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Microinjection of a growth factor cocktail affects activated microglia in the neocortex of adult rats

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Neural Regeneration Research 2020年第9期15卷 1709-1715页

作者： Ruo-Xu Liu Jie Ma Ning Guo Shao-Jun Liu State Key Laboratory of Proteomics and Department of Neurobiology Institute of Military Cognition and Brain Sciences

Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factors can activate multiple signaling pathways in central nervous system microglia and can regulate their immune effects, but whether growth factors can affect the morphological characteristics and ultrastructure of microglia has not been reported. After microinjecting 300 nL of a growth factor cocktail, including 10 μg/mL epidermal growth factor, 10 μg/mL basic fibroblast growth factor, 10 μg/mL hepatocyte growth factor and 10 μg/mL insulin-like growth factor into adult rat cortex, we found that the number of IBA1-positive microglia around the injection area increased significantly, indicating local activation of microglia. All CD68-positive labeling co-localized with IBA1 in microglia. Cell bodies and protrusions of CD68-positive cells were strongly attached to or were engulfing neurons. Characteristic huge phagosomes were observed in activated phagocytes by electron microscopy. The phagosomes generally included non-degraded neuronal protrusions and mitochondria, yet they contained no myelin membrane or remnants, which might indicate selective phagocytosis by the phagocytes. The remnant myelin sheath after phagocytosis still had regenerative ability and formed "myelin-like" structures around phagocytes. These results show that microinjection of a growth factor cocktail into the cerebral cortex of rodents can locally activate microglia and induce selective phagocytosis of neural structures by phagocytes. The study was approved by the Institute of laboratory Animal Science, Beijing Institute of Basic Medical Sciences(approval No. IACUC-AMMS-2014-501) on June 30, 2014.

关键词： adult neocortex CD68 IBA1 microinjection phagocyte selective phagocytosis ultrastructure

TGF-β signaling in aortic aneurysm: another round of controversy

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Journal of Genetics and Genomics 2010年第9期37卷 583-591页

作者： Fuyu Lin Xiao Yang State Key Laboratory of Proteomics Genetic Laboratory of Development and Diseases Institute of Biotechnology Beijing 100071 China

Aortic aneurysm （AA） is a common health problem with high mortality and no effective drugs. Transforming growth factor-β （TGF-β） superfamily members regulate various cellular processes, and TGF-β signaling has key roles in development, tissue homeo- stasis, and diseases. Interest in the role of TGF-β signaling in the pathogenesis of AAs has recently emerged, particularly since genetic studies demonstrated an association between gene mutations in components of TGF-β signaling and AAs. However, paradoxical discoveries have implicated dysregulated TGF-β signaling in aneurysm formation, complicating the precise functional role for TGF-β in aneurysm development and progression. Furthermore, interventions targeting towards TGF-β signaling using losartan, which may represent a suitable therapeutic option for AAs, were subject to skepticism especially because of conflicting experimental results obtained from TGF-β antibody treatment without knowledge of the underlying mechanism. We propose a TGF-β aneurysm paradox, which would provide a good opportunity for the development of genetic mouse models of AA. These models would be used to clarify the mechanisms underlying TGF-β signaling, which would translate into novel pharmacologic therapies based on the new molecular discoveries.

关键词： aneurysm TGF-β signaling mouse model

Odontoblast β-catenin signaling regulates fenestration of mouse Hertwig's epithelial root sheath

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Science China(Life Sciences) 2015年第9期58卷 876-881页

作者： ZHANG Ran TENG Yan ZHU Liang LIN JingTing YANG Xiao YANG Guan LI TieJun Department of Oral Pathology Peking University School and Hospital of Stomatology State Key Laboratory of Proteomics Genetic Laboratory of Development and Diseases Institute of Biotechnology

The interaction between Hertwig's epithelial root sheath(HERS) and the adjacent mesenchyme is vitally important in mouse tooth root development. We previously generated odontoblast-specific Ctnnb1(encoding β-catenin) deletion mice, and demonstrated that odontoblast β-catenin signaling regulates odontoblast proliferation and differentiation. However, the role of odontoblast β-catenin signaling in regulation of HERS behavior has not been fully investigated. Here, using the same odontoblast-specific Ctnnb1 deletion mice, we found that ablation of β-catenin signaling in odontoblasts led to aberrant HERS formation. Mechanistically, odontoblast-specific Ctnnb1 deletion resulted in elevated bone morphogenetic protein 7(Bmp7) expression and reduced expression of noggin and follistatin, both of which encode extracellular inhibitors of BMPs. Furthermore, the levels of phosphorylated Smad1/5/8 were increased in HERS cells. In vitro tissue culture confirmed that BMP7 treatment disrupted the HERS structure. Taken together, we demonstrated that odontoblast β-catenin signaling may act through regulation of BMP signaling to maintain the integrity of HERS cells.

关键词：成牙本质细胞骨形态发生蛋白信号调节小鼠 β-catenin 上皮细胞特异性开窗

Potential protective effects of Clostridium butyricum on experimental gastric ulcers in mice

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World Journal of Gastroenterology 2015年第27期21卷 8340-8351页

作者： Fang-Yan Wang Jia-Ming Liu Hai-Hua Luo Ai-Hua Liu Yong Jiang state key laboratory of Organ Failure Research Nanfang Hospital key laboratory of Transcriptomics and proteomics of Ministry of Education of China Key Laboratory of Proteomics of Guangdong Province Department of Pathophysiology Southern Medical University Department of Pathophysiology Wenzhou Medical University School of Environmental Science and Public Health Wenzhou Medical University

AIM: To investigate the effects of Clostridium butyricum(C. butyricum) on experimental gastric ulcers(GUs) induced by alcohol, restraint cold stress, or pyloric ligation in mice, respectively.METHODS: One hundred and twenty mice were randomly allocated into three types of gastric ulcer models(n = 40 each), induced by alcohol, restraint cold stress, or pyloric ligation. In each GU model, 40 mice were allocated into four groups(n = 10 each): the sham control group; model group(GU induction without pretreatment); C. butyricum group(GU induction with C. butyricum pretreatment); and Omeprazole group(GU induction with Omeprazole pretreatment). Theeffects of C. butyricum were evaluated by examining the histological changes in the gastric mucosal erosion area, the activities of superoxide dismutase(SOD) and catalase(CAT), the level of malondialdehyde(MDA), and the contents of interleukin(IL)-1b, tumor necrosis factor(TNF)-α, leukotriene B4(LTB4) and 6-keto-PGF-1α(degradation product of PGI2) in the gastric tissue.RESULTS: Our data showed that C. butyricum significantly reduced the gastric mucosal injury area and ameliorated the pathological conditions of the gastric mucosa. C. butyricum not only minimized the decreases in activity of SOD and CAT, but also reduced the level of MDA in all three GU models used in this study. The accumulation of IL1-b, TNF-α and LBT4 decreased, while 6-keto-PGF-1α increased with pretreatment by C. butyricum in all three GU models.CONCLUSION: Our data demonstrated the protective effects of pretreatment with C. butyricum on antioxidation and anti-inflammation in different types of GU models in mice. Further studies are needed to explore its potential clinical benefits.

关键词： Inflammation Probiotics Oxidative stress Clostridium butyricum Gastric ulcer

Three-dimensional reconstruction of light microscopy image sections： present and future

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Frontiers of Medicine 2015年第1期9卷 30-45页

作者： Yuzhen Wang Rui Xu Gaoxing Luo Jun Wu Institute of Burn Research Southwest Hospital State Key Laboratory of Trauma Burns and Combined lnjury Chongqing Key Laboratory for Diseases Proteomics the Third Military Medical University Chongqing 400038 China

Three-dimensional （3D） image reconstruction technologies can reveal previously hidden microstruc-tures in human tissue. However, the lack of ideal, non-destructive cross-sectional imaging techniques is still a problem. Despite some drawbacks, histological sectioning remains one of the most powerful methods for accurate high-resolution representation of tissue structures. Computer technologies can produce 3D representations of interesting human tissue and organs that have been serial-sectioned, dyed or stained, imaged, and segmented for 3D visualization. 3D reconstruction also has great potential in the fields of tissue engineering and 3D printing. This article outlines the most common methods for 3D tissue section reconstruction. We describe the most important academic concepts in this field, and provide critical explanations and comparisons. We also note key steps in the reconstruction procedures, and highlight recent progress in the development of new reconstruction methods.

关键词： microtomy 3D imaging computer-assisted image processing 3D printing tissue scaffold

Recent advances in CRISPR-based genome editing technology and its applications in cardiovascular research

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Military Medical Research 2023年第6期10卷 862-880页

作者： Zhen-Hua Li Jun Wang Jing-Ping Xu Jian Wang Xiao Yang State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein SciencesBeijing Institute of LifeomicsBeijing 100071China Yaneng BIOScience(Shenzhen)Co. Ltd.Shenzhen 518102GuangdongChina

The rapid development of genome editing technology has brought major breakthroughs in the fields of life science and medicine. In recent years, the clustered regularly interspaced short palindromic repeats(CRISPR)-based genome editing toolbox has been greatly expanded, not only with emerging CRISPR-associated protein(Cas) nucleases, but also novel applications through combination with diverse effectors. Recently, transposon-associated programmable RNA-guided genome editing systems have been uncovered, adding myriads of potential new tools to the genome editing toolbox. CRISPR-based genome editing technology has also revolutionized cardiovascular research. Here we first summarize the advances involving newly identified Cas orthologs, engineered variants and novel genome editing systems, and then discuss the applications of the CRISPR-Cas systems in precise genome editing, such as base editing and prime editing. We also highlight recent progress in cardiovascular research using CRISPR-based genome editing technologies, including the generation of genetically modified in vitro and animal models of cardiovascular diseases(CVD) as well as the applications in treating different types of CVD. Finally, the current limitations and future prospects of genome editing technologies are discussed.

关键词： Genome editing CRISPR-Cas system Base editing Prime editing Transposon-associated genome editing Cardiovascular disease Heart Blood vessel Gene therapy

Central projections and connections of lumbar primary afferent fibers in adult rats:effectively revealed using Texas red-dextran amine tracing

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Neural Regeneration Research 2017年第10期12卷 1695-1702页

作者： Shi-de Lin Tao Tang Ting-bao Zhao Shao-jun Liu State Key Laboratory of Proteomics Department of NeurobiologyBeijing Institute of Basic Medical Sciences Department of Spinal Cord Injury the General Hospital of Jinan Military Command

Signals from lumbar primary afferent fibers are important for modulating locomotion of the hind-limbs.However,silver impregnation techniques,autoradiography,wheat germ agglutinin-horseradish peroxidase and cholera toxin B subunit-horseradish peroxidase cannot image the central projections and connections of the dorsal root in detail.Thus,we injected 3-k Da Texas red-dextran amine into the proximal trunks of L4 dorsal roots in adult rats.Confocal microscopy results revealed that numerous labeled arborizations and varicosities extended to the dorsal horn from T12–S4,to Clarke＇s column from T10–L2,and to the ventral horn from L1–5.The labeled varicosities at the L4 cord level were very dense,particularly in laminae I–Ⅲ,and the density decreased gradually in more rostral and caudal segments.In addition,they were predominately distributed in laminae I–IV,moderately in laminae V–VⅡ and sparsely in laminae VⅢ–X.Furthermore,direct contacts of lumbar afferent fibers with propriospinal neurons were widespread in gray matter.In conclusion,the projection and connection patterns of L4 afferents were illustrated in detail by Texas red-dextran amine-dorsal root tracing.

关键词： nerve regeneration spinal cord injury dorsal root central projection connection Texas red-dextran amine neural regeneration

Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1853-1866页

作者： Yi Qian Meimei Zhao Qinghua Han Jingkang Wang Lixi Liao Heng Yang Dan Liu Pengfei Tu Hong Liang Kewu Zeng state key laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China proteomics laboratory Medical and Healthy Analytical CenterPeking University Health Science CenterBeijing 100191China

Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins.Thus,targeting myosin eactin molecular motor is considered as a promising strategy for anti-cancer.In this study,we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular motor.Here,we found J13 could directly target myosin-9(MYH9)eactin molecular motor to promote mitochondrial fission progression,and markedly inhibited cancer cells survival,proliferation and migration.Mechanism study revealed that J13 impaired MYH9 eactin interaction to inactivate molecular motor,and caused a cytoskeleton-dependent mitochondrial dynamics imbalance.Moreover,stable isotope labeling with amino acids in cell culture(SILAC)technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9 eactin molecular motor to mitochondrial fission.Taken together,we reported the first natural small-molecule directly targeting MYH9 eactin molecular motor for anti-cancer translational research.Besides,our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.

关键词： Anti-cancer Liver hepatocellular carcinoma Mitochondrial fission Small molecule Target identification Molecular motor MYH9 HSPA9

Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity

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Signal Transduction and Targeted Therapy 2021年第3期6卷 975-987页

作者： Ke-Wu Zeng Jing-Kang Wang Li-Chao Wang Qiang Guo Ting-Ting Liu Fu-Jiang Wang Na Feng Xiao-Wen Zhang Li-Xi Liao Mei-Mei Zhao Dan Liu Yong Jiang Pengfei Tu state key laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China proteomics laboratory Medical and Healthy Analytical CenterPeking University Health Science CenterBeijing 100191China

Mitochondrial fusion/hission dynamics plays a fundamental role in neuroprotection;however,there is till a severe lack oftherapeutic targets for this biological process.Here,we found that the naturally derived small molecule echinacoside(ECH)signifhcantly promotes mitochondrial fusion progression.ECH selectively binds to the previously uncharacterized casein kinase 2(CK2)α'subunit(CK2a)as a direct cellular target,and genetic knockdown of CK2α'abolishes ECH-mediated mitochondrial fusion.Mechanistically,ECH allosterically regulates CK2α'conformation to recruit basic transcription factor 3(BTF 3)to form a binary proteincomplex.Then,the CK2α'/BTF3 complex facilitatesβ-catenin nuclear translocation to activate TCF/AEF transcription factors andstimulate transcription of the mitochondrial fusion gene Mfn2.trikingly,in a mouse middle cerebral artery occlusion(MCAO)model,ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2expression in wild-type but not CK2α'^(+/-)mice.Taken together,our findings reveal,for the first time,that CK2 is essential forpromoting mitochondrial fusion in a Wnt/B-catenin-dependent manner and suggest that pharmacologically targeting CK2 is apromising therapeutic strategy for ischemic stroke.

关键词： injuries cerebral Small