519000, Guangdong Province, China)
    2. Department of Nephrology and Immunology, Shenzhen Children′s Hospital, Shenzhen 518026, Guangdong Province, China
  • Received:2019-05-07 Revised:2020-02-21 Published:2020-04-01
  • Corresponding author: Chengrong Li
  • About author:
    Corresponding author: Li Chengrong, Email:
  • Supported by:
    Special Scientific Research Project of Public Welfare Profession of National Health and Family Planning Commision(201402012)
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

刘光磊, 杨军, 李成荣. 儿童特发性肾病综合征低IgG血症机制：哺乳动物雷帕霉素靶蛋白过表达对滤泡辅助性T细胞数量的可能影响[J/OL]. 中华妇幼临床医学杂志(电子版), 2020, 16(02): 171-180.

Guanglei Liu, Jun Yang, Chengrong Li. Mechanism of hypo-IgG in children with idiopathic nephrotic syndrome: the possible influence of mammalian target of rapamycin over expression on follicular helper T cells[J/OL]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2020, 16(02): 171-180.

目的

探讨儿童特发性肾病综合征(INS)的低免疫球蛋白(Ig)G血症可能机制。

方法

选择2015年9月至2016年10月，于深圳市儿童医院接受治疗的40例激素敏感型INS患儿为研究对象。按照患儿病情，将其分为INS初发组(n＝20)和INS缓解组(n＝20)，选择同期在该院接受健康体检的同年龄健康儿童纳入对照组(n＝20)。采用流式细胞术(FCM)检测受试儿外周血单个核细胞(PBMC)中滤泡辅助性T细胞(Tfh，CD4＋CXCR5＋ICOShighT)、初始B细胞(CD19＋CD27－IgD＋B细胞)、转化前记忆B细胞(CD19＋CD27＋IgD＋ B细胞)、转化后记忆B细胞(CD19＋CD27＋IgD－ B细胞)及浆细胞(CD19＋CD27＋IgD－CD38highB细胞)百分比；采用逆转录-聚合酶链反应(RT-PCR)，检测受试儿外周血CD4＋T细胞相关基因mRNA表达水平；采用酶联免疫吸附试验、免疫荧光吸附试验，分别检测受试儿血浆白细胞介素(IL)-2水平、丙二醛浓度。采用单因素方差分析及最小显著性差异(LSD)-t法，对上述指标分别进行3组间及组间两两比较；对其中部分指标的相关性，采用Pearson相关分析法。本研究通过深圳市儿童医院伦理委员会批准(批准日期：2016-04-11)，所有受试对象监护人知情并同意。

结果

①INS初发组患儿血清总蛋白及白蛋白水平，以及血浆总IgG、IgG1、IgG2、IgG4水平等6项指标，均显著低于对照组健康儿童，血清总胆固醇浓度，则显著高于对照组，并且差异均有统计学意义(P<0.05)。②INS初发组患儿PBMC中Tfh百分比为(3.9±1.2)%，显著低于对照组的(5.2±1.1)%及INS缓解组的(4.9±1.2)%，并且差异均有统计学意义(P＝0.001，P＝0.021)。③INS初发组患儿PBMC中，转化后记忆B细胞、浆细胞百分比为(8.4±3.6)%、(7.5±2.0)%，均低于INS缓解组患儿的(11.6±2.7)%、(11.4±3.9)%及对照组健康儿童的(12.2±3.7)%、(12.5±3.4)%，并且差异均有统计学意义(均为P<0.001)。④INS初发组患儿的8项指标，如CD4＋T细胞相关基因B淋巴细胞诱导成熟蛋白(Blimp)-1、IL-2Rα、IL-2Rβ、IL-2Rγ、磷脂酰肌醇3激酶(PI3K)、丝氨酸/苏氨酸蛋白激酶(AKT)、哺乳动物雷帕霉素靶蛋白(mTOR)及雷帕霉素结合蛋白复合物(mTORC)1mRNA表达水平为(3.2±1.1)、(14.4±5.7)、(18.5±4.6)、(7.2±1.7)、(10.3±3.6)、(2.2±0.3)、(1.84±0.68)、(7.2±1.4)，均高于INS缓解组患儿的(2.4±1.1)、(10.5±2.5)、(15.5±3.5)、(5.5±1.1)、(8.5±2.2)、(1.8±0.5)、(1.44±0.29)、(6.1±1.2)及对照组健康儿童的(2.4±1.1)、(10.3±5.5)、(14.6±4.8)、(5.6±2.5)、(1.56±0.42)、(2.4±1.1)、(10.3±5.5)、(14.6±4.8)；而B细胞淋巴瘤因子(BCL)-6 mRNA表达水平为(1.22±0.29)，则低于INS缓解组患儿的(1.49±0.35)及对照组健康儿童的(1.56±0.42)，并且上述差异均有统计学意义(均为P<0.05)。⑤INS初发组患儿血浆IL-2水平及丙二醛浓度为(28.9±6.1) ng/L、(15.0±9.2) μmol/L，均高于INS缓解组患儿的(18.0±5.9) ng/L、(7.3±5.4) μmol/L及对照组健康儿童的(16.2±7.6) ng/L、(8.8±5.1) μmol/L，并且差异均有统计学意义(P<0.001、P＝0.022，P<0.001、P＝0.004)。⑥INS缓解组患儿与对照组健康儿童上述21项指标比较，差异均无统计学意义(P>0.05)。⑦60例受试儿PBMC中Tfh百分比与血浆IgG水平、浆细胞百分比，均呈正相关关系(r＝0.692、0.809，P<0.001)。INS初发组20例患儿血浆丙二醛浓度与mTOR、mTORC1mRNA表达水平，亦均呈正相关关系(r＝0.627、P＝0.003，r＝0.794、P<0.001)。

结论

INS患儿PBMC中Tfh百分比下降影响B细胞分化成熟，可能是导致患儿低IgG血症的原因之一。血浆IL-2水平升高和高脂血症导致的mTOR和mTORC1过表达，可能是抑制INS患儿Tfh分化的重要原因。

关键词: 肾病综合征, 丙种球蛋白缺乏血症, 免疫，体液, 免疫球蛋白G, T淋巴细胞，辅助诱导, 雷帕霉素靶蛋白复合物1, 雷帕霉素靶蛋白复合物2, 儿童
Objective

To investigate the possible mechanism of hypogammaglobulinemia in pediatric idiopathic nephrotic syndrome (INS).

Methods

A total of 40 children with steroid-sensitive INS from September 2015 to October 2016 in Shenzhen Children′s Hospital were selected as research subjects. According to pathogenetic condition, they were divided into new onset INS group (n=20) and remission INS group (n=20). Meanwhile, in the same hospital there were 20 undergoing physical examination children with age matching the research subjects were enrolled into control group (n=20). The percentage of follicular helper T cell(Tfh, CD4+ CXCR5+ ICOShigh T cell), naive B cells (CD19+ CD27-IgD+ B cells), pre-transformed memory B cells (CD19+ CD27+ IgD+ B cells), transformed memory B cells (CD19+ CD27+ IgD- B cells) and plasma cells (CD19+ CD27+ IgD-CD38high B cells) in peripheral blood mononuclear cell (PBMC) were analyzed by flow cytometry (FCM). Reverse transcription-polymerase chain reaction (RT-PCR) was performed to analyze mRNA expression level of CD4+ T cells related genes in peripheral blood. Plasma level of interleukin (IL)-2 and plasma concentrations of malondialdehyde were detected by enzyme linked immunosorbent assay and immunofluorescence adsorption test, respectively. Clinical data were compared among three groups and pairwise compared between two groups using one-way ANOVA and least significant difference (LSD)-t test, respectively. And Pearson′s correlation analysis was used to analyze the correlation between some of two indexes.The study was approved by the Ethics Committee of Shenzhen Children′s Hospital (Approval date: April 11, 2016), and all guardians of children signed the informed consent forms for clinical study.

Results

①The serum levels of total protein and albumin, also plasma immunoglobulin (Ig)G, IgG1, IgG2 and IgG4 of children with INS in new onset INS group were lower than those of control group, while serum total cholesterol concentration was higher than that of control group, and the differences were statistically significant (P<0.05). ②The percentage of Tfh in PBMC of children with INS in new onset INS group was (3.9±1.2)%, which was lower than that of (5.2±1.1)% in control group and (4.9±1.2)% in remission INS group, and the differences were statistically significant (P=0.001, P=0.021). ③The percentage of transformed memory B cells and plasma cells in PBMC of children with INS in new onset INS group were (8.4±3.6)% and (7.5±2.0)%, which were lower than those of (11.6±2.7)% and (11.4±3.9)% in remission INS group and (12.2±3.7)% and (12.5±3.4)% in control group, and the differences were statistically significant (all P<0.001). ④The mRNA expression levels of CD4+ T cells related genes of B lymphocyte induced maturation protein (Blimp)-1, IL-2Rα, IL-2Rβ, IL-2Rγ, phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), mammalian target of rapamycin (mTOR) and mechanistic target of rapamycin complex (mTORC)1 of children with INS in new onset INS group were (3.2±1.1), (14.4±5.7), (18.5±4.6), (7.2±1.7), (10.3±3.6), (2.2±0.3), (1.84±0.68) and (7.2±1.4), which were higher than those of (2.4±1.1), (10.5±2.5), (15.5±3.5), (5.5±1.1), (8.5±2.2), (1.8±0.5), (1.44±0.29) and (6.1±1.2) in remission INS group and (2.4±1.1), (10.3±5.5), (14.6±4.8), (5.6±2.5), (1.56±0.42), (2.4±1.1), (10.3±5.5) and (14.6±4.8) in control group; while mRNA expression level of B-cell lymphoma (BCL)-6 in new onset INS group was (1.22±0.29), which was lower than that of (1.49±0.35) in remission INS group and (1.56±0.42) in control group, and all the differences above were statistically significant (all P<0.05). ⑤Plasma level of IL-2 and concentration of malondialdehyde of children with INS in new onset INS group were (28.9±6.1) ng/L, (15.0±9.2) μmol/L, which were higher than those of (18.0±5.9) ng/L, (7.3±5.4) μmol/L in remission INS group and (16.2±7.6) ng/L, (8.8±5.1) μmol/L in control group, and the differences were statistically significant(P<0.001, P=0.022; P<0.001, P=0.004). ⑥There were no significant differences between remission INS group and control group in all these above mentioned 21 indexes (P>0.05). ⑦ The percentage of Tfh in PBMC of 60 participants were positively correlated with their plasma IgG levels and the percentage of plasma cells (r=0.692, 0.809; P<0.001). Plasma concentration of malondialdehyde of 20 children with INS in new onset INS group were positively correlated with mRNA expression levels of mTOR and mTORC1 genes (r=0.627, P=0.003; r=0.794, P<0.001).

Conclusions

Decrease of percentage of Tfh in PBMC of children with INS effected on differentiation and maturation of B cells, which might be one of the reasons that resulted in hypogammaglobulinemia. Over expression of mTOR and mTORC1 caused by increased plasma IL-2 level and hyperlipidemia could be an important reason to inhibit the differentiation of Tfh in children with INS.

Key words: Nephrotic syndrome, Agammaglobulinemia, Immunity, humoral, Immunoglobulin G, T-lymphocytes, helper-inducer, Mechanistic target of rapamycin complex 1, Mechanistic target of rapamycin complex 2, Child
表1 本研究CD4＋T细胞相关基因引物信息
基因 正向引物(5′→3′) 反向引物(5′→3′) 退火温度(℃) 扩充片段长度(bp)
BCL-6 ATGAGGAGTTTCGGATGTC CCTCTTCTGGGATTGTTTCC 58 177
Blimp-1 CTTAAATTGTGAGCCAAGCCATGTA GTAGGCAAGGGTGCCCAATC 60 148
mTOR ATGCTTGGAACCGGACCTG TCTTGACTCATCTCGGAGTT 60 173
mTORC1 GCGAATTGAGACGGACTTTGA GAGTCTGCGCGTGTTGTTTAC 60 90
mTORC2 CAGAAACCCTAAAGCTGCATTGTAA GTCTGTTCAGTGACCTACAAACACC 60 180
IL-2Rα ATGAATGAGGTCCCAGGCAGAG TAGTGCAGGCCAAATTCAGGGTA 60 126
IL-2Rβ AGGACCTTGGGTTCCCAATACA ATTCAGGACCCTATGGCAGGAG 60 187
IL-2Rγ TGAACCACTGTTTGGAGCACTTG GTAGCGTTTCTGCCCATCCAC 60 122
PI3K AGCATTGGGACCTCACATTACACA ACTGGAAACACAGTCCATGCACATA 60 138
AKT CTTGCTTTCAGGGCTGCTCA TACACGTGCTGCCACACGATAC 60 117
GAPDH CAAGAAGGTGGTGAAGCAGG AGGTGGAGGAGTGGGTGTCG 54～60 110
表2 3组受试儿一般临床资料比较
组别 例数 性别[例数(%)] 年龄(月，±s) 血清总蛋白水平(g/L, ±s) 血清白蛋白水平(g/L, ±s) 血清总胆固醇浓度(μmol/L, ±s)
男 女
INS初发组 20 12(60.0) 8(40.0) 38±16 41.5±5.4 16.0±5.0 10.5±2.7
INS缓解组 20 13(65.0) 7(35.0) 41±18 66.2±4.9 42.9±2.2 4.5±1.4
对照组 20 14(70.0) 6(30.0) 40±15 68.3±3.9 43.6±3.2 4.3±1.5
检验值 ? χ2＝12.000 F＝0.103 F＝192.141 F＝341.150 F＝66.836
P值 ? 0.285 0.902 <0.001 <0.001 <0.001
表3 3组受试儿血浆免疫球蛋白水平比较(g/L，±s)
组别 例数 总IgG IgG1 IgG2 IgG3 IgG4 IgA IgM
INS初发组 20 3.2±1.9 3.9±1.7 1.2±0.7 0.34±0.16 0.26±0.19 1.2±0.8 1.8±0.5
INS缓解组 20 8.2±2.1 5.7±1.7 1.7±1.0 0.40±0.24 0.54±0.45 1.1±0.7 1.4±0.5
对照组 20 8.4±2.2 6.8±2.2 2.1±0.9 0.43±0.25 0.81±0.79 1.1±0.9 1.3±0.5
F值 ? 8.157 6.388 4.690 0.604 3.016 0.023 0.867
P值 ? <0.001 0.001 0.007 0.616 0.039 0.978 0.467
图1 3组受试儿外周血中的Tfh流式细胞术检测示意图[图1A：CD4＋T细胞的SSC与FSC散点图；图1B：CD4＋CXCR5＋T细胞(方框内)；图1C：3组受试儿PBMC中Tfh百分比(对照组为5.2%、INS初发组为3.9%、INS缓解组为4.9%)]
图2 60例受试儿PBMC中Tfh百分比与血浆IgG水平相关性分析的散点图
图3 3组受试儿外周血单个核细胞中不同分化阶段B细胞流式细胞术检测示意图[图3A：SSC与FSC散点图；图3B：外周血中B细胞(方框内)；图3C：3组受试儿FBMC中不同分化阶段B细胞百分比；图3D：3组受试儿PBMC中浆细胞百分比]
图4 60例受试儿PBMC中Tfh百分比与浆细胞百分比相关性分析的散点图
表4 3组受试儿外周血单个核细胞中不同分化阶段B细胞百分比比较(%，±s)
组别 例数 初始B细胞 转化前记忆B细胞 转化后记忆B细胞 浆细胞
INS初发组 20 62.9±11.2 12.9±8.1 8.4±3.6 7.5±2.0
INS缓解组 20 67.7±6.1 13.7±8.4 11.6±2.7 11.4±3.9
对照组 20 69.2±10.5 13.5±9.8 12.2±3.7 12.5±3.4
F值 ? 1.185 0.468 16.928 41.622
P值 ? 0.313 0.629 <0.001 <0.001
表5 3组受试儿外周血CD4＋T细胞相关基因mRNA相对表达水平比较(±s)
组别 例数 BCL-6基因(×10－2) Blimp-1基因(×10－2) IL-2Rα基因(×10－3) IL-2Rβ基因(×10－3) IL-2Rγ基因(×10－1)
①INS初发组 20 1.22±0.29 3.2±1.1 14.4±5.7 18.5±4.6 7.2±1.7
②INS缓解组 20 1.49±0.35 2.4±1.1 10.5±2.5 15.5±3.5 5.5±1.1
③对照组 20 1.56±0.42 2.4±1.1 10.3±5.5 14.6±4.8 5.6±2.5
总体比较 ? ? ? ? ? ?
? F值 ? 3.382 10.439 6.404 4.027 4.418
? P值 ? 0.027 <0.001 0.004 0.024 0.016
组间两两比较P值a ? ? ? ? ? ?
? ① vs ② ? 0.019 0.001 0.007 0.041 0.010
? ① vs ③ ? 0.018 <0.001 0.001 0.009 0.011
? ② vs ③ ? 0.723 0.408 0.296 0.521 0.922
组别 例数 PI3K基因(×10－3) AKT基因(×10－3) mTOR基因(×10－3) mTORC1基因(×10－2) mTORC2基因(×10－1)
①INS初发组 20 10.3±3.6 2.2±0.3 1.84±0.68 7.2±1.4 1.9±0.7
②INS缓解组 20 8.5±2.2 1.8±0.5 1.44±0.29 6.1±1.2 1.6±0.5
③对照组 20 7.5±2.5 1.8±0.4 1.30±0.45 5.5±1.7 1.7±0.6
总体比较 ? ? ? ? ? ?
? F值 ? 6.561 9.782 4.622 6.999 1.768
? P值 ? 0.003 <0.001 0.014 0.002 0.180
组间两两比较P值a ? ? ? ? ? ?
? ① vs ② ? 0.015 0.004 0.028 0.018 0.072
? ① vs ③ ? 0.001 <0.001 0.005 <0.001 0.169
? ② vs ③ ? 0.306 0.209 0.643 0.166 0.626
图5 20例INS初发组患儿血浆丙二醛浓度与mTOR、mTORC1基因mRNA相对表达水平相关性分析的散点图
表6 3组受试儿血浆IL-2水平及丙二醛浓度比较(±s)
组别 例数 血浆IL-2水平(ng/L) 血浆丙二醛浓度(μmol/L)
INS初发组 20 28.9±6.1 15.0±9.2
INS缓解组 20 18.0±5.9 7.3±5.4
对照组 20 16.2±7.6 8.8±5.1
F值 ? 21.659 4.944
P值 ? <0.001 0.011
[1]
Eddy AA, Symons JM. Nephrotic syndrome in childhood[J]. Lancet, 2003, 362(9384): 629-639. DOI: 10.1016/S0140-6736(03)14184-0.
[2]
Kemper MJ, Altrogge H, Ganschow R, et al. Serum levels of immunoglobulins and IgG subclasses in steroid sensitive nephrotic syndrome[J]. Pediatr Nephrol, 2002, 17(6): 413-417. DOI: 10.1007/s00467-001-0817-7.
[3]
Peterson PA, Berggård I. Urinary immunoglobulin components in normal, tubular, and glomerular proteinuria: quantities and characteristics of free light chains, IgG, IgA, and Fcγ fragment[J]. Eur J Clin Invest, 1971, 1(4): 255-264. DOI: 10.1111/eci.1971.1.4.255.
[4]
Heslan JM, Lautie JP, Intrator L, et al. Impaired IgG synthesis in patients with the nephrotic syndrome[J]. Clin Nephrol, 1982, 18(3): 144-147.
[5]
Schaerli P, Willimann K, Lang AB, et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function[J]. J Exp Med, 2000, 192(11): 1553-1562. DOI: 10.1084/jem.192.11.1553.
[6]
Ma CS, Deenick EK. Human T follicular helper (Tfh) cells and disease[J]. Immunol Cell Biol, 2014, 92(1): 64-71. DOI: 10.1038/icb.2013.55.
[7]
Ballesteros-Tato A, León B, Graf BA, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation[J]. Immunity, 2012, 36(5): 847-856. DOI: 10.1016/j.immuni.2012.02.012.
[8]
Nurieva RI, Podd A, Chen Y, et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function[J]. J Biol Chem, 2012, 287(14): 11234-11239. DOI: 10.1074/jbc.M111.324046.
[9]
Ray JP, Staron MM, Shyer JA, et al. The interleukin-2-mTORC1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells[J]. Immunity, 2015, 43(4): 690-702. DOI: 10.1016/j.immuni.2015.08.017.
[10]
Glazer HP, Osipov RM, Clements RT, et al. Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling[J]. Cell Cycle, 2009, 8(11): 1738-1746. DOI: 10.4161/cc.8.11.8619.
[11]
Sarbassov DD, Sabatini DM. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex[J]. J Biol Chem, 2005, 280(47): 39505-39509. DOI: 10.1074/jbc.M506096200.
[12]
中华医学会儿科学分会肾脏学组. 儿童激素敏感、复发/依赖肾病综合征诊治循证指南(2016)[J]．中华儿科杂志，2017, 55(10): 729-732. DOI: 10.3760/cma.j.issn.0578-1310.2017.10.003.
[13]
Craft JE. Follicular helper T cells in immunity and systemic autoimmunity[J]. Nat Rev Rheumatol, 2012, 8(6): 337-347. DOI: 10.1038/nrrheum.2012.58.
[14]
Good-Jacobson KL, Szumilas CG, Chen L, et al. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells[J]. Nat Immunol, 2010, 11(6): 535-542. DOI: 10.1038/ni.1877.
[15]
Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes[J]. Nat Rev Immunol, 2013, 13(2): 118-132. DOI: 10.1038/nri3383.
[16]
Tsai LM, Yu D. Follicular helper T-cell memory: establishing new frontiers during antibody response[J]. Immunol Cell Biol, 2014, 92(1): 57-63. DOI: 10.1038/icb.2013.68.
[17]
Laplante M, Sabatini DM. mTOR signaling in growth control and disease[J]. Cell, 2012, 149(2): 274-293. DOI: 10.1016/j.cell.2012.03.017.
[18]
Delgoffe GM, Pollizzi KN, Waickman AT, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2[J]. Nat Immunol, 2011, 12(4): 295-303. DOI: 10.1038/ni.2005.
[19]
Tan P, Wang YJ, Li S, et al. The PI3K/Akt/mTOR pathway regulates the replicative senescence of human VSMCs[J]. Mol Cell Biochem, 2016, 422(1-2): 1-10. DOI: 10.1007/s11010-016-2796-9.
[20]
Sahin K, Orhan C, Tuzcu M, et al. Orally administered lycopene attenuates diethylnitrosamine-induced hepatocarcinogenesis in rats by modulating Nrf-2/HO-1 and Akt/mTOR pathways[J]. Nutr Cancer, 2014, 66(4): 590-598. DOI: 10.1080/01635581.2014.894092.
[21]
Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment[J]. Immunity, 2009, 30(6): 832-844. DOI: 10.1016/j.immuni.2009.04.014.
[22]
Powell JD, Pollizzi KN, Heikamp EB, et al. Regulation of immune responses by mTOR[J]. Annu Rev Immunol, 2012, 30: 39-68. DOI: 10.1146/annurev-immunol-020711-075024.
[23]
Zeng H, Cohen S, Guy C, et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation[J]. Immunity, 2016, 45(3): 540-554. DOI: 10.1016/j.immuni.2016.08.017.
[1] 陶宏宇, 叶菁菁, 俞劲, 杨秀珍, 钱晶晶, 徐彬, 徐玮泽, 舒强. 右心声学造影在儿童右向左分流相关疾病中的评估价值[J/OL]. 中华医学超声杂志（电子版）, 2024, 21(10): 959-965.
[2] 刘琴, 刘瀚旻, 谢亮. 基质金属蛋白酶在儿童哮喘发生机制中作用的研究现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(05): 564-568.
[3] 向韵, 卢游, 杨凡. 全氟及多氟烷基化合物暴露与儿童肥胖症相关性研究现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(05): 569-574.
[4] 王雅楠, 刘丹, 曹正浓, 贾慧敏. 儿童迟发性先天性膈疝患儿的临床诊治特点分析[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(04): 410-419.
[5] 陈桂华, 钟小玲, 谢雨, 王慧, 谢江, 杨涛毅. 合并肝脏疾病特殊健康状态儿童疫苗预防接种及时性临床分析[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(04): 431-439.
[6] 雷丽莉, 于晓峰, 王媛媛, 徐迎军. 人鼻病毒感染喘息急性发作儿童外周血NLRP3和TLR4水平及临床意义[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(04): 440-445.
[7] 张梦思, 麻艺群, 蒙礼娟, 朱辉, 付晋凤. 压力手套与指蹼加压带及泡沫型硅凝胶贴膜联合应用于儿童瘢痕性并指术后的效果观察[J/OL]. 中华损伤与修复杂志(电子版), 2024, 19(04): 329-334.
[8] 赖全友, 高远, 汪建林, 屈士斌, 魏丹, 彭伟. 三维重建技术结合腹腔镜精准肝切除术对肝癌患者术后CD4+、CD8+及免疫球蛋白水平的影响[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 651-654.
[9] 刘冉佳, 崔向丽, 周效竹, 曲伟, 朱志军. 儿童肝移植受者健康相关生存质量评价的荟萃分析[J/OL]. 中华移植杂志(电子版), 2024, 18(05): 302-309.
[10] 丁荷蓓, 王珣, 陈为国. 七氟烷吸入麻醉与异丙酚静脉麻醉在儿童腹股沟斜疝手术中的应用比较[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(05): 570-574.
[11] 中华医学会器官移植学分会, 中华医学会外科学分会外科手术学学组, 中华医学会外科学分会移植学组, 华南劈离式肝移植联盟. 劈离式供肝儿童肝移植中国临床操作指南[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 593-601.
[12] 刘军, 丘文静, 孙方昊, 李松盈, 易述红, 傅斌生, 杨扬, 罗慧. 在体与离体劈离式肝移植在儿童肝移植中的应用比较[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(05): 688-693.
[13] 张琛, 秦鸣, 董娟, 陈玉龙. 超声检查对儿童肠扭转缺血性改变的诊断价值[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(06): 565-568.
[14] 陈晓胜, 何佳, 刘方, 吴蕊, 杨海涛, 樊晓寒. 直立倾斜试验诱发31 秒心脏停搏的植入心脏起搏器儿童一例并文献复习[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(05): 488-494.
[15] 曹亚丽, 高雨萌, 张英谦, 李博, 杜军保, 金红芳. 儿童坐位不耐受的临床进展[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(05): 510-515.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号