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Pei Zhang, Jie-Si Chen, Qi-Ye Li, Long-Xiang Sheng, Yi-Xing Gao, Bing-Zheng Lu, Wen-Bo Zhu, Xiao-Yu Zhan, Yuan Li, Zhi-Bing Yuan, Gang Xu, Bi-Tao Qiu, Min Yan, Chun-Xue Guo, You-Qiong Wang, Yi-Jun Huang, Jing-Xia Zhang, Fu-Yu Liu, Zhong-Wei Tang, Sui-Zhen Lin, David N. Cooper, Huan-Ming Yang, Jian Wang, Yu-Qi Gao, Wei Yin, Guo-Jie Zhang, Guang-Mei Yan. Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys. Zoological Research, 2020, 41(1): 3-19. doi: 10.24272/j.issn.2095-8137.2020.012
Citation: Pei Zhang, Jie-Si Chen, Qi-Ye Li, Long-Xiang Sheng, Yi-Xing Gao, Bing-Zheng Lu, Wen-Bo Zhu, Xiao-Yu Zhan, Yuan Li, Zhi-Bing Yuan, Gang Xu, Bi-Tao Qiu, Min Yan, Chun-Xue Guo, You-Qiong Wang, Yi-Jun Huang, Jing-Xia Zhang, Fu-Yu Liu, Zhong-Wei Tang, Sui-Zhen Lin, David N. Cooper, Huan-Ming Yang, Jian Wang, Yu-Qi Gao, Wei Yin, Guo-Jie Zhang, Guang-Mei Yan. Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys. Zoological Research, 2020, 41(1): 3-19. doi: 10.24272/j.issn.2095-8137.2020.012

doi: 10.24272/j.issn.2095-8137.2020.012

Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

Funds: This study was supported by the National Natural Science Foundation of China (81773711) to W. Y., Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13000000) to G. J. Z., Science and Technology Program of Guangzhou, China (201704020103) to W. Y., Introduction of Innovative R&D Team Program of Guangdong Province (2013Y104), Leading Talent Project in Science and Technology of Guangzhou Development District (2019-L002), and National Major Scientific and Technological Special Project for“Significant New Drugs Development” (2016ZX09101026) to S.Z.L., and Key Projects of the Military Science and Technology PLA (AWS14C007 and AWS16J023) to Y.Q.G
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    #Authors contributed equally to this work
  • Figure  1.  Acute HH-induced behavioral and cerebral impairments were attenuated by PROG and TRIOL treatments

    A: Experimental procedure for HH treatment of cynomolgus monkeys (HH group, n=6). Vertical bars along y-axis indicate medical definitions of high, very high, and extreme altitudes. Horizontal bars represent duration spent at each altitude. Blood drop and brain icons indicate altitudes and

    Figure  2.  Transcriptomic dynamics of WBCs in response to acute HH.

    A: Principal component analysis (PCA) using genes robustly expressed in at least one of six HH stages (A–F). Colors denote stages of HH at which WBC samples were collected, as described in Figure 1A. B: Numbers of differentially expressed genes (DEGs) between stage A and each of the other five stages. C: Expression patterns of DEGs in three HH-responding modules, shown as log2-transformed reads per kilobase of transcript per million mapped reads (RPKM) fold changes of DEGs in each stage compared to stage A. Red and light blue lines indicate expression patterns of individual DEGs up- and down-regulated by HH, respectively. Bold lines show mean expression levels of all up- or down-regulated DEGs, with error bars indicating SD. UP and DOWN indicate exact number of up- or down-regulated DEGs by HH in each module. D: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in three HH-responding modules. Only significantly enriched pathways with a false discovery rate (FDR)-adjusted P-value of <0.05 were plotted. Dot color denotes P-value after FDR correction, and dot size denotes ratio of DEGs versus all expressed genes in each pathway. Different background colors denote classification of pathways. E: Interaction of pathways and symptoms according to reported articles. Blue color denotes pathways of impulse module; red color denotes pathways of late-responding module. Solid arrow line denotes reported direct interaction; dashed arrow line denotes reported associated relationship. F: Local co-expression network revealing genes in vitamin D receptor (VDR) complex as hub genes. Dark blue circles denote DEGs in impulse module; red circles denote genes in VDR complex and HIF1A as hub genes.

    Figure  3.  Regulation of WBC transcriptomic dynamics by PROG and TRIOL

    A: Principal component analysis (PCA) using genes robustly expressed in at least one of nine sample groups (i.e., no-drug treated group, PROG-treated group, and TRIOL-treated group in stages A, D, and F, respectively). Colors denote HH stages at which WBC samples were collected during HH+drug experiments, as described in Figure 1B, whereas shapes denote treatments. B: Number of differentially expressed genes (DEGs) between drug-treated and untreated groups in each HH stage studied. Stage A samples from both PROG and TRIOL groups were collected prior to drug injection; thus, DEGs of A/PROG*-A and A/TRIOL*-A reflect random variations between two groups of experimental monkeys rather than drug-specific effects. C: Erythrocyte-associated DEGs up-regulated by PROG. Red color and arrows denote genes up-regulated by PROG. D: Expression patterns and functions of TRIOL-induced DEGs in three HH-responding modules, shown as log2-transformed reads per kilobase of transcript per million mapped reads (RPKM) fold changes of DEGs in each sample group compared to stage A samples without TRIOL treatment. Light red and blue lines indicate expression patterns of individual DEGs in TRIOL-treated and untreated groups, respectively. Bold lines show mean expression levels of all TRIOL up- or down-regulated DEGs in each group, with error bars representing SD. UP and DOWN indicate exact number of up- or down-regulated DEGs by TRIOL in each module. Text below each module outlines functions associated with TRIOL-induced DEGs, with up and down arrows denoting gene-associated functions up- or down-regulated by TRIOL, respectively.

    Figure  4.  Transcriptomic changes in frontal cortex in response to acute HH, PROG, and TRIOL

    A: Principal component analysis (PCA) using genes robustly expressed in at least one of four sample groups (normobaric normoxia [NN], HH, HH+ PROG, and HH+TRIOL). Colors denote sample group. B: Expression changes of HH-induced differentially expressed genes (DEGs) after PROG or TRIOL treatment, shown as log2-transformed reads per kilobase of transcript per million mapped reads (RPKM) fold changes of DEGs in each sample group compared to NN group. HH-induced DEGs are categorized into strongly responsive genes (SRGs), weakly responsive genes (WRGs), and non-responsive genes (NRGs) according to their degree of expression level recovery after drug treatment. Red and light blue lines denote expression patterns of individual DEGs up- and down-regulated by HH, respectively. Bold lines show mean expression levels of all HH up- or down-regulated DEGs in each group, with error bars representing SD. Percentages of SRGs and WRGs versus all HH-induced DEGs are presented above each plot. C: Expression changes of drug DEGs after PROG or TRIOL treatment, shown as log2-transformed RPKM fold changes of DEGs in each sample group compared to NN group. Red and light blue lines denote expression patterns of individual DEGs up- or down-regulated by drugs, respectively. Bold lines show mean expression levels of all DEGs up- or down-regulated by drugs in each group, with error bars representing SD. D: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in HH-induced or drug-recovered DEGs. Only significantly enriched pathways with a false discovery rate (FDR)-adjusted P-value of <0.05 are plotted. In HH DEGs, SRGs, WRGs, and NRGs, red and blue dots denote pathways enriched in DEGs up- and down-regulated by HH, respectively. In drug DEGs (PROG DEGs and TRIOL DEGs), red and blue dots denote pathways enriched in DEGs up- and down-regulated by drugs, respectively. Color intensity of dot indicates level of significance, and size of dot denotes ratio of DEGs versus all expressed genes in each pathway. E: Postulated regulation of excitatory glutamate signaling by TRIOL. Rectangles represent proteins of TRIOL DEGs involved in glutamate signaling pathway. Blue colors denote down-regulation by HH. Gene symbols of DEGs associated with each protein in the pathway are listed below. F: Time-course showing intraneuronal calcium [Ca2+]i in primary cultured rat cortical neurons stimulated by glutamate with different doses of TRIOL. Glutamate stimulation was added at the fiftieth second in the experiment.

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  • 收稿日期:  2019-12-02
  • 录用日期:  2019-12-11
  • 网络出版日期:  2019-12-13
  • 刊出日期:  2020-01-18

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