| 1 | Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma显示文摘Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants.We identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites.Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific.Functional annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency related.Our results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments. | Na Qin Yuancheng Li Cheng Wang Meng Zhu Juncheng Dai Tongtong Hong Demetrius Albanes Stephen Lam Adonina Tardon Chu Chen Gary Goodman Stig EBojesen Maria Teresa Landi Mattias Johansson Angela Risch H-Erich Wichmann Heike Bickeboller Gadi Rennert Susanne Arnold Paul Brennan John KField Sanjay Shete Loic Le Marchand Olle Melander Hans Brunnstrom Geoffrey Liu Rayjean JHung Angeline Andrew Lambertus AKiemeney Shan Zienolddiny Kjell Grankvist Mikael Johansson Neil Caporaso Penella Woll Philip Lazarus Matthew BSchabath Melinda CAldrich Victoria LStevens Guangfu Jin David CChristiani Zhibin Hu Christopher IAmos Hongxia Ma Hongbing Shen | 2021 | Frontiers of Medicine2021，15，2： | 3 |
| 2 | Glycyrrhiza uralensis flavonoids inhibit brain microglial cell TNF-α secretion,p-IκB expression,and increase brain-derived neurotropic factor(BDNF)secretion显示文摘Objective:Asthma sufferers exhibit high prevalence of anxiety/depression.Elevated tumor-necrosis factor-alpha(TNF-α)levels in peripheral system and central nervous system(CNS)are associated with anxiety/depression,whereas brain-derived neurotropic factor(BDNF)has anti-depressant effects.An anti-asthma herbal medicine intervention ASHMI inhibits peripheral TNF-αsecretion in an animal model of asthma.We hypothesize that ASHMI and its compounds may have modulatory effects on CNS TNF-αand BDNF production.We sought to determine the effect of ASHMI and individual herb constituents on brain microglial cell TNF-αproduction,and identify the active compounds that suppress TNF-αand increase BDNF.Methods:BV-2 mouse microglial cells were pre-treated with ASHMI or extracts of Ganoderma lucidum(G.lucidum),Sophora flavescens Ait(S.flavescens),and Glycyrrhiza uralensis Fischer(G.uralensis),the herbal constituents in ASHMI,or individual compounds isolated from G.uralensis at different concentrations and then stimulated with LPS.TNF-αlevels in culture supernatants were measured by ELISA.The effect of active compounds on NFkB signaling pathway and on BDNF production were determined by western blotting and ELISA,respectively.Results:ASHMI produced dose-dependent inhibition of TNF-αsecretion by cultured-mousemicroglia BV2 cells.Of the three herb extracts in ASHMI,only G.uralensis significantly and dosedependently inhibited TNF-αproduction.Among the 5 flavonoids isolated from G.uralensis,isoliquiritigeninwas themost effective.Isoliquiritigenin suppression of TNF-αproduction was associated with attenuation of p-NF-kB expression,andwas accompanied by increased BDNF secretion.Conclusion:ASHMI and its effective flavonoid,isoliquiritigenin,inhibited TNF-αproduction by LPS stimulatedmicroglial cells and elevated BDNF levels,which may prove to have anti-CNS inflammatory and anti-anxiety effects. | Sangita P.Patil Changda Liu Joseph Alban Nan Yang Xiu-Min Li | 2014 | Journal of Traditional Chinese Medical Sciences2014，1，1： | 3 |
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