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Identification of novel biomarkers and Therapeutic target candidates for stasis-heat symptom pattern of acute intracerebral hemorrhage by quantitative plasma proteomics

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Journal of Traditional Chinese Medicine 2022年第4期42卷 622-632页

作者： WEI Lexin LI Weiyi TIAN Ting ZHANG Ning YANG Shijing YANG Dongqing LI Guochun YE Fang Department of Public Health School of Medicine and Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing 210023China Emergency Department Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineNanjing 210001China the Key Laboratory Department of Stasis-heat Pathogenesis of Traditional Chinese Medicine the First Clinical Medical CollegeNanjing University of Chinese MedicineNanjing 210001China

OBJECTIVE:To explore the novel biomarkers and Therapeutic target candidates related to the stasis-heat syndrome of acute intracerebral hemorrhage(AICH).METHODS:Applying an isobaric tagging for relative and absolute quantitation-(i TRAQ-)based quantitative proteomic approach,plasma samples from AICH patients with stasis-heat,and AICH patients with non-stasis-heat and healthy control subjects were collected and analyzed to distinguish differentially expressed proteins(DEPs)correlated to AICH with stasis-heat in this block design.The standard Western blot was applied to verify DEPs.Additionally,DEPs were analyzed via bioinformatic platforms and further approved via Ingenuity Pathway Analysis(IPA).RESULTS:A total of 26 DEPs were found among AICH with the stasis-heat,AICH with non-stasis-heat,and healthy control group.The seven DEPs compared with the non-stasis-heat group are closely related to the pathogenesis of stasis heat.These proteins showed three different protein expression patterns.The alpha-1-b glycoprotein(A1 BG)and copper-protein(CP)were upregulated in the stasis-heat group,but down-regulated in the non-stasis-heat group.Compared with the non-stasisheat group,the expression abundance of actinin,alpha 1(ACTN1),carbonic anhydrase I(CA1),peroxiredoxin 2(PRDX2),and vinculin(VCL)is higher in the stasis-heat group,while the CD44 is the opposite.These differences reflect that stasis-heat syndrome has more severe inflammatory immune response,coagulation disorders and damage.Bioinformatics analysis revealed that a wide variety of cellular and metabolic processes and some signaling pathways were involved in the pathophysiology of AICH with stasis-heat.AICH with stasis-heat syndrome showed more severe inflammatory reactions,tissue damage,and coagulation disorders than non-stasis heat syndrome.CONCLUSIONS:There are differences in the protein expression patterns between the stasis-heat syndrome and non-stasis-heat syndrome.These differences reflect that stasis-heat syndrome has more severe damage.CD44,CP,ACTN1,CA1,VCL,

关键词： cerebral hemorrhage stasis-heat syndrome biomarkers Therapeutic target quantitative plasma proteomics

Elevated intraspinal pressure in traumatic spinal cord injury is a promising Therapeutic target

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Neural Regeneration Research 2022年第8期17卷 1703-1710页

作者： Chao-Hua Yang Zheng-Xue Quan Gao-Ju Wang Tao He Zhi-Yu Chen Qiao-Chu Li Jin Yang Qing Wang Department of Orthopedics The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Orthopedics The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

The currently recommended management for acute traumatic spinal cord injury aims to reduce the incidence of secondary injury and promote functional recovery.Elevated intraspinal pressure(ISP)likely plays an important role in the processes involved in secondary spinal cord injury,and should not be overlooked.However,the factors and detailed time course contributing to elevated ISP and its impact on pathophysiology after traumatic spinal cord injury have not been reviewed in the literature.Here,we review the etiology and progression of elevated ISP,as well as potential therapeutic measures that target elevated ISP.Elevated ISP is a time-dependent process that is mainly caused by hemorrhage,edema,and blood-spinal cord barrier destruction and peaks at 3 days after traumatic spinal cord injury.Duraplasty and hypertonic saline may be promising treatments for reducing ISP within this time window.Other potential treatments such as decompression,spinal cord incision,hemostasis,and methylprednisolone treatment require further validation.

关键词： blood-spinal cord barrier decompression duraplasty durotomy edema hemorrhage intraspinal pressure myelotomy spinal cord injury Therapeutic target

Exosomes: a novel Therapeutic target for Alzheimer's disease?

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Neural Regeneration Research 2018年第5期13卷 930-935页

作者： Zhi-You Cai Ming Xiao Sohel H.Quazi Zun-Yu Ke Department of Neurology Chongqing General Hospital Department of Anatomy Nanjing Medical University Department of Biological and Health Sciences Texas A & M University-Kingsville Department of Neurology Renmin Hospital Hubei University of Medicine

Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer＇s disease. An important role of exosomes in Alzheimer＇s disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer＇s disease.

关键词： nerve regeneration microvesicle beta-amyloid tau neuroinflammation oxidative stress Therapeutic target neurodegeneration dementia neural regeneration

HBV cccDNA and Its Potential as a Therapeutic target

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Journal of Clinical and Translational Hepatology 2019年第3期7卷 258-262页

作者： Anjing Zhu Xinzhong Liao Shuang Li Hang Zhao Limin Chen Min Xu Xiaoqiong Duan Institute of Blood Transfusion Chinese Academy of Medical Sciences and Peking Union Medical CollegeChengduChina Institute of Blood Transfusion Chinese Academy of Medical Sciences and Peking Union Medical CollegeChengdu 610052China

Chronic hepatitis B virus infection continues to be a major health burden worldwide.It can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma.Covalently closed circular DNA in the nucleus of infected cells cannot be disabled by present therapies which may lead to HBV persistence and relapse.In this review,we summarized the current knowledge on hepatitis B virus covalently closed circular DNA and its potential role as a Therapeutic target.

关键词： Hepatitis B virus(HBV) Covalently closed circular DNA(cccDNA) Therapeutic target

Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis:a novel Therapeutic target for fatty liver disease

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Journal of Molecular Cell Biology 2016年第6期8卷 492-504页

作者： Shuai Chen Yujia Kang Yan Sun Yanhong Zhong Yanli Li Lijuan Deng Jin Tao Yang Li Yingpu Tian Yinan Zhao Jianghong Cheng Wenjie Liu Gen-Sheng Feng Zhongxian Lu School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress BiologyXiamen UniversityXiamenFujian 361005China Department of Pathology and Division of Biological SciencesUniversity of California San DiegoLa JollaCA 92093USA

Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders.The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent Therapeutic targets due to multifaceted and interdependent disease factors.In this study,we investigated the role of a signaling adaptor protein,GRB2-associated-binding protein 2(Gab2),in fatty liver using an animal disease model.Gab2 expression in hepatocytes responded to various disease factor stimulations,and Gab2 knockout mice exhibited resistance to fat-induced obesity,fat-or alcohol-stimulated hepatic steatosis,as well as methionine and choline deficiency-induced steatohepatitis.Concordantly,the forced expression or knockdown of Gab2 enhanced or diminished oleic acid(OA)-or ethanol-induced lipid production in hepatocytes in vitro,respectively.During lipid accumulation in hepatocytes,both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT,ERK,and Stat3.Therefore,Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver.Our research provides a novel potential target for the prevention and intervention of fatty liver disease.

关键词： alcoholic fatty liver disease non-alcoholic fatty liver disease knockout mouse disease-associated protein Therapeutic target

MicroRNAs: a novel promising Therapeutic target for cerebral ischemia/reperfusion injury?

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Neural Regeneration Research 2015年第11期10卷 1799-1808页

作者： Xiao-li Min Ting-yong Wang Yi Cao Jia Liu Jin-tao Li Ting-hua Wang Institute of Neuroscience Kunming Medical University Faculty of Clinical Medicine Yunnan University of Traditional Chinese Medicine the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine School of Economics of Sichuan University Department of Neurosurgery the Second Affiliated Hospital of Kunming Medical University

To determine the molecular mechanism of cerebral ischemia/reperfusion injury, we examined the micro RNA（mi RNA） expression profile in rat cortex after focal cerebral ischemia/reperfusion injury using mi RNA microarrays and bioinformatic tools to systematically analyze Gene Ontology（GO） function classifications, as well as the signaling pathways of genes targeted by these differentially expressed mi RNAs. Our results show significantly changed mi RNA expression profiles in the reperfusion period after focal cerebral ischemia, with a total of 15 mi RNAs up-regulated and 44 mi RNAs down-regulated. target genes of these differentially expressed mi RNAs were mainly involved in metabolic and cellular processes, which were identified as hub nodes of a mi RNA-GO-network. The most correlated pathways included D-glutamine and D-glutamate metabolism, the renin-angiotensin system, peroxisomes, the PPAR signaling pathway, SNARE interactions in vesicular transport, and the calcium signaling pathway. Our study suggests that mi RNAs play an important role in the pathological process of cerebral ischemia/reperfusion injury. Understanding mi RNA expression and function may shed light on the molecular mechanism of cerebral ischemia/reperfusion injury.

关键词： nerve regeneration microRNA Therapeutic target cerebral ischemia/reperfusion injury miRNA expression profiles bioinformatics analysis Gene Ontology analysis molecular mechanism KEGG pathway neural regeneration

FXYD6： a novel Therapeutic target toward hepatocellular carcinoma

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Protein & Cell 2014年第7期5卷 532-543页

作者： Qian Gao Xiongfei Chen Hongxia Duan Zhaoqing Wang Jing Feng Dongling Yang Lina Song Ningxin Zhou Xiyun Yan Key Laboratory of Protein and Peptide Pharmaceuticals CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Medical College of Soochow University Industrial Park Suzhou 215123 China Institute of Hepatobiliary Gastrointestinal Disease General Hospital of PLA Second Artillery Beijing 100088 China

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential Therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

关键词： FXYD6 hepatocellular carcinoma （HCC）tumor progression Therapeutic target Na＋/K＋-ATPase,Src-ERK signaling pathway

Leukocyte immunoglobulin-like receptor B2 overexpression as a promising Therapeutic target and noninvasive screening biomarker for colorectal cancer

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世界胃肠病学杂志:英文版 2023年第37期29卷 5313-5326页

作者： Qian-Qian Wang Lei Zhou Geng Qin Chang Tan Yuan-Chen Zhou Shu-Kun Yao Department of Gastroenterology Peking University China-Japan Friendship School of Clinical MedicineBeijing 100029China Department of General Surgery China-Japan Friendship HospitalBeijing 100029China Department of Gastroenterology China-Japan Friendship HospitalBeijing 100029China

BACKGROUND Colorectal cancer(CRC)has become the second most deadly malignancy in the world,and the exploration of screening markers and precise Therapeutic targets is urgent.Our previous research identified leukocyte immunoglobulin-like receptor B2(LILRB2)protein as a characteristic protein of CRC,but the association between LILRB2 expression and clinicopathological features,the internal mechanism related to CRC progression,and screening diagnostic efficacy are not clear.Therefore,we hypothesized that LILRB2 is significantly highly expressed in CRC tissues,correlated with advanced stage and a poor prognosis,and could be used as a Therapeutic target and potential screening biomarker for CRC.AIM To explore whether LILRB2 can be used as a potential Therapeutic target and noninvasive screening biomarker for CRC.METHODS Patients who underwent radical surgery for CRC at China-Japan Friendship Hospital between February 2021 and October 2022 were included.Cancer and paracancerous tissues were collected to verify LILRB2 expression,and the association between LILRB2 expression and clinicopathological features was analysed.Serum was collected from CRC patients,adenoma patients and healthy controls during the same period to assess the diagnostic value of LILRB2 as a noninvasive screening biomarker,and its diagnostic value was further compared with that of the traditional markers carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9).RESULTS A total of 58 CRC patients were included,and LILRB2 protein was significantly overexpressed in cancer tissues compared with paracancerous tissues(P<0.001).Angiopoietin-like protein 2(ANGPTL2)protein,as the ligand of LILRB2,was synergistically overexpressed in CRC tissues(P<0.001),and overexpression of LILRB2 and ANGPTL2 protein was significantly correlated with poor to moderate differentiation,vascular involvement,lymph node metastasis,distant metastasis,advanced tumor-node-metastasis stage and a poor prognosis(P<0.05),which suggested that LILRB2 and ANGPTL2 are closely associ

关键词： Colorectal cancer Leukocyte immunoglobulin-like receptor B2 Angiopoietin-like protein 2 Therapeutic target Noninvasive screening biomarker

Potential role of long noncoding RNA RP5-881L22.5 as a novel biomarker and Therapeutic target of colorectal cancer

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World Journal of Gastrointestinal Oncology 2022年第11期14卷 2108-2121页

作者： Hua Zong Jian-Qiang Zou Jian-Peng Huang Shi-Ting Huang Department of Gastrointestinal Surgery The Third People’s Hospital of ShenzhenShenzhen 518000Guangdong ProvinceChina

BACKGROUND The incidence of colorectal cancer in humans is high,and it is in the top five for cancer-related morbidity and mortality.It is one of the main threats to human health.The function of long noncoding RNAs in tumor occurrence and development has gradually gained attention in recent years.In increasing numbers of studies,researchers have demonstrated that it plays an important role in the pathogenesis of colorectal cancer.AIM To find out if long noncoding RNA RP5-881L22.5 played a role in the pathogenesis of colorectal cancer in relation to the tumor microenvironment.METHODS We analyzed the transcriptome data and clinical data in The Cancer Genome Atlas-colon adenocarcinoma.The CIRBERSORT algorithm was applied to evaluate these tumor-infiltrating immune cells in The Cancer Genome Atlas-colon adenocarcinoma cancer tissue samples.Using the“estimate”package in R,we assessed the tumor immune microenvironment.The expression level of RP5-881L22.5 in tumor tissue and adjacent normal tissue samples from 4 pairs of colorectal cancer patients was determined by quantitative reverse transcription PCR.Colorectal cancer cells were tested for invasiveness using a transwell invasion assay after RP5-881L22.5 expression was knocked down.RESULTS The expression of lncRNA RP5-881L22.5 was related to the clinical characteristics of the tumors,and it was negatively related to the infiltration level of immune cells in the tumor microenvironment and the expression of T cell inhibitory receptors.A major function of its coexpressed mRNA was to regulate tumor immunity,such as the immune response.When quantitative reverse transcription PCR was performed on tumor tissues from 4 pairs of colorectal cancer patients,the results showed that RP5-881L22.5 was highly expressed.Subsequently,knocking down the expression of RP5-881L22.5,the invasiveness of colorectal cancer cell lines was reduced,and the apoptosis rate was increased.CONCLUSION RP5-881L22.5 plays a crucial role in the microenvironment of tumors as well as in the pathogenesis of

关键词： Colorectal cancer Long noncoding RNA RP5-881L22.5 Tumor immune microenvironment Biomarker Therapeutic target