饱和的碳氢键氧化是合成化学和化学工业中一类重要的化学反应.然而,饱和C(sp^(3))−H键离解能(BDEs)较高、极性较弱,导致了底物难以活化和催化转化效率较低等问题.在过去的几十年,C(sp^(3))−H键的定向活化转化取得了重要的进展.其中,关于...饱和的碳氢键氧化是合成化学和化学工业中一类重要的化学反应.然而,饱和C(sp^(3))−H键离解能(BDEs)较高、极性较弱,导致了底物难以活化和催化转化效率较低等问题.在过去的几十年,C(sp^(3))−H键的定向活化转化取得了重要的进展.其中,关于C(sp^(3))−H键催化氧化的研究主要涉及一些键能低的、预活化的C−H键,包括苄基型、亚甲基型、脂肪族X−CH_(2)(X=O,N)和甲苯等,含有未活化C(sp^(3))−H键的复杂化合物的选择性氧化仍具有挑战性.例如,芳基醚C(sp^(3))−H键功能化通常采用计量的过氧化物氧化剂,或者通过单电子氧化和碱促进的去质子化进一步构建C−C/C−N键,产物选择性较低,也带来了一些不利的环境影响.因此,有必要开发高效、温和的芳基醚C(sp^(3))−H键选择氧化方法,并将其应用于有机合成和药物开发.近年来,光催化C(sp^(3))−H键氧化因其操作简便、氧化还原中性等优点,已发展成为一种有用且多样的催化研究工具.本文发展了一种利用氧气作为氧化剂,在可见光驱动下选择性地将芳基醚C(sp^(3))−H键氧化成为甲酸苯酯类产物的新方法.使用Mes-10-phenyl-Acr^(+)−BF_(4)^(-)光催化剂,高效活化多种氯源(如盐酸、无机氯盐和有机氯化物)得到氯自由基,由于其具有较高的氧化能力(+2.03 V vs.SCE)和对氢原子的亲和力,能够通过氢原子转移过程活化芳基醚C(sp^(3))−键,攫取氢自由基得到相应的烷基碳自由基(•CH_(2)OPh)中间体,进一步被分子氧选择氧化得到酯类目标产物.研究结果表明,多种链状芳基醚和不同取代(如给电子基和吸电子基)芳基醚均可发生氧化反应,高收率地合成了一系列官能团丰富的甲酸苯酯类化合物.本文方法具有反应条件温和、操作简单、官能团耐受性好以及可规模化放大等优点,并且少量的水对反应没有明显影响.机理实验研究结果表明,芳基醚C(sp^(3))−H键的断裂是反应过程的决速步骤.紫外可见吸收光谱结果表明,氯离子与催化剂之间的相互作用强于底物,并且自由基捕获实验证实反应体系中存在氯自由基和烷基碳自由基物种,表明反应经历自由基路径.此外,电子顺磁共振测试结果表明,反应过程中存在单线态氧物种,可能是激发态的光催化剂直接与氧气发生能量转移得到;同位素实验(18O)揭示了甲酸苯酯类化合物氧的来源.综上,本文实现了温和条件下光催化芳基醚C(sp^(3))−H键选择氧化反应,高收率合成了一系列甲酸苯酯类化合物.该方法避免了化学计量的过氧化物和碱等添加剂的使用以及底物的过度氧化,阐明了催化反应机制,为其他醚类化合物的C(sp^(3))−H键氧化功能化提供了新思路,为后续化学合成和药物开发提供了参考和启示.展开更多
Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were establi...Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.展开更多
Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to vi...Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to virtual screening.Sesamin and its metabolites,sesamin monocatechol(SC-1)and sesamin dicatechol(SC-2),were identified as potential SYK inhibitors,showing high binding affinity and inhibition efficiency towards SYK.Compared with R406(a traditional SYK inhibitor),sesamin,SC-1,and SC-2 had lower binding energy and inhibition constant(Ki)during molecular docking,exhibited higher bioavailability,safety,metabolism/clearance rate,and distribution uniformity ADMET predictions,and showed high stability in occupying the ATP-binding pocket of SYK during molecular dynamics simulations.In anti-dinitrophenyl-immunoglobulin E(Anti-DNP-Ig E)/dinitrophenyl-human serum albumin(DNP-HSA)-stimulated rat basophilic leukemia(RBL-2H3)cells,sesamin in the concentration range of 5-80μmol/L influenced significantly the degranulation and cytokine release,with 54.00%inhibition againstβ-hexosaminidase release and 58.45%decrease in histamine.In BALB/c mice,sesamin could ameliorate Anti-DNP-Ig E/DNP-HSA-induced passive cutaneous anaphylaxis(PCA)and ovalbumin(OVA)-induced active systemic anaphylaxis(ASA)reactions,reduce the levels of allergic mediators(immunoglobulins and pro-inflammatory cytokines),partially correct the imbalance of T helper(Th)cells differentiation in the spleen,and inhibit the phosphorylation of SYK and its downstream signaling proteins,including p38 mitogen-activated protein kinases(p38 MAPK),extracellular signalregulated kinases(ERK),and p65 nuclear factor-κB(p65 NF-κB)in the spleen.Thus,sesamin may be a safe and versatile SYK inhibitor that can alleviate Ig E-mediated food allergies.展开更多
The precise mechanism underlying the effects of anti-CD4 antibody and calcium ions(Ca^(2+)) in peanut allergy remains unknown.C3 H/HeJ mice sensitized with peanut protein extract(PPE)were injected with anti-CD4 antibo...The precise mechanism underlying the effects of anti-CD4 antibody and calcium ions(Ca^(2+)) in peanut allergy remains unknown.C3 H/HeJ mice sensitized with peanut protein extract(PPE)were injected with anti-CD4 antibodies for 4 weeks.Stimulation with PPE increased the specific immunoglobulin E(IgE),cytokine,histamine,and mMcp-1 levels,upregulated decorin(Dcn)expression,induced Ca^(2+) inflow in the spleen,and augmented the expression of the transcription factors GATA-3 and Foxp3,which resulted in Th2 and Treg cell activation.Notably,the Ca^(2+) levels were positively correlated with the histamine,interleukin(IL)-4,IL-5,and IL-13 levels,and negatively correlated with IL-10 levels.However,administration of anti-CD4 antibodies markedly alleviated allergic symptoms,activated T cells,and reduced Ca^(2+) inflow,cytokine,histamine,mMcp-1,and the IgHG3,CXCLI2,MMP2 and FABP4 gene.Our results indicated that anti-CD4 antibodies can ameliorate PPE-induced allergy,which is probably related to the suppression of Ca^(2+) inflow,and inhibiting histamine,cytokine and IgHG3,CXCL12,MMP2,and FABP4,thus exerting a protective effect against PPEsensitized food allergy.展开更多
文摘饱和的碳氢键氧化是合成化学和化学工业中一类重要的化学反应.然而,饱和C(sp^(3))−H键离解能(BDEs)较高、极性较弱,导致了底物难以活化和催化转化效率较低等问题.在过去的几十年,C(sp^(3))−H键的定向活化转化取得了重要的进展.其中,关于C(sp^(3))−H键催化氧化的研究主要涉及一些键能低的、预活化的C−H键,包括苄基型、亚甲基型、脂肪族X−CH_(2)(X=O,N)和甲苯等,含有未活化C(sp^(3))−H键的复杂化合物的选择性氧化仍具有挑战性.例如,芳基醚C(sp^(3))−H键功能化通常采用计量的过氧化物氧化剂,或者通过单电子氧化和碱促进的去质子化进一步构建C−C/C−N键,产物选择性较低,也带来了一些不利的环境影响.因此,有必要开发高效、温和的芳基醚C(sp^(3))−H键选择氧化方法,并将其应用于有机合成和药物开发.近年来,光催化C(sp^(3))−H键氧化因其操作简便、氧化还原中性等优点,已发展成为一种有用且多样的催化研究工具.本文发展了一种利用氧气作为氧化剂,在可见光驱动下选择性地将芳基醚C(sp^(3))−H键氧化成为甲酸苯酯类产物的新方法.使用Mes-10-phenyl-Acr^(+)−BF_(4)^(-)光催化剂,高效活化多种氯源(如盐酸、无机氯盐和有机氯化物)得到氯自由基,由于其具有较高的氧化能力(+2.03 V vs.SCE)和对氢原子的亲和力,能够通过氢原子转移过程活化芳基醚C(sp^(3))−键,攫取氢自由基得到相应的烷基碳自由基(•CH_(2)OPh)中间体,进一步被分子氧选择氧化得到酯类目标产物.研究结果表明,多种链状芳基醚和不同取代(如给电子基和吸电子基)芳基醚均可发生氧化反应,高收率地合成了一系列官能团丰富的甲酸苯酯类化合物.本文方法具有反应条件温和、操作简单、官能团耐受性好以及可规模化放大等优点,并且少量的水对反应没有明显影响.机理实验研究结果表明,芳基醚C(sp^(3))−H键的断裂是反应过程的决速步骤.紫外可见吸收光谱结果表明,氯离子与催化剂之间的相互作用强于底物,并且自由基捕获实验证实反应体系中存在氯自由基和烷基碳自由基物种,表明反应经历自由基路径.此外,电子顺磁共振测试结果表明,反应过程中存在单线态氧物种,可能是激发态的光催化剂直接与氧气发生能量转移得到;同位素实验(18O)揭示了甲酸苯酯类化合物氧的来源.综上,本文实现了温和条件下光催化芳基醚C(sp^(3))−H键选择氧化反应,高收率合成了一系列甲酸苯酯类化合物.该方法避免了化学计量的过氧化物和碱等添加剂的使用以及底物的过度氧化,阐明了催化反应机制,为其他醚类化合物的C(sp^(3))−H键氧化功能化提供了新思路,为后续化学合成和药物开发提供了参考和启示.
基金supported by the National Natural Science Foundation of China(81971875,82300661)Natural Science Foundation of Anhui province(2308085QH246)+3 种基金Natural Science Foundation of the Anhui Higher Education Institutions(KJ2021A0205)Basic and Clinical Cooperative Research Program of Anhui Medical University(2019xkjT002,2019xkjT022,2022xkjT013)Talent Training Program,School of Basic Medical Sciences,Anhui Medical University(2022YPJH102)National College Students Innovation and Entrepreneurship Training Program of China(202210366024)。
文摘Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.
基金Incubation Program of Youth Innovation in Shandong ProvinceKey Research and Development Program of Shandong Province(2021TZXD007)。
文摘Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to virtual screening.Sesamin and its metabolites,sesamin monocatechol(SC-1)and sesamin dicatechol(SC-2),were identified as potential SYK inhibitors,showing high binding affinity and inhibition efficiency towards SYK.Compared with R406(a traditional SYK inhibitor),sesamin,SC-1,and SC-2 had lower binding energy and inhibition constant(Ki)during molecular docking,exhibited higher bioavailability,safety,metabolism/clearance rate,and distribution uniformity ADMET predictions,and showed high stability in occupying the ATP-binding pocket of SYK during molecular dynamics simulations.In anti-dinitrophenyl-immunoglobulin E(Anti-DNP-Ig E)/dinitrophenyl-human serum albumin(DNP-HSA)-stimulated rat basophilic leukemia(RBL-2H3)cells,sesamin in the concentration range of 5-80μmol/L influenced significantly the degranulation and cytokine release,with 54.00%inhibition againstβ-hexosaminidase release and 58.45%decrease in histamine.In BALB/c mice,sesamin could ameliorate Anti-DNP-Ig E/DNP-HSA-induced passive cutaneous anaphylaxis(PCA)and ovalbumin(OVA)-induced active systemic anaphylaxis(ASA)reactions,reduce the levels of allergic mediators(immunoglobulins and pro-inflammatory cytokines),partially correct the imbalance of T helper(Th)cells differentiation in the spleen,and inhibit the phosphorylation of SYK and its downstream signaling proteins,including p38 mitogen-activated protein kinases(p38 MAPK),extracellular signalregulated kinases(ERK),and p65 nuclear factor-κB(p65 NF-κB)in the spleen.Thus,sesamin may be a safe and versatile SYK inhibitor that can alleviate Ig E-mediated food allergies.
基金supported by the National Natural Science Foundation of China(31972185)。
文摘The precise mechanism underlying the effects of anti-CD4 antibody and calcium ions(Ca^(2+)) in peanut allergy remains unknown.C3 H/HeJ mice sensitized with peanut protein extract(PPE)were injected with anti-CD4 antibodies for 4 weeks.Stimulation with PPE increased the specific immunoglobulin E(IgE),cytokine,histamine,and mMcp-1 levels,upregulated decorin(Dcn)expression,induced Ca^(2+) inflow in the spleen,and augmented the expression of the transcription factors GATA-3 and Foxp3,which resulted in Th2 and Treg cell activation.Notably,the Ca^(2+) levels were positively correlated with the histamine,interleukin(IL)-4,IL-5,and IL-13 levels,and negatively correlated with IL-10 levels.However,administration of anti-CD4 antibodies markedly alleviated allergic symptoms,activated T cells,and reduced Ca^(2+) inflow,cytokine,histamine,mMcp-1,and the IgHG3,CXCLI2,MMP2 and FABP4 gene.Our results indicated that anti-CD4 antibodies can ameliorate PPE-induced allergy,which is probably related to the suppression of Ca^(2+) inflow,and inhibiting histamine,cytokine and IgHG3,CXCL12,MMP2,and FABP4,thus exerting a protective effect against PPEsensitized food allergy.
