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TREM-2 Drives Development of Multiple sclerosis by Promoting Pathogenic Th17 Polarization

Neuroscience Bulletin 2024年第1期40卷 17-34页

作者： siying Qu shengfeng Hu Huiting Xu Yongjian Wu siqi Ming Xiaoxia Zhan Cheng Wang Xi Huang Center for Infection and Immunity and Guangdong Provincial Engineering research Center of Molecular Imaging The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China The state Key Laboratory of Respiratory Disease Guangdong Provincial Key Laboratory of Allergy and Clinical ImmunologyThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China Department of Laboratory Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China Division of Nephrology Department of Medicinethe Fifth Affliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

Multiple sclerosis(Ms)is a neuroinflammatory demyelinating disease,mediated by pathogenic T helper 17(Th17)cells.However,the therapeutic effect is accompa-nied by the fluctuation of the proportion and function of Th17 cells,which prompted us to find the key regulator of Th17 differentiation in Ms.Here,we demonstrated that the triggering receptor expressed on myeloid cells 2(TREM-2),a modulator of pattern recognition receptors on innate immune cells,was highly expressed on pathogenic CD4-positive T lymphocyte(CD4^(+)T)cells in both patients with Ms and experimental autoimmune encephalomyelitis(EAE)mouse models.Conditional knockout of Trem-2 in CD4^(+)T cells significantly alleviated the disease activity and reduced Th17 cell infiltration,activation,differentiation,and inflammatory cytokine production and secretion in EAE mice.Furthermore,with Trem-2 knockout in vivo experiments and in vitro inhibitor assays,the TREM-2/zeta-chain associated protein kinase 70(ZAP70)/signal transducer and activator of transcription 3(sTAT3)signal axis was essential for Th17 activation and differentiation in EAE progression.In conclusion,TREM-2 is a key regulator of pathogenic Th17 in EAE mice,and this sheds new light on the potential of this therapeutic target for Ms.

关键词： Multiple sclerosis Experimental autoimmune encephalomyelitis T helper 17 Triggering receptor expressed on myeloid cells 2

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Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability

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Acta Pharmaceutica sinica B 2022年第10期12卷 3877-3890页

作者： Xueping Lei Zhan Li Yihang Zhong songpei Li Jiacong Chen Yuanyu Ke sha Lv Lijuan Huang Qianrong Pan Lixin Zhao Xiangyu Yang Zisheng Chen Qiudi Deng Xiyong Yu guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China Department of Respiratory and Critical Care Medicine the Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalQingyuan 511518China GMU-GIBH Joint school of Life sciences Guangzhou Medical UniversityGuangzhou 511436China

Metastasis is crucial for the mortality of non-small cell lung carcinoma(NsCLC) patients.The epithelial-mesenchymal transition(EMT) plays a critical role in regulating tumor metastasis.Glioma-associated oncogene 1(Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NsCLC metastasis have not yet been identified. Herein,we reported Gli1 promoted NsCLC metastasis. High Gli1 expression was associated with poor survival of NsCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NsCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NsCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NsCLC. Collectively, our study reveals that Gli1 is a critical regulator for NsCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NsCLC.

关键词： Non-small cell lung carcinoma Metastasis Epithelialemesenchymal transition Glioma-associated oncogene 1 Promote snail Protein stability GANT-61

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Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

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Cancer Biology & Medicine 2022年第7期19卷 1061-1077页

作者： Leyi Yao Qian Zhao Ding Yan Ziying Lei Yali Hao Jinghong Chen Qian Xue Xiaofen Li Qingtian Huang Daolin Tang QPing Dou Xin Chen Jinbao Liu affiliated Cancer hospital&Institute of guangzhou medical university Guangzhou 510095China guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation State Key Laboratory of Respiratory DiseaseSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511436China Institute of Digestive Disease of guangzhou medical university The Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalQingyuan 511518China school of Public Health Guangzhou Medical UniversityGuangzhou511436China Department of surgery UT Southwestern Medical CenterDallasTX 75390USA Barbara Ann Karmanos Cancer Institute and Departments of Oncology Pharmacology&PathologySchool of MedicineWayne State UniversityDetroitMI 48201USA

Objective:sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(Pses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(Psorafenib-induced activation of GsK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

关键词： Apoptosis bilirubin hepatocellular carcinoma MCL-1 sorafenib

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sARs-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

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signal Transduction and Targeted Therapy 2023年第8期8卷 3780-3793页

作者： Kai Yang shiyun Liu Han Yan Wenju Lu Xiaoqian shan Haixia Chen Changlei Bao Huazhuo Feng Jing Liao shuxin Liang Lei Xu Haiyang Tang Jason X-J.Yuan Nanshan Zhong Jian Wang state Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangdong Key Laboratory of Vascular DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina guangzhou National Laboratory Guangzhou International Bio IslandGuangzhouGuangdongChina Department of Pulmonary and Critical Care Medicine The Affiliated Hospital of Inner Mongolia Medical UniversityHohhotInner Mongolia Autonomous RegionChina Department of Pathology The Affiliated Cancer Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina school of Medicine Southern University of Science and TechnologyShenzhenGuangdongChina section of Physiology Division of PulmonaryCritical Care and Sleep MedicineDepartment of MedicineUniversity of California San DiegoLa JollaCAUSA

Exposure to the spike protein or receptor-binding domain(s-RBD)of sARs-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy.In this study,angiotensin-converting enzyme 2 humanized inbred(hACE2 Tg)mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/s-RBD impacts pulmonary vascular endothelium.Results show that s-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration([Ca^(2+)]i)via acute activation of TRPV4,and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel(sOCC)key component Orai1 in cultured human pulmonary arterial endothelial cells(PAECs).In mechanism,s-RBD interacts with ACE2 to induce formation of clusters involving Orai1,Piezo1 and TRPC1,facilitate the channel activation of Piezo1 and sOCC,and lead to elevated apoptosis.These effects are blocked by Kobophenol A,which inhibits the binding between s-RBD and ACE2,or intracellular calcium chelator,BAPTA-AM.Blockade of Piezo1 and sOCC by GsMTx4 effectively protects the s-RBDinduced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated[Ca^(2+)]i.Comparing to prototypic strain,Omicron variants(BA.5.2 and XBB)of s-RBD induces significantly less severe cell apoptosis.Transcriptomic analysis indicates that prototypic s-RBD confers more severe acute impacts than Delta or Lambda s-RBD.In summary,this study provides compelling evidence that s-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering[Ca^(2+)]i through upregulation of Piezo1 and Orai1.Targeted inhibition of ACE2-Piezo1/sOCC-[Ca^(2+)]i axis proves a powerful strategy to treat s-RBD-induced pulmonary vascular diseases.

关键词： ACE2 elevated homeostasis

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spatial transcriptome unveils a discontinuous inflammatory pattern in proficient mismatch repair colorectal adenocarcinoma

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Fundamental research 2023年第4期3卷 640-646页

作者： Rongxin Zhang Yu Feng Wenjuan Ma Yanying Guo Mei Luo Young Li Yupeng Zang Xuan Dong shixun Lu Qiang Guo Qumiao Xu Huanyi Chen Yijian Li Longqi Liu Ao Chen Gong Chen Xun Xu Department of Colorectal surgery Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina BGI-shenzhen Beishan Industrial ZoneShenzhen 518083China state Key Laboratory of Oncology in south China Guangzhou 510060GuangdongChina Collaborative Innovation Center of Cancer Medicine Guangzhou 510060GuangdongChina Intensive Care Unit Department Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina College of Life sciences University of Chinese Academy of SciencesBeijing 100049China Department of Pathology Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina shenzhen Bay Laboratory Shenzhen 518000China Department of Biology University of CopenhagenCopenhagen DK-2200Denmark Guangdong Provincial Key Laboratory of Genome Read and Write Shenzhen 518120China

The preexistence of immune cells in the tumor microenvironment substantiates the efficacy of immunotherapy in cancer patients.Although the complex intratumoral immune heterogeneity has been extensively studied in single cell resolution,hi-res spatial investigations are limited.In this study,we performed a spatial transcriptome analysis of 4 colorectal adenocarcinoma specimens and 2 paired distant normal specimens to identify the molecular pattern involved in a discontinuous inflammatory response in pathologically annotated cancer regions.Based on the location of spatially varied gene expression,we unmasked the spatially-varied immune ecosystem and identified the locoregional“warmed-up”immune response in predefined“cold”tumor with substantial infiltration of immune components.This“warmed-up”immune profile was found to be associated with the in-situ copy number variance and the tissue remodeling process.Further,“warmed-up”signature genes indicated improved overall survival in CRC patients obtained from TCGA database.

关键词： Colorectal adenocarcinoma Mismatch repair Inflammation spatial transcriptomics Tumor microenvironment

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Multi-phase separation in mitochondrial nucleoids and eukaryotic nuclei

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Biophysics Reports 2023年第3期9卷 113-119页

作者： Qi Long Yanshuang Zhou Jingyi Guo Hao Wu Xingguo Liu CAs Key Laboratory of Regenerative Biology Joint School of Life Sciences The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's Hospital Guangzhou Medical University guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangdong Provincial Key Laboratory of stem Cell and Regenerative Medicine China-New Zealand Joint Laboratory on Biomedicine and Health CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine Institute for Stem Cell and Regeneration Institute for Stem Cell and Regeneration Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Centre for Regenerative Medicine and Health Hong Kong Institute of Science & Innovation Chinese Academy of Sciences

In mammalian cells, besides nuclei, mitochondria are the only semi-autonomous organelles possessing own DNA organized in the form of nucleoids. While eukaryotic nuclear DNA compaction, chromatin compartmentalization and transcription are regulated by phase separation, our recent work proposed a model of mitochondrial nucleoid self-assembly and transcriptional regulation by multi-phase separation. Herein, we summarized the phase separation both in the nucleus and mitochondrial nucleoids,and did a comparison of the organization and activity regulating, which would provide new insight into the understanding of both architecture and genetics of nucleus and mitochondrial nucleoids.

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乳酸与蛋白质乳酸化修饰:能量代谢的“丑小鸭”变为“蛋白质雕塑艺术家”

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science Bulletin 2023年第21期68卷 2510-2514页

作者：李林鹏孙山虎邬毅陆江焕何静彩陈可实陈伟仪刘兴国 GMU-GIBH Joint school of Life sciences The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and DiseasesThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityCAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510000China Guangdong Provincial Key Laboratory of stem Cell and Regenerative Medicine China-New Zealand Joint Laboratory on Biomedicine and HealthCUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative MedicineGuangzhou Institutes of Biomedicine and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesGuangzhou 510000China Centre for Regenerative Medicine and Health Hong Kong Institute of Science&InnovationChinese Academy of SciencesHong KongChina CUHK-GIBH Joint research Laboratory on stem Cells and Regenerative Medicine CUHK-Jinan University Key Laboratory for Regenerative MedicineMinistry of EducationSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongHong KongChina

Metabolites play important roles in numerous cell biology processes,such as cell proliferation,differentiation,stress response,and cell death[1].Recently,lactate and lactate-derived lysine residue lactylation(Kla)have emerged as newly discovered epigenetic modifications that play critical roles in various physiological and pathological processes.In the history of lactate research,we can categorize the studies into three mile stones(Fig.s1 online).

关键词： death residue 能量代谢

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