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FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 1605-1623页

作者： Zhifeng Huang Tongtong Pan Liang Xu lu Shi Xiong Ma Liya Zhou luyao Wang jiaojiao Wang Guoqing Zhu Dazhi Chen Lingtao Song Xiaomin Pan Xiaodong Wang Xiaokun Li Yongde luo Yongping Chen Hepatology Diagnosis and Treatment Center Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseasesthe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325035China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)&School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325035China School of Laboratory Medicine and Life Sciences Wenzhou Medical University&Key Laboratory of Laboratory MedicineMinistry of EducationWenzhou Medical UniversityWenzhou 325035China Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200001China Hangzhou Medical College Hangzhou 311300China

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine;however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

关键词： Fibroblast growthfactor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca^(2+)/Calmodulin dependent protein

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考虑导引头耦合作用的带落角约束制导律设计

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航空兵器 2023年第1期30卷 44-50页

作者：鲁娇娇董蒙郭正玉中国空空导弹研究院河南洛阳471009 空装驻洛阳地区第一军事代表室河南洛阳471009 空基信息感知与融合全国重点实验室河南洛阳471009

针对制导火箭弹弹体与导引头之间的动力学耦合等问题,提出了一种带落角约束的制导律设计方法。首先,考虑到飞行过程中导引头和弹体之间的耦合作用,建立了方位俯仰捷联式导引头的二自由度数学模型以及制导火箭弹的六自由度数学模型,然后... 详细信息

针对制导火箭弹弹体与导引头之间的动力学耦合等问题,提出了一种带落角约束的制导律设计方法。首先,考虑到飞行过程中导引头和弹体之间的耦合作用,建立了方位俯仰捷联式导引头的二自由度数学模型以及制导火箭弹的六自由度数学模型,然后,考虑到实际工程应用中导引头与弹体之间的动力学耦合因素,将导引头框架偏转角作为制导信息,设计了一种带落角约束的制导律,实现最大毁伤效果。最后,通过仿真分析验证了所设计的带落角约束制导律能够在保证落角精度的同时降低脱靶量。

关键词：制导火箭弹方位俯仰捷联式导引头落角约束比例制导律动力学滞后

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Combined anti-HBV and anti-PD1 gRNA/cas9 produces a synergistic antiviral effect in HBV infection

Combined anti-HBV and anti-PD1 gRNA/cas9 produces a synergis...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： Zhen Shuai Hua Ling Liu Yunhui lu jiaojiao Chen Wei Zhao Le Li Xu the First Affiliated Hospital Xi'an Jiaotong University Rongchang Campus southwest University Department of Pharmacology and Toxicology Beijing Institute of Radiation Medicine

Objective Currently, no licensed therapy can thoroughly eradicate hepatitis B virus(HBV) from th e body, including interferon αand inhibitors of HBV reverse-transcription. Recently, clustered regu larly interspaced short palindromic repeat(CRISPR) systems, originally identified in bacteria and archaea, have been found to have effect on the pre-existing HBV covalently closed circular DN A. Targeted HBV with unique CRISPR/Cas9 therapy results in objective responses in HBV treatm ent, however the responses may be short. In contrast, treatment with immune checkpoint inhibitor s results in a lower responses rate, but the responses tend to be more durable. Based on these fi ndings, we hypothesized that surface antigen(HBs Ag)-encoding region of HBV-targeted therapy may synergize with the PD-1 pathway blockade to enhance anti-HBV activity. Method To test hypothesis, we described the effects of the CRISPR/Cas9 that was targeted to th e surface antigen(HBs Ag)-encoding region of HBV and PD1 to explore the response of transgeni c mice. HBs Ag in the media of the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay;HBV DNA levels were assessed by fluorogenic quantitative polymerase c hain reaction, immune phenotypes and cytokines expression of human dendritic cells was detecte d by flow cytometry and PCR, and HBs Ag expression in the livers of the mice was assessed by a n immunohistochemical assay. Result The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. HBs Ag secreted i n mouse serum was reduced by CRISPR/Cas9 treatment;Immunohistochemistry showed almo st no HBs Ag-positive cells in the liver tissues of CRISPR/Cas9-treated mice, especially in the co mbined groups The CRISPR/Cas9 system efficiently produced mutations in HBV *** For the first time, our studies demonstrate potent synergistic effects of combination t herapy using HBV-targeted therapy and immune checkpoint blockade PD1 could strengthen the i mmune response and

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Tuna dark muscle peptides modulate host iron metabolism in the intestine through the gut microbiota and ameliorate iron deficiency anemia

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Food Science and Human Wellness 2024年

作者： jiaojiao Han Jiayi Xiong Zhixiang Bai Yang Qin Chenyang lu Jun Zhou Ye Li Tinghong Ming Zhen Zhang Xiurong Su State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products， Ningbo University School of Marine Science， Ningbo University

Iron deficiency anemia (IDA) is a nutritional deficiency disease with a high incidence rate worldwide. Bioactive peptides are safe and effective， have multiple functions and can serve as potential candidates for alleviating IDA. In this study， the anti-anemia effects of tuna dark muscle peptides were explored in a diet-induced IDA mouse model. The results showed that tuna dark muscle peptides alleviated the IDA phenotype， oxidative stress and iron metabolism. In addition， tuna dark muscle peptides reversed gut microbiota dysbiosis in IDA mice. Furthermore， the transplanted fecal microbiota from tuna dark muscle peptide-treated mice also alleviated IDA symptoms and regulated iron metabolism and the gut microbiota， indicating that the anti-anemic effects were at least partially mediated by the gut microbiota. Thus， we identified a new and safe prebiotic material to alleviate IDA and provided ideas for the development of peptides. At the same time， these data also provided a theoretical basis for fecal microbiota transplantation (FMT) to alleviate IDA.

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德国国际组织人才培养与输送的“螺旋模式”研究

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比较教育研究 2021年第12期43卷 79-89页

作者：陆娇娇贾文键北京外国语大学德语学院北京100089

国际组织人才培养与输送对于国家参与全球治理具有重要意义。德国政府在国际组织人才发展上秉持一种长期导向的"螺旋"理念,并在实践中形成了特色鲜明的国际组织人才螺旋发展模式,为本国公民铺就一条内外联通、螺旋上升的可持续职业发展... 详细信息

国际组织人才培养与输送对于国家参与全球治理具有重要意义。德国政府在国际组织人才发展上秉持一种长期导向的"螺旋"理念,并在实践中形成了特色鲜明的国际组织人才螺旋发展模式,为本国公民铺就一条内外联通、螺旋上升的可持续职业发展路径。从整体来看,螺旋发展模式涵括人才孵化、派出历练、回巢哺育、晋升与联结四个主要阶段。在每个阶段也都有着相应的配套措施和工作机制。该理念及模式打破了一种单线型的职业发展路线,强调人员和知识的多向流动,更好融合了国家、组织和个人层面的利益。"螺旋模式"在德国国际组织人才培养实践中取得了较好成效,德国在国际组织中的人员代表性近年来从"量"和"质"上都有了明显改善。

关键词：国际组织人才培养人才输送螺旋模式德国

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Protective effect of marine animals hydrolysis-peptides on adjuvant-induced arthritis in mice by gut microbiota and SCFAs

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Food Science and Human Wellness 2024年

作者： Zhen Zhang Shasha Tang Ziyan Wang jiaojiao Han Jun Zhou Chenyang lu Bin Liu Xiaoling Sun Rongxian Yu Rixin Wang Xiurong Su School of Marine Science， Ningbo University State Key Laboratory for Quality and Safety of Argo-products， Ningbo University Vigor Technology Group

Marine fauna provides a plentiful repository of peptides and bioactive proteins. Peptides and proteins isolated from marine animals have been studied and applied in the development of food supplements， drugs， and cosmeceutical products because of their special bioactivities， such as anti-inflammatory and antioxidant effects This study focused on exploring the alleviating effects of five major marine animal-derived peptides (Apostichopus japonicus， Acaudina leucoprocta， Melanogrammus aeglefinus， Phascolosoma esculenta and Rhopilema esculentum) on adjuvant-induced arthritis (AIA). The treatment with five marine animals-derived peptides downregulated the expression levels of pro-inflammatory cytokines of IL-1β， IL-17 and TNF-α in the bones of the mice with AIA and alleviated the rough surface of bone tissues significantly. A. japonicus-treatment ameliorates inflammation by restoring NF-κB pathway in AIA mice. High-throughput sequencing of the gut microbiota based on 16S rRNA sequencing revealed that A. japonicus peptide-treated AIA mice showed alterations and imbalance of intestinal flora and an increased abundance of Lactobacillus and Clostridium. Furthermore， metabolomic analysis showed that the level of SCFAs in the feces was enhanced to different degrees in mice treated with five major marine animal-derived peptides. Taken together， we propose that major marine animal-derived peptides can alleviate arthritis by improving the imbalance in the gut flora and increasing SCFA production to varying degrees.

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共振呼吸反馈训练对射击运动员心率变异性及压力应对和情绪调节的影响

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中国运动医学杂志 2018年第9期37卷 725-731页

作者：安燕郑樊慧陆姣姣上海体育科学研究所上海200030

目的:探讨共振呼吸反馈训练对运动员压力调节和情绪的影响。方法:将30名射击运动员随机分为实验组(15名:男7人,女8人)和对照组(15名:男8人,女7人),对实验组运动员实施4周的共振呼吸反馈训练干预,对照组则无任何干预。对训练前后运动员... 详细信息

目的:探讨共振呼吸反馈训练对运动员压力调节和情绪的影响。方法:将30名射击运动员随机分为实验组(15名:男7人,女8人)和对照组(15名:男8人,女7人),对实验组运动员实施4周的共振呼吸反馈训练干预,对照组则无任何干预。对训练前后运动员的心率变异性指标[总功率(TP)、高频段功率(HF)、低频段功率(LF)]、心理指标[简式心境状态量表(POMS)]、血清皮质醇指标进行比较分析。结果:共振呼吸反馈训练后,实验组运动员TP(P0.05),但训练后男运动员的疲劳量表得分低于训练前水平,差异具有统计学意义(P<0.05);实验组女运动员血清皮质醇水平低于训练前,差异具有统计学意义(P<0.05)。结论:共振呼吸反馈训练能够改善运动员的心理和生理状态,帮助运动员更好应对压力,改善紧张和抑郁情绪,缓解疲劳,是进行自我管理的有效工具,可以作为运动员日常的心理监测和长期的心理训练手段。

关键词：共振呼吸射击运动员压力情绪

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浅谈临床医学专业毕业生就业工作体会

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浙江中医药大学学报 2007年第2期31卷 227-228页

作者：卢佼佼浙江中医药大学第二临床医学院杭州310053

在全国高校毕业生总体就业形势趋紧形势下,中医药院校的临床医学毕业生面临更大的挑战。分析了当前临床医学专业的就业形势,结合本校临床医学专业毕业生的就业工作现状,总结了中医药院校临床医学专业毕业生就业工作的几点体会。

关键词：中医药临床医学专业毕业生就业

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高等教育自学考试专本衔接模式的问题与对策研究

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中国考试 2014年第11期 51-55页

作者：路娇娇河南大学教育科学学院

在高等教育自学考试专本衔接模式中,存在课程衔接不到位、师资缺乏、培养目标单一等问题,为此应当科学衔接课程,加强师资队伍建设,严格监督助学机构,实现高等教育自学考试复合型人才培养的目标。

关键词：自学考试专本衔接

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Modulation of gut microbiota and serum metabolome by Apostichopus japonicus derived oligopeptide in high-fructose diet-induced hyperuricemia in mice

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Food Science and Human Wellness 2024年

作者： Jun Zhou Ziyan Wang Zhixuan Zhang jiaojiao Han Ying Feng Jing Zhang Zhen Zhang Ye Li Tinghong Ming Chenyang lu Rixin Wang Xiurong Su School of Marine Science， Ningbo University Faculty of Food Science， Zhejiang Pharmaceutical College Key Laboratory of Aquacultural Biotechnology Ministry of Education， Ningbo University College of Life Sciences， Tonghua Normal University State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products， Ningbo University

Fructose consumption has risen dramatically in recent decades due to the use of sucrose and high fructose corn syrup in beverages and processed foods， contributing to rising rates of hyperuricemia. The purpose of this experiment was to explore the anti-hyperuricemia effects of an active oligopeptide (GPSGRP) derived from sea cucumber in fructose induced hyperuricemia mouse model， and to clarify the underlying mechanism in sight of gut microbiota and serum metabolites. Peptide GPSGRP treatment rebalanced uric acid metabolism and alleviated inflammatory response in mice. In addition， treatment with GPSGRP decreased the abundance of Bacteroides and Proteobacteria at the phylum level， Muribaculum， Prevotella and Bacteroides at the genus level， and inhibited the related pathways of purine metabolism and glycolysis/gluconeogenesis metabolism. Moreover， serum metabolites， including linoleic acid， indole and its derivatives， arachidonic acid and uridine， as well as related metabolic pathways， such as tricarboxylic acid cycle， ketone production and sugar production， were altered in response to GPSGRP treatment. This study provides a valuable reference for the application and development of marine biological peptides in uric acid management.

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