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regulatory role of long non coding RNAs (lncRNAs) in neurological disorders:From novel biomarkers to promising therapeutic strategies

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Asian Journal of Pharmaceutical Sciences 2021年第5期16卷 533-550页

作者： Nirjhar Bhattacharyya Vedansh Pandey Malini Bhattacharyya Abhijit Dey Department of Life Sciences Presidency UniversityKolkataIndia

Long non coding RNAs(lncRNAs) are non-protein or low-protein coding transcripts that contain more than 200 nucleotides. They representing a large share of the cell’s transcriptional output, demonstrate functional attributes viz. tissue-specific expression, determination of cell fate, controlled expression, RNA processing and editing, dosage compensation, genomic imprinting, conserved evolutionary traits etc. These long non coding variants are well associated with pathogenicity of various diseases including the neurological disorders like Alzheimer’s disease, schizophrenia, Huntington’s disease, Parkinson’s disease etc. Neurological disorders are widespread and there knowing the underlying mechanisms become crucial. The lncRNAs take part in the pathogenesis by a plethora of mechanisms like decoy, scaffold, mi-RNA sequestrator, histone modifiers and in transcriptional interference. Detailed knowledge of the role of lncRNAs can help to use them further as novel biomarkers for therapeutic aspects. Here, in this review we discuss regulation and functional roles of lncRNAs in eight neurological diseases and psychiatric disorders, and the mechanisms by which they act. With these, we try to establish their roles as potential markers and viable diagnostic tools in these disorders.

关键词： Non coding rnas Alzheimer’s disease Huntington’s disease Parkinson’s disease Schizophrenia regulatory

regulatory T cell Itch reins in Th2 inflammation

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Cellular & Molecular Immunology 2014年第2期11卷 126-128页

作者： Benjamin DSinger Franco RD'Alessio Johns Hopkins University Division of Pulmonary and Critical Care Medicine Baltimore USA

Type 2 T helper （Th2） inflammation underlies common clinical disor-ders such as asthma, eczema and other atopic diseases. CD4＋ regulatory T cells （Tregs） suppress over-exuberant immune responses in a variety of inflammatory microenvironments, including Th2 con- ditions. The transcription factor fork- head box protein 3 （Foxp3） controls Treg development, function and main- tenance; however,

关键词： regulatory reins inflammation

Differences of maternal mortality rate between Shanghai and New York city from the perspective of regulatory policy

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Chinese Medical Journal 2020年第7期133卷 792-799页

作者： Li Li Cheng-Yue Li Qing-Yu Zhou Chuan Pu Ling-Zhong Xu Tian-Qiang Xu Chao Hao Zhi Hu Mo Hao Research Institute of Health Development Strategies Fudan UniversityShanghai 200032China Collaborative Innovation Center of Social Risks Governance in Health Fudan UniversityShanghai 200032China School of Public Health and Management Chongqing Medical UniversityChongqing 400016China School of Public Health Shandong UniversityJinanShandong 250012China Institute of Inspection and Supervision Shanghai Municipal Commission of Health and Family PlanningShanghai 200031China Changzhou Center for Disease Control and Prevention NanjingJiangsu 213003China Anhui Medical University HefeiAnhui 230032China

Background:regulatory policy(RP)is known as a major factor to improve health care system performance.A significant difference in maternal mortality rates(MMRs)was observed between New York city(NYC)and Shanghai(SH),both first-class international metropolises.This study aims to adopt a quantitative evaluation model to analyze whether RP differences contribute to the different MMRs of the two cities.Methods:Based on collection of all publicly released policy documents regarding maternal health in the two cities,we assessed and compared the status of their maternal health care RPs from 2006 to 2017 through a series of quantitative indicators as regulatory elements coverage rate(RECR),departmental responsibility clarity rate(DRCR),and accountability mechanism clarity rate(AMCR),based on two characteristics of comprehensiveness and effectiveness of RPs.Pearson correlation analysis,principal component analysis,and linear regression analysis were used to test the relationships between the indicators and MMR in SH and NYC.Results:By 2017,disparities of maternal health care RP are found between SH and NYC,from the indicators of RECR(100%vs.77.0%),DRCR(38.9%vs.45.1%),and AMCR(29.2%vs.22.5%).From 2006 to 2017,RECR,DRCR,and AMCR in SH have shown a higher growth of 8.7%,53.2%,and 45.2%,compared with growth of 25.0%,12.5%,and 2.9%in NYC.The three indicators were found all negatively correlated with MMR in SH(Coefficients=-0.831,-0.833,and-0.909,and P<0.01),while only RECR and DRCR had negative correlation with MMR in NYC(Coefficients=-0.736 and-0.683,and P<0.05).Linear regression showed that the principal components of the three indicators were found with significant impact on MMRs both in SH(R=0.914,R2=0.836,P<0.001)and NYC(R=0.854,R2=0.357,P=0.04).Conclusion:Compared with NYC,the more comprehensive and effective maternal health care RPs in SH had a stronger impact on MMR control,which contributed to the differences between the two cities’MMRs to some extent.The methods and indicators we adopted for assessment are reasonable

关键词： Maternal mortality regulatory policy Maternal health Shanghai New York

regulatory T Cells and Their Clinical Applications in Antitumor Immunotherapy

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Engineering 2019年第1期5卷 132-139页

作者： Feng Xie Rui Liang Dan Li Bin Li Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China Department of Immunology and Microbiology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

Cancer is a potentially life-threatening disease characterized by the immortalization of tumor cells in the host. Immunotherapy has recently gained increasing interest among researchers due to its tremendous potential for preventing tumor progression and metastasis. regulatory T cells (Tregs) are a subgroup of suppressive CD4^+ T cells that play a vital role in the maintenance of host immune homeostasis. Treg deficiency can induce severe autoimmune, hypersensitivity, and auto-inflammatory disorders, among other diseases. Tregs are commonly enriched in a tumor microenvironment, and a greater number of immune-suppressive Tregs often indicates a poorer prognosis;therefore, there is renewed interest in the function of Tregs and in their clinical application in antitumor immunotherapy. Accumulating strategies that focus on the depletion of Tregs have appeared to be effective in antitumor immunity. It is expected that Treg-targeting strategies will provide great opportunities for improving antitumor efficiency in combination with other therapeutics (e.g., chimeric antigen receptor T cell (CAR-T)-based cell therapy or immune checkpoint blockading).

关键词： regulatory T cells Cancer Immunotherapy

MicroRNA regulatory pattern in spinal cord ischemia-reperfusion injury

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Neural Regeneration Research 2020年第11期15卷 2123-2130页

作者： Zhi-Gang Liu Yin Li Jian-Hang Jiao Hao Long Zhuo-Yuan Xin Xiao-Yu Yang Department of Orthopedics The Second Hospital of Jilin UniversityChangchunJilin ProvinceChina School of Public Health Jilin UniversityChangchunJilin ProvinceChina Pain Clinic The Sixth Affiliated Hospital of Xinjiang Medical UniversityUrumqiXinjiang Uygur Autonomous RegionChina The Key Laboratory of Zoonosis Search Chinese Ministry of EducationCollege of Basic MedicineJilin UniversityChangchunJilin ProvinceChina

After spinal cord injury, dysregulated miRNAs appear and can participate in inflammatory responses, as well as the inhibition of apoptosis and axon regeneration through multiple pathways. However, the functions of miRNAs in spinal cord ischemia-reperfusion injury progression remain unclear. miRCURY LNATM Arrays were used to analyze miRNA expression profiles of rats after 90 minutes of ischemia followed by reperfusion for 24 and 48 hours. Furthermore, subsequent construction of aberrantly expressed miRNA regulatory patterns involved cell survival, proliferation, and apoptosis. Remarkably, the mitogen-activated protein kinase(MAPK) signaling pathway was the most significantly enriched pathway among 24-and 48-hour groups. Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction confirmed the persistent overexpression of miR-22-3 p in both groups. These results suggest that the aberrant miRNA regulatory network is possibly regulated MAPK signaling and continuously affects the physiological and biochemical status of cells, thus participating in the regulation of spinal cord ischemia-reperfusion injury. As such, miR-22-3 p may play sustained regulatory roles in spinal cord ischemia-reperfusion injury. All experimental procedures were approved by the Animal Ethics Committee of Jilin University, China [approval No. 2020(Research) 01].

关键词： gene regulatory networks microarray analysis microRNA miR-22-3p mitogen-activated protein kinase signaling pathway nerve regeneration neural regeneration spinal cord ischemia-reperfusion injury transcriptome

Detection and characterization of regulatory elements using probabilistic conditional random field and hidden Markov models

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Chinese Journal of Cancer 2013年第4期32卷 186-194页

作者： Hongyan Wang Xiaobo Zhou Department of Radiology the Methodist Hospital Research Institute Department of Radiology Weill Cornell Medical College

By altering the electrostatic charge of histones or providing binding sites to protein recognition molecules, Chromatin marks have been proposed to regulate gene expression, a property that has motivated researchers to link these marks to cis-regulatory elements. With the help of next generation sequencing technologies, we can now correlate one specific chromatin mark with regulatory elements (e.g. enhancers or promoters) and also build tools, such as hidden Markov models, to gain insight into mark combinations. However, hidden Markov models have limitation for their character of generative models and assume that a current observation depends only on a current hidden state in the chain. Here, we employed two graphical probabilistic models, namely the linear conditional random field model and multivariate hidden Markov model, to mark gene regions with different states based on recurrent and spatially coherent character of these eight marks. Both models revealed chromatin states that may correspond to enhancers and promoters, transcribed regions, transcriptional elongation, and low-signal regions. We also found that the linear conditional random field model was more effective than the hidden Markov model in recognizing regulatory elements, such as promoter-, enhancer-, and transcriptional elongation-associated regions, which gives us a better choice.

关键词： Epigenetics, histone modification, conditional random field, regulatory elements

Downregulation of miR-4772-3p promotes enhanced regulatory T cell capacity in malignant pleural effusion by elevating Helios levels

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Chinese Medical Journal 2019年第22期132卷 2705-2715页

作者： Wen-Qing Yu Ning-Fei Ji Cheng-Jing Gu Zhi-Xiao Sun Zheng-Xia Wang Zhong-Qi Chen Yuan Ma Zhen-Zhen Wu Yan-Li Wang Chao-Jie Wu Ming-Dong Ding Gui-Hong Dai Juan Yao Rong-Rong Jin Mao Huang Ming-Shun Zhang Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Infectious Diseases Taizhou People's Hospital Affiliated to Nantong UniversityTaizhouJiangsu 225300China Department of Pharmacy Taizhou People's Hospital Affiliated to Nantong UniversityTaizhouJiangsu 225300China Department of Pathology Taizhou People's Hospital Affiliated to Nantong UniversityTaizhouJiangsu 225300China Department of Oncology Taizhou People's Hospital Affiliated to Nantong UniversityTaizhouJiangsu 225300China Department of Immunology Nanjing Medical UniversityNanjingJiangsu 210029China

Background:Malignant pleural effusion(MPE)is a complicated condition of patients with advanced tumors.Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression.Methods:The possible involvement of microRNAs(miRNAs)in malignant pleural fluid was investigated using small RNA sequencing.regulatory T cell(Treg)markers(CD4,CD25,forkhead box P3),and Helios(also known as IKAROS Family Zinc Finger 2[IKZF2])were detected using flow cytometry.The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction.The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays.The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system.Correlation assays between miR-4772-3p and functional molecules of Tregs were performed.Results:Compared with non-malignant controls,patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells.The verified downregulation of miR-4772-3p was inversely related to the Helios*Tregs frequency and Helios expression in the MPE.Overexpression of miR-4772-3p could inhib让Helios expression in in vitro experiments.However,ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression.Additionally,miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA.Conclusion:Downregulation of miR-4772-3p,by targeting Helios,contributes to enhanced Tregs activities in the MPE microenvironment.

关键词： Helios IKAROS family zinc finger 2 Lung cancer Malignant pleural effusion MiR-4772-3p regulatory T cells

Role of regulatory Peptide in Pathogenesis of Shock

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Science China Chemistry 1994年第2期37卷 162-169页

作者：董林旺常英姿佟利家汤健苏静怡唐朝枢 Institute of Cardiovascular Disease Beijing Medical University Beijing 100083. PRC

The present study evaluated the pathogenetic roles of three kinds of regulatory peptide. The results showed that (i) plasma endothelin(ET) level elevated significantly in septic shock rats, persistent intravenous drip of low doses ET caused development of shock state in normal rats and the irreversible outcome of light hemorrhagic shock. Furthermore, i. v. administration of specific ET-antiserum was significantly effective to septic shock rats, (Ⅱ) Plasma calcitonin gene-related peptide (CGRP) increased by 260% in septic shock rats, i. v. drip of low doses CGRP both in early and late sepsis were effective to shock rats, (Ⅱi) An-giotensin-Ⅱ (ANG-Ⅱ) contents of heart and aorta increased dramatically both in early and late septic shock, and inhibiting its increase with Captopril in late sepsis significantly improved the shock state, but results were inverse in early sepsis. It could be concluded that ET was one of the most important factors participating in the pathogenesis of shock, CGRP had a

关键词： shock regulatory peptide enduthelin. calcitonin gene-related peptide tissue renin-an-giotensin system.

Transcriptome and regulatory Network Analyses of CD19-CAR-T Immunotherapy for B-ALL

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Genomics, Proteomics & Bioinformatics 2019年第2期17卷 190-200页

作者： Qiong Zhang Hui Hu Si-Yi Chen Chun-Jie Liu Fei-Fei Hu Jianming Yu Yaohui Wu An-Yuan Guo Hubei Bioinformatics and Molecular Imaging Key Laboratory Department of Bioinformatics and Systems Biology Key Laboratory of Molecular Biophysics of the Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology Wuhan 430074 China Institute of Hematology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

Chimeric antigen receptor (CAR) T cell therapy has exhibited dramatic anti-tumor effi-cacy in clinical trials. In this study,we reported the transcriptome profiles of bone marrow cells in four B cell acute lymphoblastic leukemia (B-ALL) patients before and after CD19-specific CAR-T therapy. CD19-CAR-T therapy remarkably reduced the number of leukemia cells,and three patients achieved bone marrow remission (minimal residual disease negative). The efficacy of CD19-CAR-T therapy on B-ALL was positively correlated with the abundance of CAR and immune cell subpopulations,e.g.,CD8+T cells and natural killer (NK) cells,in the bone marrow. Additionally,CD19-CAR-T therapy mainly influenced the expression of genes linked to cell cycle and immune response pathways,including the NK cell mediated cytotoxicity and NOD-like recep-tor signaling pathways. The regulatory network analyses revealed that microRNAs (e.g.,miR-148a-3p and miR-375),acting as oncogenes or tumor suppressors,could regulate the crosstalk between the genes encoding transcription factors (TFs,e.g.,JUN and FOS) and histones (e.g.,HIST1H4A and HIST2H4A) involved in CD19-CAR-T therapy. Furthermore,many long non-coding RNAs showed a high degree of co-expression with TFs or histones (e.g.,FOS and HIST1H4B) and were associated with immune processes. These transcriptome analyses provided important clues for fur-ther understanding the gene expression and related mechanisms underlying the efficacy of CAR-T immunotherapy.

关键词： CAR-T B-ALL Transcriptome profile lncRNA regulatory network