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NRF1-mediated microglial activation triggers high-altitude cerebral edema

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Journal of Molecular Cell Biology 2022年第5期14卷 43-56页

作者： Xueting Wang Guijuan Chen baolan Wan Zhangji Dong Yan Xue Qianqian Luo Dan Wang Yapeng Lu li Zhu Institute of Special Environmental Medicine Nantong UniversityNantong 226019China Co-nnovation Center of Neuroregeneration iangsu Key Laboratory of NeuroregenerationNantong UniversityNantong 226019China Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Nantong UniversityNantong 226019China

High-altitude cerebral edema(HACE)is a potentially fatal encephalopathy associated with a time-dependent exposure to the hypobaric hypoxia of altitude.The formation of HACE is affected by both vasogenic and cytotoxic edema.The over-activated microglia potentiate the damage of blood-brain barrier(BBB)and exacerbate cytotoxic edema.In light with the activation of microglia in HACE,we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE.In in vivo experiments,by exposing mice to hypobaric hypoxia(7000 m above sea level)to induce HACE model,we found that microglia were activated and migrated to blood vessels.Microglia depletion by PLX5622 obviously relieved brain edema.In in vitro experiments,we found that hypoxia induced cultured microglial activation,leading to the destruction of endothelial tight junction and astrocyte swelling.Up-regulated nuclear respiratory factor 1(NRF1)accelerated pro-inflammatory factors through transcriptional regulation on nuclearfactorkappa B p65(NF-kB p65)and mitochondrial transcription factorA(TFAM)in activated microglia under hypoxia.NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1(CAV-1)and adaptorrelated protein complex 2 subunit beta(AP2B1).The present study reveals a new mechanism in HACE:hypoxia over-activates microglia through up-regulation of NRF1,which both induces inflammatory response through transcriptionally activating NF-kB p65 and TFAM,and enhances phagocytic function through up-regulation of CAV-1 and AP2B1;hypoxia-activatedmicroglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE.

关键词： high-altitude cerebral edema hypoxia microglia inflammation nuclear respiratory factor 1 endocytosis

The expression of vascular endothelial growth factor(VEGF)/endostatin(ES)and VEGF receptor 2(VEGFR2)/ES is associated with NSCLC prognosis

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Oncology and Translational Medicine 2021年第4期7卷 149-154页

作者： Yuan Yang Baohua Lu Baolan Li Weiying li Mei Jiang Wentao Yue Qunhui Wang Tongmei Zhang General Department of Medicine Beijing Chest HospitalCapital Medical UniversityBeijing 101149China Laboratory of Cell Biotechnology Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijing 101149China

Objective The aim of our study was to detect the expression of angiogenesis inhibitory proteins and angiogenesis promotive proteins in the postoperative tumor tissue of non-small cell lung cancer(NSCLC)patients.We also investigated the relationship of protein expression with clinical characteristics and prognosis.Methods We examined the expression of vascular endothelial growth factor(VEGF),VEGF receptor 2(VEGFR2),and endostatin(ES)proteins in 255 specimens resected from NSCLC patients,using immune histochemistry(IHC).We then evaluated the relationships between the expression of the three proteins and clinical characteristics such as stage,histological type,differentiation,gender,tobacco use,and age.According to the value of VEGF/ES,we divided the cohort into angiogenesis-promoting group A,angiogenesis-inhibiting group A,and balance group A.The survival differences in the three groups were evaluated to determine the prognostic value of VEGF/ES.Similarly,we tested the prognostic value of VEGFR2/ES.Results VEGF-positive expression was observed in 93 patients(36.4%).VEGF expression was not correlated with the clinical characteristics.VEGFR2-positive expression was observed in 103 patients(40.4%).The expression of VEGFR2 was correlated with the clinical stage(χ^(2)=21.414,P=0.045)and histological type(χ^(2)=26.911,P=0.008).ES-positive expression was observed in 140 patients(54.9%).The expression of ES was correlated with the clinical stage(χ^(2)=26.504,P=0.009).When evaluating the prognostic values of VEGF/ES and VEGFR2/ES,the prognosis of the angiogenesis balance group was similar to that of the angiogenesis-inhibiting group.The minimum survival time was observed in the angiogenesis-promoting group.Conclusion VEGF/ES and VEGFR2/ES in resected tumors have prognostic value in postoperative NSCLC patients.The survival time of the population with predominant angiogenic factors was short.

关键词： non-small cell lung cancer(NSCLC) angiogenesis clinical characteristics prognosis

免疫检查点抑制剂在驱动基因阳性晚期非小细胞肺癌中的应用进展

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中国肺癌杂志 2021年第3期24卷 188-195页

作者：张同梅(综述) 李宝兰(审校) 首都医科大学附属北京胸科医院综合科北京市结核病胸部肿瘤研究所北京101149

随着肿瘤精准医学的发展,驱动基因阳性非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受靶向治疗极大地改善了生存和预后,但不管是哪代靶向药物均不可避免的会经历耐药,患者会面临无靶可用的局面。免疫检查点抑制剂因其特有的... 详细信息

随着肿瘤精准医学的发展,驱动基因阳性非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受靶向治疗极大地改善了生存和预后,但不管是哪代靶向药物均不可避免的会经历耐药,患者会面临无靶可用的局面。免疫检查点抑制剂因其特有的长拖尾效应,能给部分晚期NSCLC患者带来长生存。越来越多的研究显示免疫治疗同样可为部分驱动基因阳性NSCLC患者带来获益,但免疫治疗介入的时机、治疗方案的选择以及预测生物标记物等问题仍不十分明确,值得进一步探讨。

关键词：肺肿瘤驱动基因免疫检查点抑制剂预测

The GW2-WG1-OsbZIP47 pathway controls grain size and weight in rice

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Molecular Plant 2021年第8期14卷 1266-1280页

作者： Jianqin Hao Dekai Wang Yingbao Wu Ke Huang Penggen Duan Na li Ran Xu Dali Zeng Guojun Dong baolan Zhang limin Zhang Dirk Inze Qian Qian Yunhai li State Key Laboratory of Plant Cell and Chromosome Engineering CAS Centre for Excellence in Molecular Plant BiologyInstitute of Genetics and Developmental BiologyThe Innovative Academy of Seed DesignChinese Academy of SciencesBeijing 100101China College of life Sciences and Medicine Zhejiang Sci-Tech UniversityHangzhou 310018China State Key Laboratory of Rice Biology China National Rice Research InstituteHangzhou 310006China Ghent University Department of Plant Biotechnology and Bioinformatics9052 GhentBelgium VIB Center for Plant Systems Biology 9052 GhentBelgium University of Chinese Academy of Sciences Beijing 100039China

Regulation of seed size is a key strategy for improving crop yield and is also a basic biological question.However,the molecular mechanisms by which plants determine their seed size remain elusive.Here,we report that the GW2-WG1-OsbZIP47 regulatory module controls grain width and weight in rice.WG1,which encodes a glutaredoxin protein,promotes grain growth by increasing cell proliferation.Interestingly,WG1 interacts with the transcription factor OsbZIP47 and represses its transcriptional activity by associating with the transcriptional co-repressor ASP1,indicating that WG1 may act as an adaptor protein to recruit the transcriptional co-repressor.In contrary,OsbZIP47 restricts grain growth by decreasing cell proliferation.Further studies reveal that the E3 ubiquitin ligase GW2 ubiquitinates WG1 and targets it for degradation.Genetic analyses confirm that GW2,WG1,and OsbZIP47 function in a comm on pathway to control grain growth.Taken together,ourfindi ngs reveal a genetic and molecular framework for the control of grain size and weight by the GW2-WG1-OsbZIP47 regulatory module,providing new targets for improving seed size and weight in crops.

关键词： rice WG1 GW2 OsbZIP47 grain size and weight cell proliferation

Icotinib, an EGFR-TKI, for the treatment of brain metastases in non-small cell lung cancer:a retrospective study

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Oncology and Translational Medicine 2016年第6期2卷 268-274页

作者： Qunhui Wang Hua Zheng Ying Hu Baohua Lu Fanbin Hu Hongmei Zhang Baolan Li Department of Oncology Beijing Chest Hospital Capital Medical University

Objective Treatment of brain metastases from non-small cell lung cancer(NSCLC) is a challenge because of the poor prognosis. Icotinib is a new type of oral epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI) used in the treatment of advanced NSCLC. The aim of this study was to evaluate the efficacy of icotinib in NSCLC patients with brain metastasis.Methods This study reviewed records of 51 NSCLC patients with brain metastases who took icotinib 125 mg, 3 times a day. Response rate, progression free survival, and overall survival were analyzed. SPSS software version 17.0 was used for univariate analysis, and Cox regression analysis to analyze factors affecting survival. Results Thirty-six cases had partial response, 6 cases had stable disease, and 10 cases had progressive disease. In 31 cases, EGFR gene mutation test were performed. EGFR was mutated in 26 cases and was with wild-type in 5 cases. In patients with EGFR mutations, 23 patients responded to icotinib [the disease control rate(DCR) was 88.5%], significantly higher than in patients with wild-type EGFR(1 patient, DCR 20%)(P = 0.005). The overall median progression-free survival(PFS) was 7.6 months. PFS was longer in the patients with EGFR mutations than in those with wild type EGFR(7.8 months vs 1.2 months, P = 0.03). The overall median overall survival(OS) time was 10.7 months. OS was longer in patients with EGFR mutations than in those with wild type EGFR(15.1 months vs 6.7 months, P = 0.003). The main side effects of the treatment were skin rash and diarrhea; no stage 3 or 4 toxic effects occurred. Univariate analysis demonstrated that OS was related to sex, Eastern Cooperative Oncology Group performance status(ECOG PS), smoking history, and EGFR mutation. Multivariate analysis showed that OS was independently related to sex, ECOG PS, and EGFR mutations.Conclusion Icotinib has a favorable effect on NSCLC patients with brain metastases harboring EGFR mutations. Icotinib can be a new choice of treatment for brain metastases in patients w

关键词： non-small cell lung cancer(NSCLC) brain metastases icotinib epidermal growth factor receptor(EGFR)

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宠物疾病与人类健康

福建畜牧兽医 2020年第6期42卷 30-32页

作者：李宝兰福建省三明市农业农村局动物疫病预防控制中心福建三明365000

随着中国经济水平的发展和人们生活方式的改变,宠物作为人类理想的伴侣出现在很多城市家庭中,与宠物相关的人畜共患病也逐渐引起人们的重视。为避免和减少该类疾病给人类生活带来不必要的安全隐患,本文就几种重要的宠物人畜共患病的流... 详细信息

随着中国经济水平的发展和人们生活方式的改变,宠物作为人类理想的伴侣出现在很多城市家庭中,与宠物相关的人畜共患病也逐渐引起人们的重视。为避免和减少该类疾病给人类生活带来不必要的安全隐患,本文就几种重要的宠物人畜共患病的流行情况、诊断和防治等作介绍,以期提高大家对该类疾病的认识,防患未然。

关键词：宠物人畜共患病防治

Investigation of therapeutic modalities of G719X, an uncommon mutation in the EGFR gene in non-small cell lung cancer

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Oncology and Translational Medicine 2019年第2期5卷 91-97页

作者： Hua Zheng Yuan Gao Zan liu Zhe Qian Tongmei Zhang Jie li Hongmei Zhang Qunhui Wang Fanbin Hu Baolan Li Department of Medical Oncology Beijing Chest Hospital Capital Medical University

Objective G719 X is the most frequently seen uncommon mutation of the epidermal growth factor receptor(EGFR) gene, which is a point mutation at exon 18 with three common subtypes, G719 A/G719 C/G719 S. This study explored the clinicopathological characteristics of the G719 X mutation and investigated the efficacy of EGFR-tyrosine kinase inhibitor(TKI) treatment and chemotherapy in patients with the G719 X mutation; the survival rate after these different treatment modalities were then analyzed in order to provide evidence for clinical treatment.Methods Clinical data of 41 patients with the G719 X mutation admitted in the Beijing Chest Hospital, Capital Medical University from September 2014 to July 2018, were collected and the EGFR mutations were detected by amplification refractory mutation system-polymerase chain reaction(ARMS-PCR). The clinicopathological characteristics of the G719 X mutation were analyzed, and the relationship among the G719 X mutation, the efficacy of different treatment modalities, and the progression-free survival(PFS) was analyzed. Results Of the 41 cases, 24(58.5%) were G719 X single mutations and 17(41.5%) were compound mutations, including G719 X/S768 I, G719 X/L861 Q, G719 X/19 del, and G719 X/c-Met compound mutation. The objective response rate(ORR) of first-line EGFR-TKI therapy was 50%(6/12), the disease control rate(DCR) was 83.3%(10/12), and the median PFS(mPFS) was 9 months. After resistance to EGFR-TKI in the previous treatment, the ORR(71.4%, 5/7) and DCR(100%, 7/7) were still high following EGFR-TKIs, by an mPFS of 8 months. The ORR of chemotherapy was 33.3%(2/6), the DCR was 100%(6/6), and the mPFS was 6 months. Conclusion G719 X is an uncommon mutation of the EGFR gene and is sensitive to many EGFR-TKIs. It can be treated with the second-or third-generation EGFR-TKIs after resistance to the first-generation EGFR-TKIs. G719 X mutation also showed favorable effect to chemotherapy.

关键词： lung neoplasms EGFR uncommon mutation G719X target therapy

Control of Grain Size and Weight by the OsMKKK10-OsM KK4-OsMAPK6 Signaling Pathway in Rice

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Molecular Plant 2018年第6期11卷 860-873页

作者： Ran Xu Penggen Duan Haiyue Yu Zhengkui Zhou baolan Zhang Ruci Wang Jing li Guozheng Zhang Shangshang Zhuang Jia Lyu Na li Tuanyao Chai Zhixi Tian Shanguo Yao Yunhai li State Key Laboratory of Plant Cell and Chromosome Engineering Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China CAS Centre for Excellence in Molecular Plant Biology Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China State Key Laboratory of Plant Genomics National Centre for Plant Gene Research (Beijing) Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100039 China

Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4- OsMAPK6 signaling pathway positively regulates grain size and weight in rice. In rice, loss of OsMKKKIO function results in small and light grains, short panicles, and semi-dwarf plants, while overexpression of constitutively active OsMKKK10 （CA-OsMKKK10） results in large and heavy grains, long panicles, and tall plants. OsMKKK10 interacts with and phosphorylates OsMKK4. We identified an OsMKK4 gain-of-func- tion mutant （large11-1D）that produces large and heavy grains. OsMKK4A227T encoded by the large11-1D allele has stronger kinase activity than OsMKK4. Plants overexpressing a constitutively active form of OsMKK4 （OsMKK4oDD） also produce large grains. Further biochemical and genetic analyses revealed that OsMKKK10, OsMKK4, and OsMAPK6 function in a common pathway to control grain size. Taken together, our study establishes an important genetic and molecular framework for OsMKKK10-OsMKK4- OsMAPK6 cascade-mediated control of grain size and weight in rice.

关键词： Oryza sativa grain size MAPK signaling cell proliferation

Genetic regulation of seed size in plants

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Genetic regulation of seed size in plants