目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,...目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,并以安慰剂作为对照的所有随机对照研究。对纳入的研究进行质量评价,使用RevMan5.3对结局指标进行Meta分析。最终共4篇文献907例中重度AD患者被纳入Meta分析。结果湿疹面积和严重程度指数(EASI)评分改善50%(RR:1.57,95%CI:1.29~1.92,P<0.0001)、75%(RR:2.11,95%CI:1.20~3.73,P=0.01)、90%及研究者整体评估(IGA)评分达0或1分(RR:4.10,95%CI:2.17~7.74,P<0.0001)的患者百分比均高于对照组,差异有统计学意义。试验组与对照组不良事件发生率比较差异无统计学意义(RR:1.05,95%CI:0.94~1.17,P=0.37);试验组停药率低于对照组,差异有统计学意义(RR:0.62,95%CI:0.47~0.82,P=0.001)。结论OX40信号通路拮抗剂在中重度AD的治疗中有良好的有效性及安全性,可能成为治疗AD的新选择。展开更多
Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that ...Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.展开更多
目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(...目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率变化,并根据颈动脉狭窄程度分为轻度AS组(狭窄≤50%)、中度AS组(狭窄51%~69%)及重度AS组(狭窄≥70%),分析CD4^(+)CD28^(null)T细胞、OX40、4-1BB变化与AS进展的关联性。结果120例患者中,DM-AS组有76例,占63.33%;与DM组相比,DM-AS组的DM病程、收缩压、餐后2 h血糖(2 h PG)、糖化血红蛋白、载脂蛋白B、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)水平及CD4^(+)CD28^(null)T细胞亚群比率、OX40阳性比率、4-1BB阳性比率较高,载脂蛋白A1水平较低,差异均有统计学意义(t分别=2.57、2.49、2.78、2.19、3.12、2.94、4.31、5.97、16.91、11.47、-2.52,P均<0.05);CD4^(+)CD28^(null)T细胞、OX40、4-1BB联合诊断DM-AS的曲线下面积(AUC)为0.96。DM-AS组76例中,其中轻度AS组37例、中度AS组29例、重度AS组10例。AS程度与CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均呈正相关(r分别=0.24、0.48、0.38,P均<0.05)。结论DM-AS患者的外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均明显升高,对DM-AS具有诊断价值,与AS进展呈正相关。展开更多
Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depe...Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depending on the characteristics of tumor cells,as well as the immune status.The main purpose of this study was to experimentally prove the feasibility of combining the Karanahan technology and in situ vaccination withαOX40 antibodies into a single therapeutic platform to achieve a potent additive antitumor therapeutic effect.Methods:BALB/c mice grafted with B-cellular lymphoma A20 were treated using the Karanahan technology consisting of intraperitoneal cyclophosphamide administrations and intratumoral DNA injections according to an individually determined therapeutic regimen,together with in situ vaccination withαOX40.A pathomorphological analysis of the organs of experimental animals that died during the initial attempt to combine the two technologies was carried out.An analysis of blood cell populations was performed to determine the safe time for antibody administration:the number of immune cells capable of activating systemic inflammation(CD11b+Ly-6C+,CD11b+Ly-6G+,CD3–NKp46+CD11b+),the presence of Fc receptor and OX40 on the surface of these cells,and the number of neutrophils activated to NETosis were analyzed.Based on the analysis results,the antitumor efficacy of various modes of combining the Karanahan technology and in situ vaccination was studied.Results:WhenαOX40 was administered 5 h after each treatment using the Karanahan technology,mass death of mice caused by systemic inflammation and multiple organ failure was observed.The state of blood cells after the treatment using the Karanahan technology at the time points corresponding to antibody injections was analyzed to elucidate the reasons for this effect.It was found that at some time points,there occurs activation of the immune system and a powerful release(up to 16%)of monocytes and granulocytes carrying Fc receptor and OX40 on their surface into blood;when interacting withαOX40,they can activate the lytic potential of these cells.Activation of neutrophils to NETosis was also observed.Based on these findings,a study was carried out in different time regimes to combine the Karanahan technology andαOX40 injections.WhenαOX40 was injected into the points of minimal release of myeloid cells into the blood,increased survival rate and the greatest antitumor efficacy were observed:37%of animals survived without relapses on day 100 after experiment initiation.Conclusions:The results obtained indicate that it is possible to combine the Karanahan technology and in situ vaccination withαOX40,with obligatory constant monitoring of the number of myeloid cells in peripheral blood to determine the safe time for antibody injection.展开更多
目的:基于食欲素受体1(OX1R)/磷脂酰肌醇特异性磷酯酶Cβ-1(PLCβ-1)/蛋白激酶Cα(PKCα)/细胞外信号调节激酶1/2(ERK1/2)信号通路探讨安寐丹对失眠大鼠肝脏神经递质及昼夜节律的影响及机制。方法:SPF级SD大鼠60只,随机分为空白组、模...目的:基于食欲素受体1(OX1R)/磷脂酰肌醇特异性磷酯酶Cβ-1(PLCβ-1)/蛋白激酶Cα(PKCα)/细胞外信号调节激酶1/2(ERK1/2)信号通路探讨安寐丹对失眠大鼠肝脏神经递质及昼夜节律的影响及机制。方法:SPF级SD大鼠60只,随机分为空白组、模型组、苏沃雷生组、安寐丹低、中、高剂量组,各10只;除空白组外,其余各组通过腹腔注射对氯苯丙氨酸(PCPA)进行造模,空白组给予等容生理盐水、苏沃雷生组给予苏沃雷生溶液30 mg·kg^(-1)·d^(-1)灌胃、安寐丹低、中、高剂量组分别给予安寐丹水煎液(4.55、9.09、18.18 g·kg^(-1)·d^(-1));观察各组一般情况、体质量和24 h自主活动情况;采用苏木素-伊红(HE)和马松(Masson)染色观察肝脏病理学改变,酶联免疫吸附测定法(ELISA)检测肝脏神经递质γ-氨基丁酸(GABA)、5-羟色胺(5-HT)、肾上腺素(EPI)、去甲肾上腺素(NE)和乙酰胆碱(ACh)的表达,生化检测肝脏谷氨酸(Glu)的表达,实时荧光定量聚合酶链式反应(Real-time PCR)检测肝脏生物钟基因Per1、Per2、Cry1、Cry2、Bmal1、Bmal2的m RNA表达,蛋白免疫印迹法(Western blot)、Real-time PCR检测肝脏OX1R/PLCβ-1/PKCα/ERK1/2信号通路蛋白及m RNA表达。结果:与空白组比较,模型组体质量下降(P<0.05,P<0.01),狂躁、静止节律紊乱(P<0.01),肝脏肌纤维断裂、水肿伴炎性细胞浸润,GABA、5-HT、EPI、NE和ACh含量降低、Glu含量升高(P<0.01),Per1、Per2、Cry1和Cry2 m RNA表达降低(P<0.01),Bmal1和Bmal2 m RNA表达升高(P<0.01),OX1R、PLCβ-1、PKCα、ERK1/2蛋白及m RNA基因表达均增高(P<0.01);与模型组比较,苏沃雷生和安寐丹低、中、高剂量组可增加失眠大鼠体质量(P<0.05,P<0.01),减少狂躁状态、增加其静止时间和频率(P<0.05,P<0.01),并可上调神经递质GABA、5-HT、EPI、NE、ACh和节律基因Per1、Per2、Cry1、Cry2 m RNA表达(P<0.05,P<0.01),抑制Glu及Bmal1、Bmal2、OX1R、PLCβ-1、PKCα、ERK1/2 m RNA和OX1R、PLCβ-1、PKCα、ERK1/2蛋白表达(P<0.05,P<0.01)。结论:安寐丹可通过抑制OX1R/PLCβ-1/PKCα/ERK1/2信号通路调节失眠大鼠肝脏神经递质表达,改善昼夜节律紊乱,且安寐丹高剂量组效果最佳。展开更多
目的:探究花生红衣原花青素(peanut red proanthocyanidins,PRP)对氧化低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(Vascular Smooth Muscle Cells,VSMCs)增殖的抑制作用及其调节NF-κB(Nuclear Factor kappa-light-chain-enhancer of ac...目的:探究花生红衣原花青素(peanut red proanthocyanidins,PRP)对氧化低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(Vascular Smooth Muscle Cells,VSMCs)增殖的抑制作用及其调节NF-κB(Nuclear Factor kappa-light-chain-enhancer of activated B cells)通路的潜在机制。方法:采用体外细胞培养模型,将VSMCs分为3组:对照组(Control)、氧化低密度脂蛋白诱导组(ox-LDL)、氧化低密度脂蛋白诱导+花生红衣原花青素组(ox-LDL+PRP)。采用CCK-8法评估细胞增殖情况,流式细胞仪分析细胞周期,应用ELISA检测炎症因子TNF-α和IL-6的表达,Western blot检测NF-κB通路相关蛋白的表达情况。结果:与ox-LDL模型组相比,原花青素处理的VSMCs表现出显著的增殖抑制效果,细胞活力值明显下降(P<0.05);细胞周期检测显示:花生红衣原花青素处理组细胞在G1期的比例显著增加,而S期和G2/M期的比例则减少;同时花生红衣原花青素处理组NF-κB通路相关蛋白p65的表达水平显著下调(P<0.05),TNF-α、IL-6表达下降(均P<0.05)。结论:花生红衣原花青素能够通过抑制NF-κB通路的激活,有效减轻ox-LDL诱导的VSMCs炎症反应,抑制VSMCs增殖。展开更多
目的分析2型糖尿病(T2DM)合并失眠患者血清细胞间黏附分子1(ICAM-1)、氧化型低密度脂蛋白(ox-LDL)及血管内皮生长因子(VEGF)水平的变化特征,探讨其临床意义。方法选取2021年5月至2022年5月某医院收治的108例T2DM患者,根据匹兹堡睡眠质...目的分析2型糖尿病(T2DM)合并失眠患者血清细胞间黏附分子1(ICAM-1)、氧化型低密度脂蛋白(ox-LDL)及血管内皮生长因子(VEGF)水平的变化特征,探讨其临床意义。方法选取2021年5月至2022年5月某医院收治的108例T2DM患者,根据匹兹堡睡眠质量指数(PSQI)评分分为无失眠组(PSQI≤7分,n=53)和失眠组(PSQI>7分,n=55)。比较两组一般临床特征、糖脂代谢指标及血清ICAM-1、ox-LDL、VEGF水平,并分析PSQI总分与各指标的相关性。结果失眠组收缩压、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、糖化血红蛋白(HbA1c)、总胆固醇(TC)水平显著高于无失眠组(P<0.05);失眠组血清ICAM-1(4.03±0.83 ng/mL vs 3.18±0.60 ng/mL)、ox-LDL(14.02±4.75μg/mL vs 9.97±4.05μg/mL)水平显著高于无失眠组(P均<0.05),而两组VEGF水平差异无统计学意义(P>0.05)。Pearson相关分析显示,PSQI总分与ICAM-1(r=0.52)、ox-LDL(r=0.46)呈正相关(P均<0.05)。结论T2DM合并失眠患者血清ICAM-1、ox-LDL水平显著升高,失眠可能通过加剧炎症反应和氧化应激,促进糖尿病微血管并发症的发生与发展。展开更多
Drought stress is a devastating natural disaster driven by the continuing intensification of global warming,which seriously threatens the productivity and quality of several horticultural crops,including pear.Gibberel...Drought stress is a devastating natural disaster driven by the continuing intensification of global warming,which seriously threatens the productivity and quality of several horticultural crops,including pear.Gibberellins(GAs)play crucial roles in plant growth,development,and responses to drought stress.Previous studies have shown significant reductions of GA levels in plants under drought stress;however,our understanding of the intrinsic regulation mechanisms of GA-mediated drought stress in pear remains very limited.Here,we show that drought stress can impair the accumulation of bioactive GAs(BGAs),and subsequently identified PbrGA2ox1 as a chloroplast-localized GA deactivation gene.This gene was significantly induced by drought stress and abscisic acid(ABA)treatment,but was suppressed by GA_(3)treatment.PbrGA2ox1-overexpressing transgenic tobacco plants(Nicotiana benthamiana)exhibited enhanced tolerance to dehydration and drought stresses,whereas knock-down of PbrGA2ox1 in pear(Pyrus betulaefolia)by virus-induced gene silencing led to elevated drought sensitivity.Transgenic plants were hypersensitive to ABA,and had a lower BGAs content,enhanced reactive oxygen species(ROS)scavenging ability,and augmented ABA accumulation and signaling under drought stress compared to wild-type plants.However,the opposite effects were observed with PbrGA2ox1 silencing in pear.Moreover,exogenous GA_(3)treatment aggravated the ROS toxic effect and restrained ABA synthesis and signaling,resulting in the compromised drought tolerance of pear.In summary,our results shed light on the mechanism by which BGAs are eliminated in pear leaves under drought stress,providing further insights into the mechanism regulating the effects of GA on the drought tolerance of plants.展开更多
文摘目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,并以安慰剂作为对照的所有随机对照研究。对纳入的研究进行质量评价,使用RevMan5.3对结局指标进行Meta分析。最终共4篇文献907例中重度AD患者被纳入Meta分析。结果湿疹面积和严重程度指数(EASI)评分改善50%(RR:1.57,95%CI:1.29~1.92,P<0.0001)、75%(RR:2.11,95%CI:1.20~3.73,P=0.01)、90%及研究者整体评估(IGA)评分达0或1分(RR:4.10,95%CI:2.17~7.74,P<0.0001)的患者百分比均高于对照组,差异有统计学意义。试验组与对照组不良事件发生率比较差异无统计学意义(RR:1.05,95%CI:0.94~1.17,P=0.37);试验组停药率低于对照组,差异有统计学意义(RR:0.62,95%CI:0.47~0.82,P=0.001)。结论OX40信号通路拮抗剂在中重度AD的治疗中有良好的有效性及安全性,可能成为治疗AD的新选择。
基金supported by the National Natural Science Foundation of China(Nos.82172335,81971994,91846103,and 81871709)the Zhejiang Provincial Key Research and Development Program(No.2020C03032),China.
文摘Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.
文摘目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率变化,并根据颈动脉狭窄程度分为轻度AS组(狭窄≤50%)、中度AS组(狭窄51%~69%)及重度AS组(狭窄≥70%),分析CD4^(+)CD28^(null)T细胞、OX40、4-1BB变化与AS进展的关联性。结果120例患者中,DM-AS组有76例,占63.33%;与DM组相比,DM-AS组的DM病程、收缩压、餐后2 h血糖(2 h PG)、糖化血红蛋白、载脂蛋白B、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)水平及CD4^(+)CD28^(null)T细胞亚群比率、OX40阳性比率、4-1BB阳性比率较高,载脂蛋白A1水平较低,差异均有统计学意义(t分别=2.57、2.49、2.78、2.19、3.12、2.94、4.31、5.97、16.91、11.47、-2.52,P均<0.05);CD4^(+)CD28^(null)T细胞、OX40、4-1BB联合诊断DM-AS的曲线下面积(AUC)为0.96。DM-AS组76例中,其中轻度AS组37例、中度AS组29例、重度AS组10例。AS程度与CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均呈正相关(r分别=0.24、0.48、0.38,P均<0.05)。结论DM-AS患者的外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均明显升高,对DM-AS具有诊断价值,与AS进展呈正相关。
基金supported by Inga N.Zaitseva“Karanahan”LLC and the Ministry of Science and Higher Education of the Russian Federation via the Institute of Cytology and Genetics(State Budget Project No.FWNR-2022-0016).
文摘Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depending on the characteristics of tumor cells,as well as the immune status.The main purpose of this study was to experimentally prove the feasibility of combining the Karanahan technology and in situ vaccination withαOX40 antibodies into a single therapeutic platform to achieve a potent additive antitumor therapeutic effect.Methods:BALB/c mice grafted with B-cellular lymphoma A20 were treated using the Karanahan technology consisting of intraperitoneal cyclophosphamide administrations and intratumoral DNA injections according to an individually determined therapeutic regimen,together with in situ vaccination withαOX40.A pathomorphological analysis of the organs of experimental animals that died during the initial attempt to combine the two technologies was carried out.An analysis of blood cell populations was performed to determine the safe time for antibody administration:the number of immune cells capable of activating systemic inflammation(CD11b+Ly-6C+,CD11b+Ly-6G+,CD3–NKp46+CD11b+),the presence of Fc receptor and OX40 on the surface of these cells,and the number of neutrophils activated to NETosis were analyzed.Based on the analysis results,the antitumor efficacy of various modes of combining the Karanahan technology and in situ vaccination was studied.Results:WhenαOX40 was administered 5 h after each treatment using the Karanahan technology,mass death of mice caused by systemic inflammation and multiple organ failure was observed.The state of blood cells after the treatment using the Karanahan technology at the time points corresponding to antibody injections was analyzed to elucidate the reasons for this effect.It was found that at some time points,there occurs activation of the immune system and a powerful release(up to 16%)of monocytes and granulocytes carrying Fc receptor and OX40 on their surface into blood;when interacting withαOX40,they can activate the lytic potential of these cells.Activation of neutrophils to NETosis was also observed.Based on these findings,a study was carried out in different time regimes to combine the Karanahan technology andαOX40 injections.WhenαOX40 was injected into the points of minimal release of myeloid cells into the blood,increased survival rate and the greatest antitumor efficacy were observed:37%of animals survived without relapses on day 100 after experiment initiation.Conclusions:The results obtained indicate that it is possible to combine the Karanahan technology and in situ vaccination withαOX40,with obligatory constant monitoring of the number of myeloid cells in peripheral blood to determine the safe time for antibody injection.
文摘目的:基于食欲素受体1(OX1R)/磷脂酰肌醇特异性磷酯酶Cβ-1(PLCβ-1)/蛋白激酶Cα(PKCα)/细胞外信号调节激酶1/2(ERK1/2)信号通路探讨安寐丹对失眠大鼠肝脏神经递质及昼夜节律的影响及机制。方法:SPF级SD大鼠60只,随机分为空白组、模型组、苏沃雷生组、安寐丹低、中、高剂量组,各10只;除空白组外,其余各组通过腹腔注射对氯苯丙氨酸(PCPA)进行造模,空白组给予等容生理盐水、苏沃雷生组给予苏沃雷生溶液30 mg·kg^(-1)·d^(-1)灌胃、安寐丹低、中、高剂量组分别给予安寐丹水煎液(4.55、9.09、18.18 g·kg^(-1)·d^(-1));观察各组一般情况、体质量和24 h自主活动情况;采用苏木素-伊红(HE)和马松(Masson)染色观察肝脏病理学改变,酶联免疫吸附测定法(ELISA)检测肝脏神经递质γ-氨基丁酸(GABA)、5-羟色胺(5-HT)、肾上腺素(EPI)、去甲肾上腺素(NE)和乙酰胆碱(ACh)的表达,生化检测肝脏谷氨酸(Glu)的表达,实时荧光定量聚合酶链式反应(Real-time PCR)检测肝脏生物钟基因Per1、Per2、Cry1、Cry2、Bmal1、Bmal2的m RNA表达,蛋白免疫印迹法(Western blot)、Real-time PCR检测肝脏OX1R/PLCβ-1/PKCα/ERK1/2信号通路蛋白及m RNA表达。结果:与空白组比较,模型组体质量下降(P<0.05,P<0.01),狂躁、静止节律紊乱(P<0.01),肝脏肌纤维断裂、水肿伴炎性细胞浸润,GABA、5-HT、EPI、NE和ACh含量降低、Glu含量升高(P<0.01),Per1、Per2、Cry1和Cry2 m RNA表达降低(P<0.01),Bmal1和Bmal2 m RNA表达升高(P<0.01),OX1R、PLCβ-1、PKCα、ERK1/2蛋白及m RNA基因表达均增高(P<0.01);与模型组比较,苏沃雷生和安寐丹低、中、高剂量组可增加失眠大鼠体质量(P<0.05,P<0.01),减少狂躁状态、增加其静止时间和频率(P<0.05,P<0.01),并可上调神经递质GABA、5-HT、EPI、NE、ACh和节律基因Per1、Per2、Cry1、Cry2 m RNA表达(P<0.05,P<0.01),抑制Glu及Bmal1、Bmal2、OX1R、PLCβ-1、PKCα、ERK1/2 m RNA和OX1R、PLCβ-1、PKCα、ERK1/2蛋白表达(P<0.05,P<0.01)。结论:安寐丹可通过抑制OX1R/PLCβ-1/PKCα/ERK1/2信号通路调节失眠大鼠肝脏神经递质表达,改善昼夜节律紊乱,且安寐丹高剂量组效果最佳。
文摘目的:探究花生红衣原花青素(peanut red proanthocyanidins,PRP)对氧化低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(Vascular Smooth Muscle Cells,VSMCs)增殖的抑制作用及其调节NF-κB(Nuclear Factor kappa-light-chain-enhancer of activated B cells)通路的潜在机制。方法:采用体外细胞培养模型,将VSMCs分为3组:对照组(Control)、氧化低密度脂蛋白诱导组(ox-LDL)、氧化低密度脂蛋白诱导+花生红衣原花青素组(ox-LDL+PRP)。采用CCK-8法评估细胞增殖情况,流式细胞仪分析细胞周期,应用ELISA检测炎症因子TNF-α和IL-6的表达,Western blot检测NF-κB通路相关蛋白的表达情况。结果:与ox-LDL模型组相比,原花青素处理的VSMCs表现出显著的增殖抑制效果,细胞活力值明显下降(P<0.05);细胞周期检测显示:花生红衣原花青素处理组细胞在G1期的比例显著增加,而S期和G2/M期的比例则减少;同时花生红衣原花青素处理组NF-κB通路相关蛋白p65的表达水平显著下调(P<0.05),TNF-α、IL-6表达下降(均P<0.05)。结论:花生红衣原花青素能够通过抑制NF-κB通路的激活,有效减轻ox-LDL诱导的VSMCs炎症反应,抑制VSMCs增殖。
文摘目的分析2型糖尿病(T2DM)合并失眠患者血清细胞间黏附分子1(ICAM-1)、氧化型低密度脂蛋白(ox-LDL)及血管内皮生长因子(VEGF)水平的变化特征,探讨其临床意义。方法选取2021年5月至2022年5月某医院收治的108例T2DM患者,根据匹兹堡睡眠质量指数(PSQI)评分分为无失眠组(PSQI≤7分,n=53)和失眠组(PSQI>7分,n=55)。比较两组一般临床特征、糖脂代谢指标及血清ICAM-1、ox-LDL、VEGF水平,并分析PSQI总分与各指标的相关性。结果失眠组收缩压、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、糖化血红蛋白(HbA1c)、总胆固醇(TC)水平显著高于无失眠组(P<0.05);失眠组血清ICAM-1(4.03±0.83 ng/mL vs 3.18±0.60 ng/mL)、ox-LDL(14.02±4.75μg/mL vs 9.97±4.05μg/mL)水平显著高于无失眠组(P均<0.05),而两组VEGF水平差异无统计学意义(P>0.05)。Pearson相关分析显示,PSQI总分与ICAM-1(r=0.52)、ox-LDL(r=0.46)呈正相关(P均<0.05)。结论T2DM合并失眠患者血清ICAM-1、ox-LDL水平显著升高,失眠可能通过加剧炎症反应和氧化应激,促进糖尿病微血管并发症的发生与发展。
基金supported by grants from the China Agriculture Research System(CARS-28-14)the Technical System of Fruit Industry in Anhui Province,China(AHCYTX-10)the Scientific Research Projects for Postgraduates of Anhui Universities,China(YJS20210207).
文摘Drought stress is a devastating natural disaster driven by the continuing intensification of global warming,which seriously threatens the productivity and quality of several horticultural crops,including pear.Gibberellins(GAs)play crucial roles in plant growth,development,and responses to drought stress.Previous studies have shown significant reductions of GA levels in plants under drought stress;however,our understanding of the intrinsic regulation mechanisms of GA-mediated drought stress in pear remains very limited.Here,we show that drought stress can impair the accumulation of bioactive GAs(BGAs),and subsequently identified PbrGA2ox1 as a chloroplast-localized GA deactivation gene.This gene was significantly induced by drought stress and abscisic acid(ABA)treatment,but was suppressed by GA_(3)treatment.PbrGA2ox1-overexpressing transgenic tobacco plants(Nicotiana benthamiana)exhibited enhanced tolerance to dehydration and drought stresses,whereas knock-down of PbrGA2ox1 in pear(Pyrus betulaefolia)by virus-induced gene silencing led to elevated drought sensitivity.Transgenic plants were hypersensitive to ABA,and had a lower BGAs content,enhanced reactive oxygen species(ROS)scavenging ability,and augmented ABA accumulation and signaling under drought stress compared to wild-type plants.However,the opposite effects were observed with PbrGA2ox1 silencing in pear.Moreover,exogenous GA_(3)treatment aggravated the ROS toxic effect and restrained ABA synthesis and signaling,resulting in the compromised drought tolerance of pear.In summary,our results shed light on the mechanism by which BGAs are eliminated in pear leaves under drought stress,providing further insights into the mechanism regulating the effects of GA on the drought tolerance of plants.
