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学科主题: 药学
题名:
A Dual-Role of Gu-4 in Suppressing HMGB1 Secretion and Blocking HMGB1 Pro-Inflammatory Activity during Inflammation
作者: Zhou, HuiTing1; Ji, XueMei1; Wu, Yun1; Xuan, Ju1; Qi, ZhiLin1; Shen, Lei1; Lan, Lei1,3; Li, Qing2; Yin, ZhiMin1,3; Li, ZhongJun2; Zhao, ZhiHui1,3
刊名: PLOS ONE
发表日期: 2014-03-06
DOI: 10.1371/journal.pone.0089634
卷: 9, 期:3
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: MOBILITY GROUP BOX-1 ; CHROMATIN PROTEIN HMGB1 ; TUMOR-NECROSIS-FACTOR ; DOUBLE-BLIND ; SYSTEMIC INFLAMMATION ; LACTOSYL DERIVATIVES ; MONOCLONAL-ANTIBODY ; CYTOKINE ACTIVITY ; CELL RECRUITMENT ; CONTROLLED-TRIAL
英文摘要:

Background: High mobility group box 1(HMGB1) was first recognized as a nuclear protein that increased the chromatin remodeling and regulates transcription of many genes. In recent years, HMGB1 has been identified as a critical "late′′ proinflammatory mediator due to its unique secretion pattern and lethal effects in sepsis. Therefore, preventing the active release and inhibiting the pro-inflammatory activity of HMGB1 become promising strategies for the treatment of sepsis. Here, we reported the therapeutic effects of Gu-4, a lactosyl derivative, on sepsis and the underlying molecular mechanisms.

Methodology/Principal Findings: In an experimental rat model of sepsis caused by cecal ligation and puncture (CLP), Gu-4 administration prominently attenuated lung injury and improved the survival of the septic animals, which was positively correlated with the decrease of the serum HMGB1 level. Using RAW264.7 macrophage cell line, we further showed that Gu-4 significantly suppressed the lipopolysaccharide (LPS)-induced release and cytoplasmic translocation of HMGB1. Moreover, Gu-4 not only dose-dependently attenuated recombinant human (rhHMGB1)-induced production of TNF-alpha, IL-6, and IL-1 beta in THP-1 cells, but also greatly inhibited the adhesion of rhHMGB1-challenged THP-1 cells to HUVECs. Analyses of flow cytometry demonstrated that Gu-4 could effectively reduce the activation of CD11b elicited by rhHMGB1. Western blot analyses revealed that Gu-4 treatment could partially block the rhHMGB1-induced activation of ERK and NF-kappa B signalings. Meanwhile, CD11b knockdown also obviously attenuated the rhHMGB1-induced phosphorylations of ERK and IKK alpha/beta.

Conclusions/Significance: Taken together, our results suggest that Gu-4 possesses a therapeutic potential in the treatment of sepsis probably via inhibiting the LPS-induced release of HMGB1 from macrophages and via suppressing the proinflammatory activity of HMGB1.

语种: 英语
所属项目编号: 81273232 ; 91213301 ; 164320H106
项目资助者: Natural Science Foundation of China (NSFC) ; Priority Academic Program Development of Jiangsu Higher Education Institutions
WOS记录号: WOS:000332483600017
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/55839
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Nanjing Normal Univ, Coll Life Sci, Jiangsu Prov Key Lab Mol & Med Biotechnol, Nanjing, Jiangsu, Peoples R China
2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100871, Peoples R China
3.Collaborat Innovat Ctr Biomed Publ Hyg Emergency, Nanjing, Jiangsu, Peoples R China

Recommended Citation:
Zhou, HuiTing,Ji, XueMei,Wu, Yun,et al. A Dual-Role of Gu-4 in Suppressing HMGB1 Secretion and Blocking HMGB1 Pro-Inflammatory Activity during Inflammation[J]. PLOS ONE,2014,9(3).
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